WO2019095599A1 - 光交联水凝胶材料的制备、原料、产品及应用 - Google Patents

光交联水凝胶材料的制备、原料、产品及应用 Download PDF

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WO2019095599A1
WO2019095599A1 PCT/CN2018/080170 CN2018080170W WO2019095599A1 WO 2019095599 A1 WO2019095599 A1 WO 2019095599A1 CN 2018080170 W CN2018080170 W CN 2018080170W WO 2019095599 A1 WO2019095599 A1 WO 2019095599A1
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Prior art keywords
group
formula
nitrobenzyl
component
bond
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PCT/CN2018/080170
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English (en)
French (fr)
Inventor
朱麟勇
华宇杰
林秋宁
张依晴
包春燕
钟学鹏
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华东理工大学
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Priority to JP2020513321A priority Critical patent/JP7043096B2/ja
Priority to EP18877717.1A priority patent/EP3666761A4/en
Publication of WO2019095599A1 publication Critical patent/WO2019095599A1/zh
Priority to US16/848,372 priority patent/US11117879B2/en
Priority to JP2022035877A priority patent/JP2022091791A/ja

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    • A61L2430/00—Materials or treatment for tissue regeneration
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Definitions

  • the invention belongs to the field of biological materials, and particularly relates to the preparation, raw materials, products and applications of a photocrosslinked hydrogel material.
  • Hydrogel is a kind of highly water-containing polymer material with three-dimensional network cross-linking structure. Because of its excellent biocompatibility and certain mechanical strength, it can highly fit the micro-environment of biological tissues, so it is widely used in tissues. Engineering and Regenerative Medicine. In clinical applications, in-situ cured hydrogels have excellent tissue forming ability. Currently, in-situ curable hydrogels are mainly temperature-sensitive, two-component injection type, photosensitive type depending on the gelation mechanism. Wait.
  • the temperature-sensitive type is mainly a gel precursor which is a liquid phase at a low temperature, and when it reaches the body, it undergoes phase-change gelation under the action of body temperature to achieve in-situ solidification (such as LeGoo, hydroxybutyl chitosan, etc.).
  • Gels generally have problems such as weak gel strength, slow temperature response, and slow degradation in the body.
  • the two-component injection type mainly realizes in-situ solidification by injecting a gel precursor containing an active reactive functional group by a two-component syringe while mixing (for example, Fibrin Glue, Adherus AutoSpray, etc.), thus the crosslinking of the reactive functional group
  • a gel precursor containing an active reactive functional group for example, Fibrin Glue, Adherus AutoSpray, etc.
  • the speed of the joint has a high requirement, and the gelation speed is too slow, which often causes the gel precursor to be diluted or washed away by the blood or exudate in the body.
  • the gelation speed is too fast, which is not conducive to clinical operation, easy to block the needle, and at the same time two-component Syringes are expensive and greatly increase their application cost, and the above drawbacks limit the wide application of such materials.
  • photosensitive hydrogels are more practical in clinical practice due to their advantages in time and space.
  • the polymerization of cross-linking of unsaturated biomacromolecules by free radicals is currently the most versatile method.
  • photo-initiated radical polymerization cross-linking is fast curing (about 2s)
  • free radicals inevitably cause damage to cells or biological tissues, and free radicals and natural oxygen inhibition make in-situ construction by this method.
  • Thin layer hydrogels are very difficult, and at the same time, the lack of adhesion of such hydrogels to tissues has been a barrier to clinical transformation of the technology.
  • Zhu Linyong research group proposed non-free radical photocoupler cross-linking technology in 2014 (Yunlong Yang; Jieyuan Zhang; Zhenzhen Liu; Qiuning Lin; Xiaolin Liu; Chunyan Bao ;Yang Wang;Linyong Zhu.Adv.Mater.2016,28,2724.;Linyong Zhu et.al.PCT.No.WO2016082725 A1,issued Jun2,2016), based on o-nitrobenzyl alcohol produced by ultraviolet light Base, further cross-linking polyamine-based polymer derivatives to prepare hydrogel, completely avoiding the generation of free radicals, can effectively solve the toxicity of free radicals and oxygen inhibition, and the thickness of the rubber layer can be adjusted, at the same time, o-nitrobenzyl
  • the aldehyde group produced by the light of the alcohol is also cross-linked with the amine group of
  • a first object of the present invention is to provide a cyclic o-nitrobenzyl based light trigger, as shown in Structural Formula I-2
  • one end of the linking bond R 1 is bonded to X, and the other end is connected to any one of R 2 , R 3 , R 4 and R 5 to form a cyclic structure;
  • R' is selected from the group consisting of hydrogen, a halogen atom, a hydroxyl group, a decyl group, an amine group, a nitro group, a cyano group, an aldehyde group, a ketone group, an ester group, an amide group, a phosphonic acid group, a phosphonate group, a sulfonate group. Acid group, sulfonate group, sulfone group, sulfoxide group, aryl group, heteroaryl group, alkyl group, alkylene group, modified alkyl group or modified alkylene group;
  • R 1 is selected from the group consisting of hydrogen, an ether bond substituent, an ester bond substituent, a carbonate bond substituent, a urethane bond substituent, a carbazate bond substituent or Phosphate bond substituents, etc.;
  • R 2 , R 3 , R 4 and R 5 are freely selected from the group consisting of hydrogen, a halogen atom, a hydroxyl group, a mercapto group, an amine group, a nitro group, a cyano group, an aldehyde group, a ketone group, a carboxyl group, and an ester group. , amide, phosphonic acid, phosphonate, sulfonate, sulfonate, sulfone, sulfoxide, aryl, heteroaryl, alkyl, alkylene, modified alkyl or modified Alkylene and the like.
  • R 2 , R 3 , R 4 , R 5 may be bonded to each other, together with a carbon atom to form a saturated or unsaturated alicyclic or heteroalicyclic ring, or form an aromatic ring or Aromatic heterocycle.
  • alkyl group is a saturated or unsaturated aliphatic straight or branched alkyl group having 1 to 30 carbon atoms;
  • the alkylene group is a saturated or unsaturated aliphatic straight or branched alkylene group having 1 to 30 carbon atoms;
  • any carbon atom in which the modified alkyl group is an alkyl group is selected from a halogen atom, -OH, -SH, -NO 2 , -CN, -CHO, -COOH, ester group, amide group, aryl group, arylene group , -CO-, -O-, -S-, -SO-, -SO 2 -, primary, secondary, tertiary, quaternary ammonium, saturated or unsaturated monocyclic or bicyclic ring
  • the obtained group is substituted with at least one group of a hydrocarbon group or a bridged aliphatic heterocyclic ring having 1 to 30 atoms, and a carbon-carbon single bond thereof may be optionally a carbon-carbon double bond or a carbon-carbon ruthenium Key replacement
  • any carbon atom in which the modified alkylene group is an alkylene group is selected from a halogen atom, -OH, -SH, -NO 2 , -CN, -CHO, -COOH, ester group, amide group, aryl group, or sub Aryl, -CO-, -O-, -S-, -SO-, -SO 2 -, primary, secondary, tertiary, quaternary ammonium, saturated or unsaturated monocyclic or bicyclic
  • the resulting group is substituted with at least one group of a cycloalkylene group and a bridged aliphatic heterocyclic ring having 1 to 30 atoms, and the carbon-carbon single bond may be arbitrarily carbon-carbon double bond or Carbon-carbon ⁇ bond replacement;
  • the ether bond substituent is selected from the following structures:
  • ester bond substituent is selected from the following structures:
  • the carbonate bond substituent is selected from the following structures:
  • the urethane bond substituent is selected from the following structures:
  • the carbazate bond substituent is selected from the following structures:
  • the phosphate bond substituent is selected from the following structures:
  • the aryl group is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic structure
  • the heteroaryl group is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic structure having at least one hetero atom selected from O, S, N or Si on the ring;
  • the halogen atoms are each independently selected from the group consisting of F, Cl, Br, and I;
  • the alicyclic ring is a saturated or unsaturated 3 to 10 membered monocyclic or polycyclic alicyclic ring;
  • the heteroalicyclic ring is a saturated or unsaturated 3-10 membered monocyclic or polycyclic heterocyclic ring containing at least one hetero atom selected from O, S, N or Si, on the heteroalicyclic ring.
  • S atom When it contains an S atom, it is optionally -S-, -SO- or -SO 2 -;
  • H on the alicyclic or alicyclic ring may be optionally halogen atom, nitro group, aryl group, alkyl group or Modified alkyl substitution;
  • the aromatic ring is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic ring
  • the aromatic heterocyclic ring is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic ring containing at least one hetero atom selected from O, S, N or Si; the H on the aromatic ring or the aromatic heterocyclic ring It may also be optionally substituted by a halogen atom, a nitro group, an aryl group, an alkyl group or a modified alkyl group.
  • cyclic o-nitrobenzyl based light trigger is preferably selected from the following cyclic structures:
  • a second object of the present invention is to provide a series of photosensitive polymer derivatives.
  • the photosensitive polymer derivative provided by the invention comprises three structures:
  • a 1 An optical polymer derivative modified by an o-nitrobenzyl light trigger, referred to as A 1 , having the structure of formula A-I;
  • a photosensitive polymer derivative containing a double bond functional group abbreviated as A 2 , having the structure of formula A-II;
  • a photosensitive polymer derivative containing an o-nitrobenzyl light trigger and a double bond functional group abbreviated as A 3 , having the structure of formula A-III.
  • an o-nitrobenzyl type light trigger the structure is as shown in Formula I, and has two structures, respectively, such as Structural Formula I-1 and Structural Formula I-2.
  • the structural formula I-1 represents an o-nitrobenzyl type light trigger which does not contain a cyclic structure.
  • Structural Formula I-2 represents a cyclic o-nitrobenzyl based light trigger, symbolized as cNB.
  • R' is selected from the group consisting of hydrogen, halogen atom, hydroxyl group, mercapto group, amine group, nitro group, cyano group, aldehyde group, ketone Base, ester group, amide group, phosphonic acid group, phosphonate group, sulfonic acid group, sulfonate group, sulfone group, sulfoxide group, aryl group, heteroaryl group, alkyl group, alkylene group, modified alkane Base or modified alkylene group;
  • R 1 is selected from the group consisting of hydrogen, an ether bond substituent, an ester bond substituent, a carbonate bond substituent, a urethane bond substituent, a carbazate. a bond substituent or a phosphate bond substituent or the like;
  • R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, an aldehyde group and a ketone group. , carboxyl, ester, amide, phosphonic acid, phosphonate, sulfonate, sulfonate, sulfone, sulfoxide, aryl, heteroaryl, alkyl, alkylene, modified Alkyl or modified alkylene and the like.
  • R 2 , R 3 , R 4 , R 5 may be bonded to each other to form a saturated or unsaturated alicyclic or heteroalicyclic ring together with a carbon atom. Or form an aromatic ring or an aromatic heterocyclic ring.
  • X is O, S or NH, etc.
  • one end of the linking bond R 1 is bonded to X, and the other end is bonded to any one of R 2 , R 3 , R 4 and R 5 to form a ring. structure.
  • Formula A-I in the formula A-III, n ⁇ 2, the average number of o-nitrobenzyl type light trigger on P 1, i.e., a single polymer chain is greater than or equal to 2.
  • P 1 is a hydrophilic or water-soluble natural high polymer or synthetic polymer, or P 1 is independently selected from a plurality of hydrophilic or water-soluble natural high polymers or synthetic Polymers, etc.
  • R' 1 , R′ 2 , R′ 3 is selected from hydrogen, alkyl, modified alkyl or aryl, etc.;
  • R′ 4 is selected from alkyl, ether bond substituent, ester bond substituent, amide bond substituent Wait;
  • R' 1 , R' 2 , R' 3 may be bonded to each other to form a saturated or unsaturated alicyclic or heteroalicyclic ring together with a carbon atom.
  • P 1 is a hydrophilic or water-soluble natural high polymer or synthetic polymer, or P 1 is independently selected from a plurality of hydrophilic or water-soluble natural high polymers or synthetic polymers and the like.
  • the polymer P 1 in the above three photosensitive polymer derivatives may be a hydrophilic or water-soluble natural high polymer, or may be a hydrophilic or water-soluble synthetic polymer.
  • Hydrophilic or water-soluble natural high polymers include natural polysaccharides and their modifications or degradants, proteins and their modifications, modified substances and degraded polypeptides;
  • the natural polysaccharides include hyaluronic acid, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, alginic acid, dextran, agarose, heparin, chondroitin sulfate , ethylene glycol chitosan, propylene glycol chitosan, chitosan lactate, carboxymethyl chitosan or chitosan quaternary ammonium salt;
  • the protein includes various hydrophilic or water-soluble animal and plant proteins, collagen, serum protein, silk fibroin, elastin, and the protein degradation product comprises gelatin or a polypeptide;
  • Hydrophilic or water-soluble synthetic polymers include two-arm or multi-arm polyethylene glycol, polyethyleneimine, dendrites, synthetic peptides, polylysine, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyacrylic acid Esters, polymethacrylates, polyacrylamides, polymethacrylamides, polyvinyl alcohols, polyvinylpyrrolidone;
  • the above three photosensitive polymer derivatives may be hydrophilic or water-soluble polymers containing one or more different groups at the same time, or hydrophilic or water-soluble of one or more different groups. a mixture of polymers.
  • component A is an o-nitrobenzyl light trigger modified photosensitive polymer derivative having the structure of formula A-I,
  • R 2 One end of the P 1 R 2, R 3, R 4 , R 5 in any one or more groups are connected or linked to R 2, R 3, saturated formed between R 4, R 5 or unsaturated aliphatic a ring or an aliphatic heterocyclic ring, or an aromatic ring or an aromatic heterocyclic ring formed between R 2 , R 3 , R 4 and R 5 ,
  • One end of the P 1 R 2, R 3, R 4 , R 5 in any one or more groups are connected or linked to R 2, R 3, saturated formed between R 4, R 5 or unsaturated aliphatic a ring or an alicyclic ring, or an aromatic ring or an aromatic heterocyclic ring formed between R 2 , R 3 , R 4 , R 5 , or attached to any one of R 1 and R 2 , R 3 , R 4 , R 5 a cyclic chain formed by the connection of groups,
  • the linkage is selected from a linkage P 1 -O- obtained by a hydroxyl group; or a linkage P 1 -S- obtained from a thiol group; or a linkage P 1 -NH- obtained from an amine group Or a linking bond P 1 - obtained from an alkane or a linking bond P 1 -COO- obtained from an ester bond; or a linking bond P 1 -CONH- obtained from an amide bond,
  • One end of the connecting button is connected to P 1 and the other end is connected to the benzene ring of the molecule represented by formula A-I;
  • component A is a photosensitive polymer derivative having an o-nitrobenzyl group-based light trigger and a double bond functional group having the structure of formula A-III,
  • R 2 One end of the P 1 R 2, R 3, R 4 , R 5 in any one or more groups are connected or linked to R 2, R 3, saturated formed between R 4, R 5 or unsaturated aliphatic a ring or an aliphatic heterocyclic ring, or an aromatic ring or an aromatic heterocyclic ring formed between R 2 , R 3 , R 4 and R 5 ,
  • One end of the P 1 R 2, R 3, R 4 , R 5 in any one or more groups are connected or linked to R 2, R 3, saturated formed between R 4, R 5 or unsaturated aliphatic a ring or an alicyclic ring, or an aromatic ring or an aromatic heterocyclic ring formed between R 2 , R 3 , R 4 , R 5 , or attached to any one of R 1 and R 2 , R 3 , R 4 , R 5 a cyclic chain formed by the connection of groups,
  • the linkage is selected from a linkage bond obtained by a hydroxyl group -OP 1 -O-; or a linkage selected from a thiol group -SP 1 -S-; or a linkage selected from an amine group -NH- P 1 —NH—; or a linkage selected from an alkane, —P 1 —; or a linkage selected from an ester bond, —COO—P 1 —COO—; or obtained from an amide bond.
  • the linkage bond -CONH-P 1 -CONH-; the linkage may also be selected from the group consisting of different kinds of hydroxyl groups, mercapto groups, amine groups, alkanes, ester bonds, and amide bonds at different ends of P 1 .
  • a connecting button having one end connected to P 1 and the other end connected to a benzene ring of a molecule represented by Formula A-III.
  • the formula A-I is a photosensitive polymer derivative modified by an o-nitrobenzyl light trigger
  • the formula A-II is a photosensitive polymer derivative containing a double bond functional group
  • the formula A-III is A photosensitive polymer derivative containing an o-nitrobenzyl light trigger and a double bond functional group.
  • the structural design of formula A-III is based on the structure of formula A-I and formula A-II.
  • the o-nitrobenzyl light trigger and double bond functional group are grafted on the same polymer chain, and two kinds of simultaneous realization can be realized simultaneously.
  • the cross-linking of the method has the advantages of simultaneous photo-initiated radical polymerization cross-linking speed and the strong adhesion of the photo-coupling cross-linked structure, and the double cross-linking mode improves the mechanical properties of the hydrogel. Therefore, the optimization of the molecular structure makes the polymer derivative modified as a photosensitive group exhibit more excellent material properties, and the crosslinking speed is improved from the simple aldehyde-amine photocoupling cross-linking for about 30 s. Within 2 s, the tissue adhesion is increased to about 80-100 kPa, and the mechanical properties are improved to about 1-2 MPa.
  • the specific data are shown in the examples of one hundred and sixty-seven, one hundred and sixty-eight, one hundred and sixty-nine.
  • alkyl group is a saturated or unsaturated aliphatic straight or branched alkyl group having 1 to 30 carbon atoms;
  • the alkylene group is a saturated or unsaturated aliphatic straight or branched alkylene group having 1 to 30 carbon atoms;
  • any carbon atom in which the modified alkyl group is an alkyl group is selected from a halogen atom, -OH, -SH, -NO 2 , -CN, -CHO, -COOH, ester group, amide group, aryl group, arylene group , -CO-, -O-, -S-, -SO-, -SO 2 -, primary, secondary, tertiary, quaternary ammonium, saturated or unsaturated monocyclic or bicyclic ring
  • the obtained group is substituted with at least one group of a hydrocarbon group or a bridged aliphatic heterocyclic ring having 1 to 30 atoms, and a carbon-carbon single bond thereof may be optionally a carbon-carbon double bond or a carbon-carbon ruthenium Key replacement
  • any carbon atom in which the modified alkylene group is an alkylene group is selected from a halogen atom, -OH, -SH, -NO 2 , -CN, -CHO, -COOH, ester group, amide group, aryl group, or sub Aryl, -CO-, -O-, -S-, -SO-, -SO 2 -, primary, secondary, tertiary, quaternary ammonium, saturated or unsaturated monocyclic or bicyclic
  • the resulting group is substituted with at least one group of a cycloalkylene group and a bridged aliphatic heterocyclic ring having 1 to 30 atoms, and the carbon-carbon single bond may be arbitrarily carbon-carbon double bond or Carbon-carbon ⁇ bond replacement;
  • the ether bond substituent is selected from the following structures:
  • ester bond substituent is selected from the following structures:
  • the carbonate bond substituent is selected from the following structures:
  • the urethane bond substituent is selected from the following structures:
  • the carbazate bond substituent is selected from the following structures:
  • the phosphate bond substituent is selected from the following structures:
  • the aryl group is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic structure
  • the heteroaryl group is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic structure having at least one hetero atom selected from O, S, N or Si on the ring;
  • the halogen atoms are each independently selected from the group consisting of F, Cl, Br, and I;
  • the alicyclic ring is a saturated or unsaturated 3 to 10 membered monocyclic or polycyclic alicyclic ring;
  • the heteroalicyclic ring is a saturated or unsaturated 3-10 membered monocyclic or polycyclic heterocyclic ring containing at least one hetero atom selected from O, S, N or Si, on the heteroalicyclic ring.
  • S atom When it contains an S atom, it is optionally -S-, -SO- or -SO 2 -;
  • H on the alicyclic or alicyclic ring may be optionally halogen atom, nitro group, aryl group, alkyl group or Modified alkyl substitution;
  • the aromatic ring is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic ring
  • the aromatic heterocyclic ring is a 5- to 10-membered aromatic monocyclic or aromatic fused bicyclic ring containing at least one hetero atom selected from O, S, N or Si; the H on the aromatic ring or the aromatic heterocyclic ring It may also be optionally substituted by a halogen atom, a nitro group, an aryl group, an alkyl group or a modified alkyl group.
  • alicyclic or heteroalicyclic ring include:
  • aromatic ring or the aromatic heterocyclic ring include:
  • R' Some preferred structures for R' include:
  • R 2 , R 3 , R 4 , R 5 Some preferred structures for R 2 , R 3 , R 4 , R 5 include:
  • a preferred substituent of the alkyl substituent such as a linear alkyl-(CH 2 ) x CH 3 , a branched alkyl-(CH 2 ) x (CY'Y") y CH 3 (Y', Y" is hydrogen, An alkyl group or a modified alkyl group or the like, wherein x and y ⁇ 0 and are integers;
  • the ether substituent is preferably a structure such as -O(CH 2 ) x CH 3 , -O(CH 2 CH 2 O) x CH 3 , -O(CH 2 ) x (CH 2 CH 2 O) y CH 3 , or the like.
  • x and y ⁇ 0 and are integers;
  • Preferred structures of the thioether substituents such as -S(CH 2 ) x CH 3 , -S(CH 2 CH 2 O) x CH 3 , -S(CH 2 ) x (CH 2 CH 2 O) y CH 3 , etc.
  • x and y ⁇ 0 and are integers;
  • Amino substituents preferably have a structure such as -NH(CH 2 ) x CH 3 , -NH(CH 2 ) x (CY'Y") y CH 3 , -N(CY'Y") x (CY'Y” ) y , (Y, Y' is hydrogen, alkyl or modified alkyl), etc., wherein x and y ⁇ 0 and are integers;
  • ester substituent is, for example, -COO(CH 2 ) x CH 3 , -COO(CH 2 CH 2 O) x CH 3 , -COO(CH 2 ) x (CH 2 CH 2 O) y CH 3 , etc.
  • x and y ⁇ 0 and are integers;
  • the amide substituent preferably has a structure such as -CONH(CH 2 ) x CH 3 , -CONH(CH 2 CH 2 O) x CH 3 , -CONH(CH 2 ) x (CH 2 CH 2 O) y CH 3 , or the like.
  • x and y ⁇ 0 and are integers;
  • Aromatic substituents preferably have a structure such as -Ph, Wait.
  • the polymer P 1 in the polymer derivative modified by the o-nitrobenzyl light trigger may be a hydrophilic or water-soluble natural high polymer including natural polysaccharides and their modifications or degradants, proteins and their modifications.
  • the natural polysaccharides include hyaluronic acid, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, alginic acid, dextran, agarose, Heparin, chondroitin sulfate, ethylene glycol chitosan, propylene glycol chitosan, chitosan lactate, carboxymethyl chitosan or chitosan quaternary ammonium salt, etc.
  • the protein includes various hydrophilicities or Water-soluble animal and vegetable protein, collagen, serum protein, silk fibroin, elastin
  • the protein degradation product includes gelatin or polypeptide, etc.
  • hydrophilic or water-soluble synthetic polymer includes two-arm
  • the average number of o-nitrobenzyl-based light triggers on a single polymer chain is greater than or equal to 2 (i.e., n ⁇ 2).
  • the polymer derivative modified by the o-nitrobenzyl light trigger may be a hydrophilic or water-soluble polymer containing one or more different groups at the same time, or one or more different groups.
  • the hydrophilic or water-soluble polymer refers to a hydrophilic or water-soluble natural high polymer, or a hydrophilic or water-soluble synthetic polymer.
  • the o-nitrobenzyl light-trigger modified polymer derivative of the formula A-I may be selected from the structures of the following components A-1 to A-50:
  • the o-nitrobenzylthio-based light-trigger modified polymer derivative of the formula A-I may be selected from the structures of the following components A-51 to A-69:
  • the o-nitrobenzylamine-based light-trigger modified polymer derivative of the formula A-I may be selected from the structures of the following components A-70 to A-87:
  • the cyclic o-nitrobenzyl light-trigger modified polymer derivative of the formula A-I may be selected from the structures of the following components A-88 to A-106:
  • the double bond modified polymer derivative of the formula A-II may be selected from the structures of the following components A-107 to A-115:
  • the polymer derivative of the formula A-III containing an o-nitrobenzyl group light trigger and a double bond functional group may be selected from the structures of the following components A-116 to A-154. :
  • HA hyaluronic acid
  • CMC carboxymethylcellulose
  • Alg alginic acid
  • CS chondroitin sulfate
  • PGA polyglutamic acid
  • PEG It is polyethylene glycol
  • Chitosan is chitosan
  • Gelatin is gelatin
  • PLL polylysine
  • Dex is dextran
  • Hep is heparin.
  • the optimization of the molecular structure makes the polymer derivative modified as a photosensitive group exhibit more excellent material properties, and the crosslinking speed is improved from the simple aldehyde-amine photocoupling cross-linking for about 30 s.
  • the tissue adhesion is increased to about 80-100 kPa, and the mechanical properties are improved to about 1-2 MPa.
  • the specific data are shown in the examples of one hundred and sixty-seven, one hundred and sixty-eight, one hundred and sixty-nine.
  • N replaces the oxygen atom (O), because the nitrogen atom is a strong electron donor, which facilitates intramolecular charge transfer, speeds up the photolysis rate and photolysis efficiency of the light trigger, ie, can be faster and more thorough under illumination
  • the aldehyde group/keto group or nitroso group is released, thereby accelerating the crosslinking rate as a crosslinking site, and the released aldehyde group/keto group or nitroso group can bond with the active group on the surface of the tissue. Fixed, can greatly improve the adhesion of materials and tissues.
  • the simultaneous release and cross-linking of various reactive functional groups is only the release and cross-linking of a single reactive functional group
  • the crosslinking efficiency and cross-linking density are greatly improved, and further improved.
  • the mechanical properties of the material Therefore, the optimization of the molecular structure makes the polymer derivative modified as a photosensitive group exhibit more excellent material properties, and the crosslinking speed is improved from the simple aldehyde-amine photocoupling cross-linking for about 30 s.
  • the tissue adhesion is increased to about 80-100 kPa, and the mechanical properties are improved to about 1-2 MPa.
  • the specific data are shown in the examples of one hundred and sixty-seven, one hundred and sixty-eight, one hundred and sixty-nine.
  • Structural Formula I-2 it is a cyclic o-nitrobenzyl light trigger, specifically a cyclic o-nitrobenzyl light trigger or a cyclic o-nitrobenzylthio light trigger or a cyclic o-nitrobenzylamine.
  • the base type light trigger has an intramolecular ring structure and is designed to retain another reactive functional group (such as a mercapto group) which is released under illumination, and can be retained on the precursor of the o-nitrobenzyl group (simple aldehyde group-amino group)
  • Another reactive functional group such as a mercapto group
  • the other reactive functional group released in the photocoupled cross-linking will leave the precursor of the o-nitrobenzyl group, thereby further releasing the sulfhydryl group and further increasing the aldehyde group/keto group or nitroso group simultaneously.
  • An effective cross-linking site is designed to retain another reactive functional group (such as a mercapto group) which is released under illumination, and can be retained on the precursor of the o-nitrobenzyl group (simple aldehyde group-amino group)
  • the other reactive functional group released in the photocoupled cross-linking will leave the precursor of the o-nitrobenzyl group
  • the 3d empty orbital of the sulfur atom (S) facilitates intramolecular charge transfer; in the cyclic o-nitrobenzylamine-based light trigger, the nitrogen atom (N) is The strong electron donor facilitates intramolecular charge transfer and accelerates the photolysis rate and photolysis efficiency of the light trigger, that is, the aldehyde group/keto group or nitroso group can be released more rapidly and more completely under illumination.
  • the optimization of the molecular structure makes the polymer derivative modified as a photosensitive group exhibit more excellent material properties, and the crosslinking speed is improved from the simple aldehyde-amine photocoupling cross-linking for about 30 s.
  • the tissue adhesion is increased to about 80-100 kPa, and the mechanical properties are improved to about 1-2 MPa.
  • the specific data are shown in the examples of one hundred and sixty-seven, one hundred and sixty-eight, one hundred and sixty-nine.
  • a third object of the present invention is to provide a process for producing the photosensitive polymer derivative.
  • a method for preparing a photosensitive polymer derivative (abbreviated as A 1 ) modified by an o-nitrobenzyl light trigger is a method for preparing a photosensitive polymer derivative (abbreviated as A 1 ) modified by an o-nitrobenzyl light trigger.
  • the o-nitrobenzyl light trigger has two structures including an o-nitrobenzyl light trigger without a ring structure, a cyclic o-nitrobenzyl light trigger, and a cyclic o-nitrobenzyl group.
  • the light trigger symbol is denoted as cNB.
  • the o-nitrobenzyl light trigger comprises an o-nitrobenzyl light trigger, an o-nitrobenzylthio light trigger, an o-nitrobenzylamine based light trigger.
  • the o-nitrobenzyl group light trigger symbol is represented by NB
  • the o-nitrobenzylthio type light trigger symbol is represented by sNB
  • the o-nitrobenzylamine based light trigger symbol is represented by nNB.
  • An optical polymer derivative (abbreviated as A 1 ) modified by an o-nitrobenzyl light trigger is prepared by a chemical labeling method and a manual polymerization method.
  • the chemical labeling method is connected by a chemical reaction between a polymer and a chemical group contained in an o-nitrobenzyl type light trigger, and may be a carboxyl group-containing polymer and a hydroxyl group/mercapto group/amine group-containing neighboring nitrate.
  • Small benzylic-based molecular markers reference OPOommen, S. Wang, M. Kisiel, M. Sloff, J. Hilborn, OP Varghese, Adv. Funct. Mater. 2013, 23, 1273.
  • Hydroxyl polymer and carboxyl group-containing or bromine-containing o-nitrobenzyl small molecule label Reference K. Peng, I. Tomatsu, AV Korobko, A.
  • L. Li N. Wang, X. Jin, R. Deng, S. Nie, L. Sun, Q. Wu, Y. Wei, C. Gong, Biomaterials 2014, 35, 3903.
  • L. Li N. Wang, X. Jin, R. Deng, S. Nie, L. Sun, Q. Wu, Y. Wei, C. Gong, Biomaterials 2014, 35, 3903.
  • Molecular and carboxy-containing or bromine-containing o-nitrobenzyl small molecule markers Reference L. Li, N. Wang, X. Jin, R. Deng, S. Nie, L. Sun, Q. Wu, Y .Wei, C.Gong, Biomaterials 2014, 35, 3903.
  • the method of artificial polymerization is to use a functional monomer of o-nitrobenzyl derivative to copolymerize with other comon monomers, which may be a random radical polymerization method or a controlled radical polymerization method (such as ATRP polymerization, RAFT polymerization method), etc. .
  • the first preparation method can be carried out by dissolving a water-soluble polymer or a polymer containing a carboxyl group in distilled water, adding an o-nitrobenzyl small molecule containing a reactive functional group hydroxyl group or a mercapto group or an amine group, and then adding a condensing agent 1 -ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and the activator hydroxybenzotriazole (HOBt), then stirred at room temperature for 24-48 h. After the reaction is completed, the reaction solution is added to a dialysis bag and dialyzed against a dilute hydrochloric acid solution for 2-3 d, and then freeze-dried to obtain the o-nitrobenzyl modified photopolymer derivative.
  • EDC-HCl condensing agent 1 -ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • the carboxyl group-containing water-soluble polymer or polymer may be a polyethylene glycol or a carboxyl group-containing polysaccharide (eg, hyaluronic acid, carboxymethyl group).
  • Cellulose, alginic acid, etc., carboxyl group-containing proteins or polypeptides are preferably multi-arm carboxy polyethylene glycol, hyaluronic acid, carboxymethyl cellulose, gelatin. More preferably, it is hyaluronic acid.
  • a third exemplified preparation method is: dissolving a water-soluble polymer containing a hydroxyl group or an amine group in distilled water, adding an o-nitrobenzyl small molecule having a carboxyl group of a reactive functional group, and adding a condensing agent 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and the catalyst p-toluenesulfonic acid pyridinium salt (DPTS) were then stirred at room temperature for 24-48 h.
  • EDC-HCl 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride
  • DPTS catalyst p-toluenesulfonic acid pyridinium salt
  • the reaction solution is poured into a poorly soluble solvent to reprecipitate (for example, the modified polyethylene glycol derivative can be poured into diethyl ether to reprecipitate, the polysaccharide polymer derivative can be poured into ethanol to reprecipitate), and then It is dissolved in water and dialyzed for 2-3 days in a dialysis bag, and after lyophilization, the o-nitrobenzyl modified photosensitive polymer derivative can be obtained.
  • a poorly soluble solvent to reprecipitate for example, the modified polyethylene glycol derivative can be poured into diethyl ether to reprecipitate, the polysaccharide polymer derivative can be poured into ethanol to reprecipitate
  • the fourth method can be carried out by dissolving a water-soluble polymer containing a hydroxyl group or an amine group in distilled water, adding an o-nitrobenzyl small molecule containing a reactive functional group bromine, and adding potassium carbonate as a base at room temperature.
  • the reaction is 24-48h.
  • the reaction solution is poured into a poorly soluble solvent (for example, a modified polyethylene glycol derivative can be poured into diethyl ether, and the modified polysaccharide polymer derivative can be poured into ethanol) to be precipitated, and then dissolved.
  • the dialysis bag is dialyzed in water for 2-3 d, and after freeze-drying, the o-nitrobenzyl modified photopolymer derivative can be obtained.
  • the water-soluble polymer having a hydroxyl group or an amine group may be a hydroxyl group or an amine group-containing polyethylene glycol or a natural polysaccharide or a protein/polypeptide.
  • Preferred are multi-arm hydroxy polyethylene glycol, multi-arm amine-based polyethylene glycol, ethylene glycol chitosan, propylene glycol chitosan, carboxymethyl chitosan, chitosan lactate or natural polysaccharide.
  • polylysine, gelatin or the like is further preferably ethylene glycol chitosan or multi-arm hydroxy polyethylene glycol.
  • the molar ratio of the carboxyl group, the hydroxyl group or the amine group in the water-soluble polymer to the small molecule o-nitrobenzyl derivative is preferably 1:0.1-2; the amine-modified o-nitrobenzyl small molecule
  • the molar ratio to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and the activator hydroxybenzotriazole (HOBt) is preferably 1:2:1.5
  • the molar ratio of the amine-modified o-nitrobenzyl small molecule to 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM) is preferably 1:7.5; molar ratio of carboxyl-modified o-nitrobenzyl small molecule to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl), catalyst
  • the fifth achievable preparation method comprises the following steps: polymerizing an o-nitrobenzyl polymerizable monomer derivative with one or more polymerizable co-monomers to obtain an o-nitrobenzyl modified synthetic copolymer. It was purified by multiple dissolution-re-precipitation methods.
  • the o-nitrobenzyl polymerizable monomer derivative may be an acrylate compound, a methacrylate compound, an acrylamide compound or a methacrylamide compound, preferably a methacrylate compound and an acrylamide compound.
  • the compound is more preferably a methacrylate compound.
  • At least one of the above polymerizable comonomers must be a water-soluble comonomer, and may be polyethylene glycol methacrylate (PEG-MA), polyethylene glycol acrylate, methacrylic acid (MAA), acrylic acid ( Any water-soluble polymerizable monomer such as AA), hydroxyethyl acrylate or acrylamide (AM), preferably polyethylene glycol methacrylate (PEG-MA).
  • PEG-MA polyethylene glycol methacrylate
  • MAA methacrylic acid
  • acrylic acid Any water-soluble polymerizable monomer such as AA), hydroxyethyl acrylate or acrylamide (AM), preferably polyethylene glycol methacrylate (PEG-MA).
  • Other co-monomers are selected for different applications.
  • the polymerization molar ratio of the above o-nitrobenzyl polymerizable monomer derivative to the water-soluble comonomer may be from 1:20 to 1:2, preferably from 1:9 to 1:3, further preferably 1:4.
  • the above polymerization method may be random radical polymerization or controlled radical polymerization (such as RAFT polymerization, ATRP polymerization, etc.). It is preferably a random radical polymerization. That is, the o-nitrobenzyl polymerizable monomer derivative and the comonomer are co-dissolved in a certain solvent, and after being sufficiently dissolved by adding a radical initiator, after three freeze-vacuum cycle operations, the reaction is carried out under heating overnight. After the reaction is completed, the reaction solution is poured into anhydrous diethyl ether to precipitate, and after several times of dissolution-re-precipitation purification process, vacuum-dried to obtain an o-nitrobenzyl group-containing copolymer. (References G. Delaittre, T. Pauloehrl, M. Bastmeyer, C. Barner-Kowollik, Macromolecules 2012, 45, 1792-1802.)
  • the present invention provides a process for preparing a photosensitive polymer derivative (abbreviated as A 2 ) containing a double bond functional group.
  • the preparation method of the double bond modified photosensitive polymer derivative includes the following:
  • the first preparation method can be carried out by dissolving a water-soluble polymer containing a hydroxyl group or an amine group in deionized water, cooling to 0-4 ° C, adding acrylic anhydride or methacrylic anhydride, and slowly adding 5 M NaOH. After reacting for 24 hours, the reaction solution was poured into a dialysis bag, dialyzed against deionized water for 2-3 d, and then freeze-dried to obtain the double bond-modified photosensitive polymer derivative.
  • the above water-soluble polymer or polymer containing a hydroxyl group or an amine group may be a polyethylene glycol type, a hydroxyl group- or amine group-containing polysaccharide (eg, hyaluronic acid, alginic acid, carboxymethyl cellulose, carboxymethyl group). Chitosan, dextran, chondroitin sulfate, etc.), hydroxyl or amino group-containing proteins or polypeptides (eg, gelatin, etc.), preferably hyaluronic acid, gelatin, alginic acid, carboxymethyl cellulose, sulfated cartilage Further, it is preferably hyaluronic acid.
  • a hydroxyl group- or amine group-containing polysaccharide eg, hyaluronic acid, alginic acid, carboxymethyl cellulose, carboxymethyl group.
  • Chitosan, dextran, chondroitin sulfate, etc. hydroxyl or amino group-containing proteins or
  • the second preparation method can be carried out by dissolving a water-soluble polymer containing a hydroxyl group or an amine group in deionized water, heating to 40 ° C, stirring and dissolving, adding glycidyl acrylate or glycidyl methacrylate, and then adding 5 M. After NaOH for 2-3 hours, the reaction solution was poured into a dialysis bag, dialyzed against deionized water for 2-3 d, and then freeze-dried to obtain the double bond-modified photosensitive polymer derivative.
  • the above water-soluble polymer or polymer containing a hydroxyl group or an amine group may be a polyethylene glycol type, a hydroxyl group- or amine group-containing polysaccharide (eg, hyaluronic acid, alginic acid, carboxymethyl cellulose, carboxymethyl group). Chitosan, dextran, chondroitin sulfate, etc.), hydroxyl or amino group-containing proteins or polypeptides (eg, gelatin, etc.), preferably hyaluronic acid, gelatin, carboxymethyl chitosan, further preferably carboxy Methyl chitosan.
  • a polyethylene glycol type eg, hyaluronic acid, alginic acid, carboxymethyl cellulose, carboxymethyl group.
  • Chitosan, dextran, chondroitin sulfate, etc. hydroxyl or amino group-containing proteins or polypeptides
  • hydroxyl or amino group-containing proteins or polypeptides
  • the third exemplified preparation method is: dissolving a hydroxyl group-containing or amino group-containing water-soluble polymer in anhydrous dimethyl sulfoxide, adding triethylamine, and then adding acryloyl chloride or methacryloyl chloride (dissolving in two) In methyl chloride, the reaction is carried out for 10 hours. After the reaction is completed, the reaction solution is poured into ethanol and reprecipitated. The crude product obtained by filtration is redissolved in deionized water, dialyzed for 2-3 d, and then freeze-dried to obtain the double A key modified photopolymer derivative.
  • the water-soluble polymer or polymer containing a hydroxyl group or an amine group may be a polyethylene glycol or a hydroxyl group- or amine group-containing polysaccharide (for example, dextran), preferably a multi-arm polyethylene glycol or a grape.
  • the polysaccharide is more preferably dextran.
  • a method for preparing a photosensitive polymer derivative (abbreviated as A 3 ) containing an o-nitrobenzyl group light trigger and a double bond functional group.
  • the o-nitrobenzyl light trigger has two structures including an o-nitrobenzyl light trigger without a ring structure, a cyclic o-nitrobenzyl light trigger, and a cyclic o-nitrobenzyl group.
  • the light trigger symbol is denoted as cNB.
  • the o-nitrobenzyl light trigger comprises an o-nitrobenzyl light trigger, an o-nitrobenzylthio light trigger, an o-nitrobenzylamine based light trigger.
  • the o-nitrobenzyl group light trigger symbol is represented by NB
  • the o-nitrobenzylthio type light trigger symbol is represented by sNB
  • the o-nitrobenzylamine based light trigger symbol is represented by nNB.
  • a photopolymer derivative (abbreviated as A 3 ) containing an o-nitrobenzyl group light trigger and a double bond functional group is prepared by labeling an o-nitrobenzyl group light trigger and labeling a double bond functional group.
  • the double-bond functional group is first labeled and then labeled with an o-nitrobenzyl light trigger.
  • the specific labeling method is prepared by the above-mentioned o-nitrobenzyl light trigger or double bond functional group labeling method.
  • the o-nitrobenzyl light trigger labeling method is a chemical reaction between a polymer and a chemical group contained in an o-nitrobenzyl light trigger, and may be a carboxyl group-containing polymer and a hydroxyl group/sulfhydryl group/ Amino-based nitrobenzyl small molecule label; may also be a hydroxyl group-containing polymer and a carboxyl group-containing or bromine-containing o-nitrobenzyl group small molecule label; or may be an amine group-containing polymer and A labeling method such as a carboxyl group or a bromine-containing o-nitrobenzyl group-based small molecule label.
  • the double bond functional group labeling method is an acrylic anhydride molecule, a methacrylic acid type molecule, a glycidyl acrylate molecule, a glycidyl methacrylate molecule, an acryloyl chloride molecule, a methacryloyl chloride molecule, or the like.
  • the preparation method of the photosensitive polymer derivative (abbreviated as A 3 ) containing the o-nitrobenzyl group light trigger and the double bond functional group includes the following:
  • the first preparation method can be carried out by dissolving a water-soluble polymer containing an o-nitrobenzyl group light trigger in deionized water, cooling to 0-4 ° C, adding acrylic anhydride or methacrylic anhydride, and then slowly dropping Add 5M NaOH, react for 24h, then pour the reaction solution into dialysis bag, dialyze with deionized water for 2-3d, then freeze-dry, then get the o-nitrobenzyl-based light trigger and double bond A photosensitive polymer derivative of a functional group.
  • the second preparation method is as follows: the water-soluble polymer containing an o-nitrobenzyl group light trigger is dissolved in deionized water, heated to 40 ° C to stir and dissolve, and glycidyl acrylate or glycidyl methacrylate is added. Then, adding 5M NaOH, after reacting for 2-3 hours, pouring the reaction solution into a dialysis bag, dialysis against deionized water for 2-3 d, and then freeze-drying to obtain the optical pulser containing the o-nitrobenzyl group.
  • a photosensitive polymer derivative further containing a double bond functional group.
  • a third exemplified preparation method is: dissolving a water-soluble polymer containing an o-nitrobenzyl group light trigger in anhydrous dimethyl sulfoxide, adding triethylamine, and then adding acryloyl chloride or methacryloyl chloride. (dissolved in dichloromethane), the reaction was carried out for 10 h. After the reaction was completed, the reaction solution was poured into ethanol and reprecipitated. The crude product obtained by filtration was redissolved in deionized water, dialyzed for 2-3 d, and then freeze-dried to obtain The photosensitive polymer derivative containing an o-nitrobenzyl group light trigger and a double bond functional group.
  • the fourth method can be carried out by dissolving a water-soluble polymer or a polymer containing a double bond functional group in distilled water, adding an o-nitrobenzyl small molecule containing a reactive functional group hydroxyl group or a mercapto group or an amine group, and then adding the compound.
  • the mixture was mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and the activator hydroxybenzotriazole (HOBt), followed by stirring at room temperature for 24-48 h.
  • EDC-HCl 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HOBt activator hydroxybenzotriazole
  • reaction solution is added to a dialysis bag and dialyzed against a dilute hydrochloric acid solution for 2-3 days, and then freeze-dried to obtain the photosensitive polymer derivative containing the o-nitrobenzyl group-based light trigger and the double bond functional group. Things.
  • the hydrochloride (DMTMM) was dissolved in MES buffer solution and added to the above reaction solution in three portions (every 1 h), and reacted at 35 ° C for 24 h.
  • reaction solution is poured into a dialysis bag, dialyzed against deionized water for 2-3 d, and then freeze-dried to obtain the photopolymer derivative containing the o-nitrobenzyl group light trigger and the double bond functional group. .
  • the sixth preparation method can be carried out by dissolving a water-soluble polymer containing a double bond functional group, adding an o-nitrobenzyl small molecule having a carboxyl group of a reactive functional group, and then adding a condensing agent 1-ethyl-(3-di Methylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and the catalyst p-toluenesulfonic acid pyridinium salt (DPTS) were then stirred at room temperature for 24-48 h.
  • EDC-HCl 1-ethyl-(3-di Methylaminopropyl)carbodiimide hydrochloride
  • DPTS catalyst p-toluenesulfonic acid pyridinium salt
  • the reaction solution is poured into a poorly soluble solvent to reprecipitate (for example, the modified polyethylene glycol derivative can be poured into diethyl ether to reprecipitate, the polysaccharide polymer derivative can be poured into ethanol to reprecipitate), and then Dissolved in water and dialyzed for 2-3 days in a dialysis bag, and after lyophilization, the photosensitive polymer derivative containing the o-nitrobenzyl group light trigger and the double bond functional group can be obtained.
  • a poorly soluble solvent to reprecipitate for example, the modified polyethylene glycol derivative can be poured into diethyl ether to reprecipitate, the polysaccharide polymer derivative can be poured into ethanol to reprecipitate
  • the seventh preparation method can be carried out by dissolving a water-soluble polymer containing a double bond functional group in distilled water, adding an o-nitrobenzyl small molecule containing a reactive functional group bromine, adding potassium carbonate as a base, and reacting at room temperature. 24-48h. After the reaction is completed, the reaction solution is poured into a poorly soluble solvent (for example, a modified polyethylene glycol derivative can be poured into diethyl ether, and the modified polysaccharide polymer derivative can be poured into ethanol) to be precipitated, and then dissolved. The dialysis bag is dialyzed in water for 2-3 d, and after lyophilization, the photopolymer derivative containing the o-nitrobenzyl group light trigger and the double bond functional group can be obtained.
  • a poorly soluble solvent for example, a modified polyethylene glycol derivative can be poured into diethyl ether, and the modified polysaccharide polymer derivative can be poured into ethanol
  • a fourth object of the present invention is to provide a method of preparing a photocrosslinked hydrogel material.
  • the photocrosslinked hydrogel material is prepared by using the photosensitive polymer derivative of the second object of the invention as a raw material.
  • a method for preparing a photocrosslinked hydrogel material comprising the steps of:
  • the solution A and the solution B are uniformly mixed to obtain a hydrogel precursor solution, and the hydrogel precursor solution is photocrosslinked to form a hydrogel under irradiation of a light source.
  • the crosslinking method is as follows: the o-nitrobenzyl light trigger and/or double bond functional group and the component B-photoinitiator in component A undergo free radical crosslinking under illumination (ie, o-nitrobenzyl group) Free radical crosslinking of the light-like trigger and free radical crosslinking of the double bond functional group).
  • a method for preparing another photocrosslinked hydrogel material comprises the following steps:
  • the auxiliary component C-other biocompatible polymer derivative is dissolved in a biocompatible medium to obtain a polymer solution C, and the auxiliary component C-other biocompatible polymer derivative is an amine group-containing a polymer derivative of an amine, hydrazide or hydroxylamine functional group, or a polymer derivative containing a mercapto functional group;
  • the solution A, the solution B and the solution C are uniformly mixed to obtain a hydrogel precursor solution, and the hydrogel precursor solution is photocrosslinked to form a hydrogel under irradiation of a light source.
  • the crosslinking method is as follows: the o-nitrobenzyl light trigger and/or double bond functional group and the component B-photoinitiator in component A undergo free radical crosslinking under illumination (ie, o-nitrobenzyl group) Free radical crosslinking of the light-like trigger and free radical crosslinking of the double bond functional group), and the aldehyde group/keto group produced by the o-nitrobenzyl group light trigger in the component A and the amine in the component C
  • the photo-coupling cross-linking of the amide, hydrazine, hydrazide or hydroxylamine functional groups produces a photo-nitroso crosslink with the sulfhydryl functional group in component C, which is a complex photocrosslinking mode.
  • the configuration of the hydrogel precursor solution can be selected from component A, component B, and component C according to different needs, wherein component A and component B are essential components, and component C is auxiliary.
  • the component, thus the hydrogel precursor solution may be component A/component B or component A/component B/component C.
  • the configuration of the component A may be selected from the photosensitive polymer derivatives A 1 , A 2 , and A 3 according to different needs, and may be a mixture of one or more photosensitive polymer derivatives, but may not be a single A 2 . .
  • the biocompatible medium is selected from the group consisting of distilled water, physiological saline, a buffer, and a cell culture medium solution. Different media can be selected depending on the application.
  • the concentration of component A may be 0.1% wt-60% wt, preferably 1% wt- 10% wt
  • the concentration of component B may be 0.01% wt-10% wt, preferably 0.05% wt-1.0% wt
  • the total polymer concentration may be 0.1% wt-60% wt, preferably 1% wt-10 %wt
  • the concentration of component B may The total polymer concentration may be from 0.1% by weight to 10% by weight, preferably from 0.05% by weight to 1.0% by weight, preferably from 0.1% by weight to 60% by weight, preferably from 1% by weight to 10% by weight.
  • the wavelength of the light source is determined according to the absorption wavelength of the o-nitrobenzyl phototrigger and the photoinitiator, and may be 250-500 nm, preferably 300-450 nm, and further preferably 365, 375, 385, 395. 405nm.
  • the technical principle of the preparation method of the photocrosslinking hydrogel of the invention adopts the o-nitrobenzyl light-based trigger and/or the double-bond functional group and the component B-photoinitiator in A, respectively, under the illumination, free radicals respectively Cross-linking, while the aldehyde/ketone group produced by the o-nitrobenzyl light trigger in component A is photocoupled and crosslinked with the amine, hydrazine, hydrazide or hydroxylamine functional groups in component C, The produced nitroso group undergoes photo-nitroso cross-linking with the thiol functional group in component C, thereby achieving multiple cross-linking under one illumination, and is a composite photocrosslinking mode.
  • Component B - a photoinitiator, that is, a substance capable of generating a radical under illumination, preferably a water-soluble photoinitiator or a photoinitiator dispersible in water, further preferably I 2959 (component B-1), LAP ( Component B-2), Eosin-Y (component B-3) and the like and derivatives thereof.
  • Component C - a polymer derivative containing an amine group, a hydrazine, a hydrazide or a hydroxylamine functional group, respectively having the structural formula C-I, C-II, C-III, C-IV; a polymer derivative containing a mercapto group functional group, Has the structural formula C-V:
  • Hydrophilic or water soluble natural polymers include natural polysaccharides and their modifications or degradants, proteins and their modifications, modifications and degraded polypeptides.
  • the natural polysaccharides include hyaluronic acid, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, alginic acid, dextran, agarose, heparin, chondroitin sulfate , ethylene glycol chitosan, propylene glycol chitosan, chitosan lactate, carboxymethyl chitosan or chitosan quaternary ammonium salt.
  • the protein includes various hydrophilic or water-soluble animal and plant proteins, collagen, serum proteins, silk fibroin, elastin, and the protein degradation products include gelatin or a polypeptide.
  • Hydrophilic or water-soluble synthetic polymers include two-arm or multi-arm polyethylene glycol, polyethyleneimine, dendrites, synthetic peptides, polylysine, polyglutamic acid, poly(meth)acrylic acid, poly(A) Acrylate, poly(meth)acrylamide, polyvinyl alcohol, polyvinylpyrrolidone.
  • the polymer derivative containing an amine group, a hydrazine, a hydrazide, a hydroxylamine or a mercapto group may be a hydrophilic or water-soluble natural high polymer or a synthetic polymer containing one or more different groups at the same time, or A hydrophilic or water soluble natural high polymer or synthetic polymer of one or more different groups.
  • the structure represented by the formula C-I represents a water-soluble or hydrophilic polymer containing n amine groups.
  • the structure represented by the formula C-II represents a water-soluble or hydrophilic polymer containing n hydrazino groups.
  • the structure represented by the formula C-III represents a water-soluble or hydrophilic polymer containing n hydrazide groups.
  • the structure represented by the formula C-IV represents a water-soluble or hydrophilic polymer containing n hydroxylamine groups.
  • the structure represented by the formula C-V represents a water-soluble or hydrophilic polymer containing n mercapto groups.
  • the formula C-I may be selected from the following components C-1 to C-9; the formula C-II may be selected from the following components C-10; Formula C-III may be selected from the following components C-11 to C-13; the formula C-IV may be selected from the following components C-14 to C-15;
  • the formula C-V is selected from the structures of the following components C-16 to C-21:
  • component C-1 to component C-21 n ⁇ 2
  • component C-1 is chitosan
  • component C-2 is ethylene glycol chitosan
  • component C-3 is carboxymethyl shell Glycan
  • component C-4 is gelatin
  • component C-5 is polylysine
  • component C-6 is polyethyleneimine
  • component C-7 is biarm amine polyglycol
  • component C-8 is a four-arm amine-based polyethylene glycol
  • component C-9 is an amine-based polymer
  • component C-10 is a hydrazine-modified carboxymethylcellulose
  • component C-11 to component C- 13 is a hydrazide-modified hyaluronic acid
  • component C-14 is a tetra-arm hydroxyamine polyethylene glycol
  • component C-15 is a hydroxylamine-modified dextran
  • component C-16 is a bis-mercapto-polyethylene glycol
  • Component C-17 is tetrahedyl ruthenium glycol
  • the present invention also provides a process for the preparation of a component C-containing polymer derivative containing an amine group, a hydrazine, a hydrazide or a hydroxylamine group.
  • the amine-modified water-soluble polymer may be a synthetic polyamine polymer and a modification thereof (such as polyethyleneimine PEI, dendrimer PAMAM, two-arm or multi-arm amine-based polyethylene glycol), Or a natural amino-containing polysaccharide hydrophilic or water-soluble polymer and its modifications or degradation products (such as ethylene glycol chitosan, propylene glycol chitosan, chitosan lactate, carboxymethyl chitosan, Chitooligosaccharides, etc.); may also be biological or microbial expressed proteins and their modifications or degradants (such as collagen, serum proteins and gelatin, etc.); may also be artificially synthesized or expressed by microorganisms and extracted Hydrophilic or water-soluble polypeptides of two or more amine groups (such as polylysine, etc.) or acrylate or methacrylate or acrylamide or methacrylamide polymers and modifications thereof.
  • Preferred is gelatin or ethylene glycol,
  • the hydrazine-modified polymer derivative is prepared by dissolving a carboxyl group-containing water-soluble polymer and a diamine in distilled water, and adding a condensing agent 1-ethyl-(3-dimethylamino group).
  • a condensing agent 1-ethyl-(3-dimethylamino group) Propyl) carbodiimide hydrochloride (EDC-HCl) and the activator hydroxybenzotriazole (HOBt) were then stirred at room temperature for 24-48 h.
  • EDC-HCl Propyl) carbodiimide hydrochloride
  • HOBt activator hydroxybenzotriazole
  • the above carboxyl group-containing water-soluble polymer may be a carboxypolyethylene glycol or a carboxyl group-containing polysaccharide (such as chitosan lactate, carboxymethyl chitosan, hyaluronic acid, alginic acid, carboxymethyl fiber).
  • a carboxypolyethylene glycol or a carboxyl group-containing polysaccharide such as chitosan lactate, carboxymethyl chitosan, hyaluronic acid, alginic acid, carboxymethyl fiber.
  • it is a multi-arm carboxy polyethylene glycol or hyaluronic acid, and further preferably hyaluronic acid.
  • the molar ratio of the carboxyl group to the small molecule diamine in the water-soluble polymer is preferably 1:0.1-2; the diamine small molecule and 1-ethyl-(3-dimethylaminopropyl)
  • the molar ratio of the carbodiimide hydrochloride (EDC-HCl) to the activator hydroxybenzotriazole (HOBt) is preferably 1:2:1.5.
  • the hydrazide-modified polymer derivative is prepared by dissolving a water-soluble polymer containing a carboxyl group and a dihydrazide in distilled water, and adding a condensing agent 1-ethyl-(3-dimethylamino group).
  • a condensing agent 1-ethyl-(3-dimethylamino group) Propyl) carbodiimide hydrochloride (EDC-HCl) and the activator hydroxybenzotriazole (HOBt) were then stirred at room temperature for 24-48 h. After the completion of the reaction, the reaction solution was poured into a dialysis bag and dialyzed against a dilute hydrochloric acid solution for 2-3 d, followed by lyophilization to obtain the hydrazide-modified polymer derivative.
  • the above carboxyl group-containing water-soluble polymer may be a carboxypolyethylene glycol or a carboxyl group-containing polysaccharide (such as chitosan lactate, carboxymethyl chitosan, hyaluronic acid, alginic acid, carboxymethyl fiber).
  • a carboxypolyethylene glycol or a carboxyl group-containing polysaccharide such as chitosan lactate, carboxymethyl chitosan, hyaluronic acid, alginic acid, carboxymethyl fiber.
  • it is a multi-arm carboxy polyethylene glycol or hyaluronic acid, and further preferably hyaluronic acid.
  • the small molecule dihydrazide may be carbodihydrazide, oxalic acid dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide, gly.
  • Any dihydrazide such as diacid dihydrazide is preferably a carbon dihydrazide, an oxalic acid dihydrazide or an adipic acid dihydrazide, and more preferably a carbon dihydrazide.
  • the molar ratio of the carboxyl group to the small molecule dihydrazide in the water-soluble polymer is preferably 1:0.1-2; the dihydrazide small molecule and 1-ethyl-(3-dimethylaminopropyl)carbodiimide
  • the molar ratio of hydrochloride (EDC-HCl) and activator hydroxybenzotriazole (HOBt) is preferably 1:2:1.5.
  • the hydroxylamine-modified polymer derivative is prepared by dissolving a hydroxyl group-containing polymer and N-hydroxyphthalimide in a dichloromethane solution, and slowly adding triphenylphosphine. After adding diisopropyl azodicarboxylate dropwise and reacting for 16-24 hours, the polymer is precipitated in diethyl ether, and then re-dissolved in a dichloromethane solution, and added to hydrazine hydrate for 1-3 hours. Hydroxylamine modified polymer derivative.
  • the above hydroxyl group-containing polymer may be a polyethylene glycol, a polysaccharide (such as dextran or chitosan), and preferably a multi-arm hydroxy polyethylene glycol.
  • the molar ratio of the hydroxyl group in the polymer to N-hydroxyphthalimide, triphenylphosphine, diisopropylazodicarboxylate, hydrazine hydrate is preferably 1:10:10: 10:10.
  • the present invention also provides a process for the preparation of a component C-mercapto group-containing polymer derivative.
  • the method for preparing a polymer derivative containing a fluorenyl group is a chemical labeling method, specifically, a chemical reaction between a polymer and a chemical group contained in a thiol-containing derivative. It may be a carboxyl group-containing polymer and an amine group-containing or hydrazide-containing or hydroxylamine-containing small molecule label (Reference Amy Fu, Kihak Gwon, Julia A. Kornfield, Biomacromolecules.
  • Tugba Ozdemir, Swati Pradhan- Bhatt, Xinqiao Jia, ACS Biomater.Sci.Eng.2016, 2,2217. can also be a hydroxyl-containing polymer with a carboxyl- or bromine-containing small molecule label (Reference Rayun Choi, Yong-Min Huh, Seungjoo) Haam, Langmuir. 2010, 26, 17520.), may also be an amine-containing polymer with a carboxyl- or bromine-containing small molecule label (Reference Hanwei Zhang, Aisha Qadeer, Weiliam Chen, Biomacromolecules. 2011, 12, 1428 .) and other marking methods.
  • the preparation method of the thiol-modified polymer derivative includes the following:
  • the first preparation method can be carried out by dissolving a water-soluble polymer or a polymer containing a carboxyl group in distilled water, adding a small molecule having a mercapto group containing a reactive functional group amine group or a hydrazide or a hydroxylamine, and then adding a condensing agent 1 Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and the activator hydroxybenzotriazole (HOBt) were then stirred at room temperature for 24-48 h. After the reaction is completed, the reaction solution is added to a dialysis bag and dialyzed against a dilute hydrochloric acid solution for 2-3 d, and then freeze-dried to obtain the thiol-modified polymer derivative.
  • EDC-HCl Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HOBt activator hydroxybenz
  • the water-soluble polymer or polymer containing a carboxyl group may be a polyethylene glycol or a carboxyl group-containing polysaccharide (for example, hyaluronic acid, carboxymethylcellulose, alginic acid, heparin, etc.), preferably a multi-arm carboxyl group.
  • Polyethylene glycol, hyaluronic acid, and heparin are more preferably hyaluronic acid or heparin.
  • the second preparation method can be carried out by dissolving a water-soluble polymer or a polymer containing a hydroxyl group or an amine group in distilled water, adding a small molecule having a thiol group containing a reactive functional group carboxyl group, and then adding a condensing agent 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and the catalyst 4-(dimethylamino)pyridine were then stirred at room temperature for 24-48 h.
  • EDC-HCl 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride
  • the reaction solution is poured into a poorly soluble solvent to reprecipitate (for example, the modified polyethylene glycol derivative can be poured into diethyl ether to reprecipitate, the polysaccharide polymer derivative can be poured into ethanol to reprecipitate), and then It is dissolved in water and dialyzed for 2-3 days in a dialysis bag, and after lyophilization, the thiol-modified polymer derivative can be obtained.
  • a poorly soluble solvent to reprecipitate for example, the modified polyethylene glycol derivative can be poured into diethyl ether to reprecipitate, the polysaccharide polymer derivative can be poured into ethanol to reprecipitate
  • the water-soluble polymer or polymer containing a hydroxyl group may be a polyethylene glycol or a natural polysaccharide, preferably a multi-arm polyethylene glycol or a dextran, and more preferably a dextran.
  • the above-mentioned amino group-containing water-soluble polymer or polymer may be polyethylene glycol or natural polysaccharide or protein and polypeptide, preferably polyarm amine-based polyethylene glycol, ethylene glycol chitosan, propylene glycol shell
  • the polysaccharide, carboxymethyl chitosan, chitosan lactate or protein and polypeptide are more preferably carboxymethyl chitosan.
  • a third implementation method is: dissolving a water-soluble polymer or a polymer containing a hydroxyl group or an amine group in distilled water, adding a small molecule having a thiol protecting group containing a reactive functional group bromine, and then adding potassium carbonate as a base.
  • the reaction was carried out at room temperature for 24-48 h.
  • the reaction solution is poured into a poorly soluble solvent (for example, the modified polyethylene glycol derivative can be poured into diethyl ether, the modified polysaccharide polymer derivative can be poured into ethanol), and then precipitated, and then coarse.
  • the product is dissolved in distilled water and deprotected by adding DTT.
  • the reaction solution is poured into a dialysis bag for 2-3 days, and after lyophilization, the thiol-modified polymer derivative is obtained.
  • the water-soluble polymer or polymer containing a hydroxyl group may be a polyethylene glycol or a natural polysaccharide, preferably a multi-arm polyethylene glycol or a dextran, and more preferably a dextran.
  • the above-mentioned amino group-containing water-soluble polymer or polymer may be polyethylene glycol or natural polysaccharide or protein and polypeptide, preferably polyarm amine-based polyethylene glycol, ethylene glycol chitosan, propylene glycol shell
  • the polysaccharide, carboxymethyl chitosan, chitosan lactate or protein and polypeptide are more preferably carboxymethyl chitosan.
  • the molar ratio of the carboxyl group, the hydroxyl group or the amine group to the small molecule mercapto derivative in the water-soluble polymer is preferably 1:0.1-2; an amine group or a hydrazide or hydroxylamine-modified small group containing a mercapto group and 1
  • the molar ratio of ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) and activator hydroxybenzotriazole (HOBt) is preferably 1:1.5:1.5, carboxyl group Molar ratio of modified thiol-containing small molecule to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl), catalyst 4-(dimethylamino)pyridine
  • it is 1:1.5:1.5
  • the molar ratio of the brominated fluorenyl group-containing small molecule to potassium carbonate is
  • a fifth object of the present invention is to provide a product obtained by the method for preparing a photocrosslinked hydrogel material according to the fourth aspect of the invention, that is, a photocrosslinked hydrogel material, which may also be called a composite photocrosslinking hydrogel. material.
  • a sixth object of the present invention is to provide a kit for preparing a hydrogel for use in the method of the present invention.
  • the first kit comprises: component A-photosensitive polymer derivative; component B-photoinitiator, and instructions for preparation and application of the hydrogel;
  • the component A-photosensitive polymer derivative includes two structures:
  • a 1 An optical polymer derivative modified by an o-nitrobenzyl light trigger, referred to as A 1 , having the structure of the above formula A-I;
  • a photosensitive polymer derivative containing an o-nitrobenzyl light trigger and a double bond functional group abbreviated as A 3 , having the structure of the above formula A-III.
  • the o-nitrobenzyl group light trigger has a structure as shown in the above formula I, and has two structures, respectively, the structural formula I-1 and the above structural formula I-2.
  • the structural formula I-1 represents an o-nitrobenzyl type light trigger which does not contain a cyclic structure.
  • Structural Formula I-2 represents a cyclic o-nitrobenzyl based light trigger, symbolized as cNB.
  • Component B - a photoinitiator, that is, a substance capable of generating a radical under illumination, preferably a water-soluble photoinitiator or a photoinitiator dispersible in water, further preferably I 2959 (component B-1), LAP ( Component B-2), Eosin-Y (component B-3) and the like and derivatives thereof.
  • a photosensitive polymer derivative containing a double bond functional group is further added to the component A-photosensitive polymer derivative of the first kit, and the double bond functional group is contained.
  • the photosensitive polymer derivative abbreviated as A 2 , has the structure of the above formula A-II.
  • the third kit further comprises an auxiliary component C, which is another biocompatible polymer derivative, including an amine group, a hydrazine, a hydrazide.
  • auxiliary component C is another biocompatible polymer derivative, including an amine group, a hydrazine, a hydrazide.
  • the definition of the auxiliary component C is the same as the definition of the auxiliary component C in the method for preparing the photocrosslinked hydrogel material of the fourth object of the invention.
  • the fourth kit on the basis of the second kit, further comprises an auxiliary component C, which is another biocompatible polymer derivative, including an amine group, a hydrazine, a hydrazide.
  • auxiliary component C is another biocompatible polymer derivative, including an amine group, a hydrazine, a hydrazide.
  • the definition of the auxiliary component C is the same as the definition of the auxiliary component C in the method for preparing the photocrosslinked hydrogel material of the fourth object of the invention.
  • Biocompatible media such as distilled water, physiological saline, buffer, and cell culture media may also be included in the above four kits.
  • hydrogels in the instructions in the above four kits includes postoperative wound closure, tissue fluid leak closure, hemostatic material, tissue engineering scaffold material, 3D printed bio-ink and as cells, proteins or Application on drug carriers.
  • a seventh object of the present invention is to provide a product obtained by a method for preparing a photocrosslinked hydrogel material, that is, a photocrosslinking hydrogel.
  • the present invention provides the use of the above-mentioned photocrosslinked hydrogel as a preparation for postoperative wound closure-skin repair material or medicament.
  • the invention also provides the above-mentioned photocrosslinking hydrogel as a preparation for postoperative wound closure-postoperative anti-adhesion material or medicine.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a material for preparing a postoperative wound closure-oral ulcer material or medicament.
  • the invention also provides the above-mentioned photocrosslinking hydrogel as an application for preparing a tissue fluid leakage plugging-enteric leak sealing material or medicine.
  • the invention also provides the use of the above photocrosslinked hydrogel as a preparation for tissue fluid leakage sealing-surgical suture material or medicament.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a hemostatic material-hepatic hemostatic material or medicament.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a hemostatic material-bone section hemostatic material or medicament.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a hemostatic material-arterial hemostatic material or drug.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a hemostatic material-cardiac hemostatic material or medicament.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a preparation material for tissue engineering scaffolds - cartilage repair materials or drugs.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a preparation material for tissue engineering scaffolds - bone repair materials or drugs.
  • the present invention also provides the use of the above photocrosslinked hydrogel as a preparation material or a bone/cartilage composite defect repair material or a drug for preparing a tissue engineering scaffold material.
  • the present invention also provides the use of the above photocrosslinked hydrogel in 3D printing (FDM) material-bio-ink.
  • FDM 3D printing
  • the present invention also provides the use of the above photocrosslinked hydrogel in 3D printing (DLP) material-bio-ink.
  • DLP 3D printing
  • the invention also provides the use of the above photocrosslinked hydrogel as a carrier for preparing cells, proteins and medicaments.
  • the formula A-I is a photopolymer derivative modified by an o-nitrobenzyl type light trigger
  • the formula A-II is a photosensitive polymer derivative containing a double bond functional group
  • the formula A- III is a photosensitive polymer derivative containing an o-nitrobenzyl group light trigger and a double bond functional group.
  • the solution A and the solution B (or the addition solution C) are uniformly mixed to obtain a hydrogel precursor solution, and the hydrogel precursor solution is photocrosslinked to form a hydrogel under irradiation of a light source.
  • the way of cross-linking can be divided into the following two types:
  • Method 1 Mixing solution A and solution B uniformly to obtain a hydrogel precursor solution, and the hydrogel precursor solution is photocrosslinked to form a hydrogel under irradiation of a light source.
  • the crosslinking method is as follows: the o-nitrobenzyl light trigger and/or double bond functional group and the component B-photoinitiator in component A undergo free radical crosslinking under illumination (ie, o-nitrobenzyl group) Free radical crosslinking of the light-like trigger and free radical crosslinking of the double bond functional group).
  • the free radical cross-linking of the o-nitrobenzyl light trigger is a free radical generated by the nitroso-trapping photoinitiator produced by the o-nitrobenzyl group under illumination, forming an extremely active nitroso radical.
  • the resulting nitroso radical may undergo dimerization crosslinking by itself, or may be carried out with other reactive groups in component A (such as mercapto, hydroxyl, amine, carboxyl, sulfonate, carbonyl, double bond, etc.). Adding a deal to form a hydrogel. Since the reactivity of the nitroso radical is higher than that of the simple nitroso group, the crosslinking speed and crosslinking efficiency of the hydrogel can be further improved.
  • the free radical crosslinking of the double bond functional group is a transfer of a radical generated by a photoinitiator under illumination to a double bond, thereby initiating polymerization crosslinking of the double bond.
  • the above two kinds of free radical crosslinking methods may be carried out only one type of crosslinking, that is, the component A alone is selected from the photosensitive polymer derivative represented by the formula A-I or the formula A-II; or may be simultaneously carried out under one illumination, that is, Component A alone selects the photosensitive polymer derivative described in Formula A-III, or simultaneously selects two or more photosensitive polymer derivatives of Formula A-I, Formula A-II, and Formula A-III.
  • the photocrosslinking mode can simultaneously have the advantages of photo-initiated free radical polymerization cross-linking speed, and the strong adhesion of the o-nitrobenzyl-based light trigger cross-linking structure, and the multi-crosslinking mode can be further improved.
  • Method 2 Mixing solution A, solution B and solution C uniformly to obtain a hydrogel precursor solution, and the hydrogel precursor solution is photocrosslinked to form a hydrogel under irradiation of a light source.
  • the crosslinking method is as follows: the o-nitrobenzyl light trigger and/or double bond functional group and the component B-photoinitiator in component A undergo free radical crosslinking under illumination (ie, o-nitrobenzyl group) Free radical crosslinking of the light-like trigger and free radical crosslinking of the double bond functional group).
  • the free radical cross-linking of the o-nitrobenzyl light trigger is a free radical generated by the nitroso-trapping photoinitiator produced by the o-nitrobenzyl group under illumination, forming an extremely active nitroso radical.
  • the resulting nitroso radical may undergo dimerization crosslinking by itself, or may be carried out with other reactive groups in component A (such as mercapto, hydroxyl, amine, carboxyl, sulfonate, carbonyl, double bond, etc.). Adding a deal to form a hydrogel. Since the reactivity of the nitroso radical is higher than that of the simple nitroso group, the crosslinking speed and crosslinking efficiency of the hydrogel can be further improved.
  • the free radical crosslinking of the double bond functional group is a transfer of a radical generated by a photoinitiator under illumination to a double bond, thereby initiating polymerization crosslinking of the double bond.
  • the aldehyde group/keto group produced by the o-nitrobenzyl light trigger in the component A is crosslinked with the amine group, the hydrazine, the hydrazide or the hydroxylamine functional group in the component C to form a Schiff base.
  • the nitroso group undergoes photoinduced nitroso crosslinking with the thiol functional group in component C.
  • the above two kinds of free radical crosslinking methods may be carried out only one type of crosslinking, that is, the component A alone is selected from the photosensitive polymer derivative represented by the formula A-I or the formula A-II; or may be simultaneously carried out under one illumination, that is, Component A alone selects the photosensitive polymer derivative described in Formula A-III, or simultaneously selects two or more photosensitive polymer derivatives of Formula A-I, Formula A-II, and Formula A-III.
  • the photocrosslinking mode can simultaneously have the advantages of photo-initiated free radical polymerization cross-linking speed, and the strong adhesion of the o-nitrobenzyl-based light trigger cross-linking structure, and the multi-crosslinking mode can be further improved.
  • the mechanical properties of hydrogels can simultaneously have the advantages of photo-initiated free radical polymerization cross-linking speed, and the strong adhesion of the o-nitrobenzyl-based light trigger cross-linking structure, and the multi-crosslinking mode can be further
  • the crosslinking speed is increased from about 30s to 30s in the simple aldehyde-amine photocoupling cross-linking, the adhesion of the tissue is increased to about 80-100kPa, and the mechanical properties are improved to about 1-2MPa. Examples are one hundred and sixty-seven, one hundred and sixty-eight, one hundred and sixty-nine.
  • the photocrosslinking hydrogel is based on the existing photocrosslinking mode (ie, simple aldehyde-amine photocoupling crosslinking or photoinitiated free radical crosslinking).
  • New photocrosslinking gel technology The introduction of the component B-photoinitiator not only improves the crosslinking speed and crosslinking efficiency of the original o-nitrobenzyl light trigger (crosslinking by generating a highly reactive nitroso radical), and
  • the photopolymer-initiated free-radical polymerization cross-linked polymer derivative and the photo-coupling cross-linked polymer derivative can be mixed to form a composite photosensitive polymer solution, which can activate the initiator to generate free radicals under one illumination, and respectively freely Cross-linking (ie, free radical cross-linking of an o-nitrobenzyl light trigger and free radical cross-linking of a double bond functional group) can also be photocoupled by cross-linking (ie, an o-nitrobenzyl light trigger under illumination)
  • the light curing speed is fast, the gelation point can be reached in 1-2s, and the final modulus is reached in 10-20s. Since multiple photocrosslinking is realized at one time, the photocuring speed is better than the simple photoinitiated radical polymerization crosslinking. Cross-linking with light;
  • the tissue has strong adhesion and can gel in situ on the surface of the tissue.
  • the aldehyde/keto group and nitroso group produced by the light can react with the sulfhydryl group, amine group and carboxyl group on the surface of the tissue to realize the hydrogel.
  • the raw materials are mainly derived from natural polymer materials, and the formed hydrogel can be degraded;
  • the hydrogel precursor solution can be applied or sprayed on the wound tissue during use, and rapid gelation synchronization and tissue integration under illumination without primer , one step to achieve wound closure;
  • the chemical structure, composition and degradability of the gel as well as the strength and thickness are adjustable.
  • the composition and properties of the gel material can be flexibly adjusted according to different applications, especially in the case of in-situ thinning of the wound surface, especially suitable for Post-operative wound closure and repair are also suitable for tissue fluid leakage and can be used as hemostatic materials, as tissue engineering scaffold materials, 3D printed bio-ink, and for cells, proteins or drugs.
  • An in situ carrier that is effectively applied to regenerative medicine.
  • NB is an o-nitrobenzyl light trigger in component A-1 of the invention
  • cNB is a cyclic o-nitrobenzyl light trigger in component A-88 of the invention
  • cNB-MA is the invention
  • Component A-144 contains both a cyclic o-nitrobenzyl light trigger and a double bond functional group.
  • HA-NB is component A-1
  • HA-cNB is component A-88
  • HA-cNB-MA is component A-144.
  • Figure 1 shows a hydrogel precursor solution (2% HA-NB/6% Gelatin/1% HAMA/0.2% LAP or 2% HA-cNB/1% HA-cNB-MA/0.2% LAP) Real-time rheological map.
  • Figure 2 is a graph showing the adhesion test of the hydrogel (2% HA-NB/6% Gelatin/1% HAMA/0.2% LAP or 2% HA-cNB/1% HA-cNB-MA/0.2% LAP). .
  • Figure 3 is a compression test plot of the hydrogel (2% HA-NB/6% Gelatin/1% HAMA/0.2% LAP or 2% HA-cNB/1% HA-cNB-MA/0.2% LAP).
  • Figure 4 is a biocompatibility test chart of the hydrogel (HA-NB/Gelatin/HAMA/LAP or HA-cNB/HA-cNB-MA/LAP).
  • Figure 5 is a graphical representation of the effect of wound closure of the hydrogel (component A-1 / component A-107 / component C-4 / component B-2).
  • Figure 6 is a visual representation of the effect of the hydrogel (component A-1 / component A-107 / component C-4 / component B-2) as a postoperative anti-adhesion.
  • Figure 7 is a visual representation of the effect of the hydrogel (component A-1 / component A-107 / component C-4 / component B-2) as a hemostasis in the liver.
  • Figure 8 is a graphical representation of the effect of the hydrogel (component A-1 / component A-107 / component C-4 / component B-2) as a bone/cartilage tissue engineering scaffold material.
  • Figure 9 is a visual representation of the printing effect of the hydrogel (component A-1 / component A-107 / component C-4 / component B-2) as a bio-ink.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-1 (1.85 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 1 was approximately 3.42%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-2 (1.92 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 3 was approximately 3.29%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-3 (1.73 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 5 was approximately 2.97%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-4 (1.78 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 7 was approximately 2.49%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-5 (1.76 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 9 was approximately 3.08%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-6 (1.79 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 11 was about 2.34%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-7 (1.72 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 13 was approximately 2.38%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-8 (1.86 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 15 was approximately 3.43%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-9 (1.82 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 17 was approximately 3.24%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-10 (1.88 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 19 was approximately 3.01%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-11 (1.76 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 21 was approximately 3.15%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-12 (1.88 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 23 was approximately 3.01%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-13 (1.73 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 24 was approximately 3.08%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-14 (1.72 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 25 was approximately 3.09%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-15 (1.88 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 26 was approximately 3.28%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-16 (1.68 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 27 was approximately 2.98%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-17 (1.76 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 28 was approximately 3.02%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-18 (1.82 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 29 was approximately 3.15%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-19 (1.74 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 30 was approximately 3.12%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-20 (1.81 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 31 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-21 (1.76 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 33 was approximately 2.84%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-22 (1.83 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 35 was approximately 3.12%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-23 (1.84 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 37 was approximately 3.17%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-24 (1.87 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 39 was approximately 3.06%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-25 (1.82 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 41 was approximately 3.12%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-26 (1.87 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 43 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-27 (1.78 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of compound 45 was about 2.12%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-28 (1.85 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 47 was approximately 3.43%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-29 (1.86 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 49 was approximately 3.52%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-30 (1.82 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 51 was approximately 3.39%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-31 (1.87 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 53 was approximately 3.45%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-32 (1.81 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 55 was approximately 3.09%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-34 (1.82 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 57 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-35 (1.87 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 59 was approximately 2.76%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-36 (1.76 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 61 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive carboxymethylcellulose derivative A-37 (1.89 g) according to a nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 1 can be calculated to be approximately 2.25%.
  • the hydrochloride DMTMM (0.4 g, 1.5 mmol) was dissolved in 3 mL of MES buffer solution, and added to the above reaction solution three times (every 1 h), and reacted at 35 ° C for 24 h. Then, the reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive alginic acid derivative A-38 (1.82 g), which can be calculated from the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 1 was approximately 3.17%.
  • the phytate hydrochloride DMTMM (0.4 g, 1.5 mmol) was dissolved in 3 mL of MES buffer solution, and added to the above reaction solution three times (every 1 h), and reacted at 35 ° C for 24 h. Then, the reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive chondroitin sulfate derivative A-39 (1.73 g), which can be calculated according to the nuclear magnetic resonance spectrum. The labeling rate of Compound 1 was approximately 2.98%.
  • component A-40 Polyglutamic acid PGA (1 g) was dissolved in 50 mL of distilled water until completely dissolved, hydroxybenzotriazole (HOBt, 0.3 g, 2.3 mmol) was added, and then the compound dissolved in methanol was added. 1 (0.5 g, 1.6 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 0.5 g, 2.6 mmol) were added to the above solution at room temperature for reaction.
  • HOBt hydroxybenzotriazole
  • EDC-HCl 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • component A-41 Four-arm polyethylene glycol carboxylic acid derivative 4-PEG-COOH (0.5 g, 10 kDa) was dissolved in 20 mL of anhydrous dimethyl sulfoxide DMSO until completely dissolved, and compound 1 was taken ( 130 mg, 0.4 mmoL) was dissolved in 5 mL of anhydrous dimethyl sulfoxide DMSO, and the above reaction solution was added, 0.2 mL of triethylamine TEA was added, and benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate was further added.
  • Phosphorus PyBop (210 mg, 0.4 mmol) was reacted at room temperature for 24 h, then re-precipitated in diethyl ether.
  • the crude product was dissolved in water, poured into a dialysis bag (MWCO 3500), dialyzed against deionized water for 2-3 d, freeze-dried
  • the photosensitive polyethylene glycol derivative A-41 (0.45 g) was obtained, and according to the nuclear magnetic hydrogen spectrum, the labeling rate of the compound 1 was calculated to be about 98%.
  • Hyaluronic acid Hyaluronic acid (1 g, 340 kDa) was dissolved in 50 mL of water, compound 62 (0.2 g, 0.48 mmol), EDC-HCl (0.76 g, 3.96 mmol) and DPTS. (0.12 g, 0.48 mmol) was added to the above solution in this order, and the reaction was stirred at room temperature for 48 h. After the reaction is completed, the reaction solution is poured into cold ethanol and re-precipitated and purified several times. The collected precipitate is dried, dissolved in anhydrous DMSO, and the dihydropyran protecting group is removed by adding p-toluenesulfonic acid. A photosensitive hyaluronic acid derivative A-42 (0.86 g) was obtained. According to its nuclear magnetic resonance spectrum, the degree of modification of Compound 62 can be calculated to be about 10%.
  • the compound 63-labeled chitosan is dissolved in DMSO, and the dihydropyran is removed by adding p-toluenesulfonic acid to obtain the photosensitive chitosan derivative A-43. According to the nuclear magnetic resonance spectrum, the compound 63 can be calculated. The degree of modification is approximately 12.5%.
  • component A-44 Polylysine PLL (1 g) was dissolved in 50 mL of water, compound 63 (0.2 g, 0.54 mmol), EDC-HCl (0.76 g, 3.96 mmol) and NHS (0.46 g, 4.0) Methyl) was added to the above solution in this order, and the reaction was stirred at room temperature for 48 h. After the reaction is completed, the reaction solution is poured into cold ethanol and re-precipitated and purified several times. The collected precipitate is dried, dissolved in anhydrous DMSO, and the dihydropyran protecting group is removed by adding p-toluenesulfonic acid. A photosensitive polylysine derivative A-44 (0.84 g) was obtained. According to its nuclear magnetic resonance spectrum, the degree of modification of Compound 63 can be calculated to be about 15.6%.
  • component A-45 Gelatin Gelatin (1 g) was dissolved in 50 mL of distilled water until completely dissolved. Compound 63 (0.2 g, 0.54 mmol), EDC-HCl (0.76 g, 3.96 mmol) and NHS (0.46 g, 4.0 mmol) was added to the above solution in this order, and the reaction was stirred at room temperature for 48 h. After the reaction is completed, the reaction solution is poured into cold ethanol and re-precipitated and purified several times. The collected precipitate is dried, dissolved in anhydrous DMSO, and the dihydropyran protecting group is removed by adding p-toluenesulfonic acid. A photosensitive gelatin derivative A-45 (0.83 g) was obtained, and according to its nuclear magnetic resonance spectrum, the degree of modification of the compound 63 was calculated to be about 11.2%.
  • component A-46 Dextran (1 g) was dissolved in 50 mL of water, compound 63 (0.23 g, 0.54 mmol), EDC-HCl (0.76 g, 3.96 mmol) and DPTS (0.12 g, 0.48 mmol) The solution was added to the above solution in this order, and the reaction was stirred at room temperature for 48 h. After the reaction is completed, the reaction solution is poured into cold ethanol and re-precipitated and purified several times. The collected precipitate is dried, dissolved in anhydrous DMSO, and the dihydropyran protecting group is removed by adding p-toluenesulfonic acid. A photosensitive dextran derivative A-46 (0.92 g) was obtained. According to its nuclear magnetic resonance spectrum, the degree of modification of Compound 63 can be calculated to be about 18.2%.
  • the compound 65-labeled chitosan is dissolved in DMSO, and the dihydropyran is removed by adding p-toluenesulfonic acid to obtain a photosensitive chitosan derivative A-48 (0.84 g), which can be obtained according to the nuclear magnetic resonance spectrum.
  • the degree of modification of Compound 65 was calculated to be approximately 12.4%.
  • component A-49 PEG-4OH (1 g, 0.05 mmol) was dissolved in anhydrous acetonitrile, and K 2 CO 3 (55.3 mg, 0.4 mmol) was added and stirred for 30 min, then compound 65 (0.17 g, 0.4 mmol) was added. The reaction was continued at room temperature for 24 h. After the reaction is completed, most of the solvent is removed, reprecipitated in diethyl ether, and washed several times, then the compound 65-labeled polyethylene glycol is dissolved in DMSO, and p-toluenesulfonic acid is added to remove dihydropyran protection. A photosensitive polyethylene glycol derivative A-49 (0.93 g) was obtained, and according to the nuclear magnetic hydrogen spectrum, the degree of modification of the compound 65 was calculated to be about 95%.
  • a photosensitive copolymer derivative A-50 (0.84 g) was obtained. From the NMR chart, it can be calculated that the content of the compound 67 in the copolymer is about 15.5%. According to GPC, the molecular weight of the synthetic polymer was about 25 kDa. According to the feed ratio, n was 12, x was 10, and y was 40.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-51 (1.85 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 68 was approximately 3.34%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-52 (1.92 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of the compound 71 was about 3.32%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-53 (1.75 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 74 was approximately 2.34%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-54 (1.8 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 77 was approximately 3.35%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-55 (1.89 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 78 was approximately 3.42%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-56 (1.87 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 79 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-57 (1.74 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 80 was approximately 2.34%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-58 (1.72 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 81 was approximately 2.56%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-59 (1.74 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of compound 82 was approximately 2.34%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-60 (1.72 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 83 was approximately 2.36%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-61 (1.73 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 84 was approximately 3.02%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-62 (1.92 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 85 was approximately 3.14%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-63 (1.88 g), which can be calculated according to the nuclear magnetic hydrogen spectrum.
  • the labeling rate of Compound 86 was approximately 3.45%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-64 (1.85 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 87 was approximately 3.32%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-65 (1.89 g), which can be calculated according to the NMR spectrum.
  • the labeling ratio of the NB mixture (Compound 68/Compound 71) was approximately 3.41%.
  • Methylmorpholine hydrochloride DMTMM (0.4 g, 1.5 mmol) was dissolved in 3 mL of MES buffer solution and added to the above reaction solution three times (every 1 h), and reacted at 35 ° C for 24 h. Then, the reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive carboxymethylcellulose derivative A-66 (1.74 g) according to a nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 71 can be calculated to be about 2.34%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-70 (1.8 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 92 was approximately 3.26%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-71 (1.87 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 95 was approximately 3.42%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-72 (1.84 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 96 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-73 (1.78 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 97 was approximately 3.14%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-74 (1.88 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 98 was approximately 3.38%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-75 (1.85 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 99 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-76 (1.69 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 100 was approximately 2.31%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-77 (1.82 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 101 was approximately 3.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-78 (1.74 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 102 was approximately 3.09%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-79 (1.76 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 103 was approximately 2.45%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-80 (1.86 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 104 was approximately 3.32%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-81 (1.89 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 105 was approximately 3.28%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-82 (1.91 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 106 was approximately 3.26%.
  • Methylmorpholine hydrochloride DMTMM (0.4 g, 1.5 mmol) was dissolved in 3 mL of MES buffer solution and added to the above reaction solution three times (every 1 h), and reacted at 35 ° C for 24 h. Then, the reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive carboxymethylcellulose derivative A-84 (1.72 g) according to a nuclear magnetic resonance spectrum. It can be calculated that the labeling rate of the compound 95 molecule is about 2.21%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-88 (1.87 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of the compound 123 molecule was about 3.49%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-89 (1.82 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 124 was approximately 3.15%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-90 (1.87 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 125 was approximately 3.27%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-91 (1.73 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of Compound 126 was approximately 3.14%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-92 (1.78 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 127 was approximately 3.09%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-93 (1.73 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 128 was approximately 3.15%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-94 (1.84 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 129 was approximately 2.47%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-95 (1.75 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 130 was approximately 3.07%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-96 (1.76 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 131 was approximately 3.24%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-97 (1.82 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 132 was approximately 3.05%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive hyaluronic acid derivative A-98 (1.78 g), which can be calculated according to the NMR spectrum.
  • the labeling rate of the compound 133 was about 3.31%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-99 (1.84 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 134 was approximately 3.06%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-100 (1.84 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of compound 135 was approximately 3.16%.
  • reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-101 (1.77 g), which can be calculated according to the nuclear magnetic resonance spectrum.
  • the labeling rate of Compound 136 was approximately 3.21%.
  • the cNB mixture (Compound 123/Compound 136, 60 mg, mass ratio 1:1) was weighed and dissolved in 10 mL of dimethyl sulfoxide DMSO, and the above reaction solution was added to weigh 4-(4,6-dimethoxytriazine).
  • Methylmorpholine hydrochloride DMTMM (0.4 g, 1.5 mmol) was dissolved in 3 mL of MES buffer solution and added to the above reaction solution three times (every 1 h), and reacted at 35 ° C for 24 h. Then, the reaction solution was poured into a dialysis bag (MWCO 7000), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive carboxymethylcellulose derivative A-103 (1.71 g) according to a nuclear magnetic resonance spectrum. The labeling rate of Compound 123 was calculated to be approximately 2.41%.
  • Hyaluronic acid Hyaluronic acid (1g, 48kDa) was dissolved in 100mL of deionized water, cooled to 0-4 ° C, 4mL of methacrylic anhydride was added, and 2mL of 5M NaOH was slowly added dropwise for 24h. Then, the reaction solution is poured into a dialysis bag (MWCO 3500), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive hyaluronic acid derivative A-107 (0.92 g), which can be obtained according to the nuclear magnetic resonance spectrum. The double bond content was calculated to be approximately 54%.
  • component A-108 Carboxymethyl cellulose (1 g, 90 kDa) was dissolved in 100 mL of deionized water, cooled to 0-4 ° C, 4 mL of methacrylic anhydride was added, and 2 mL of 5 M NaOH was slowly added dropwise. After reacting for 24 h, the reaction solution was poured into a dialysis bag (MWCO 3500), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive carboxymethylcellulose derivative A-108 (0.89 g) according to nuclear magnetic hydrogen. The spectrum can be calculated to have a double bond content of about 43%.
  • component A-109 Alginate (1g, 48kDa) was dissolved in 100mL of deionized water, cooled to 0-4 ° C, 4mL of methacrylic anhydride was added, and 2mL of 5M NaOH was slowly added dropwise for 24h, then The reaction solution was poured into a dialysis bag (MWCO 3500), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive alginic acid derivative A-109 (0.87 g). According to the nuclear magnetic resonance spectrum, a double can be calculated. The bond content is approximately 57%.
  • component A-110 Chondroitin sulfate (1g) was dissolved in 100mL of deionized water, cooled to 0-4 ° C, 4mL of methacrylic anhydride was added, and 2mL of 5M NaOH was slowly added dropwise for 24h, then The reaction solution was poured into a dialysis bag (MWCO 3500), dialyzed against deionized water for 2-3 d, and lyophilized to obtain a photosensitive chondroitin sulfate derivative A-110 (0.91 g), which can be calculated from the NMR spectrum. The double bond content is approximately 49%.
  • component A-111 Dextran Dextran (6 g, 70 kDa) was dissolved in 60 mL of anhydrous dimethyl sulfoxide DMSO, 2 mL of triethylamine TEA was added, and 0.56 mL of acryloyl chloride (dissolved in 10 mL of dichloride) was added. In methane DCM), the reaction is carried out for 10 h. After the reaction is completed, the reaction solution is poured into ethanol and reprecipitated. The crude product obtained by filtration is redissolved in deionized water, dialyzed for 2-3 d, and freeze-dried to obtain a photosensitive glucan derivative.
  • A-111 (5.8g), according to the nuclear magnetic resonance spectrum, the double bond content can be calculated to be about 24%.
  • component A-112 Carboxymethyl chitosan
  • Carboxymethylchitosan (1g) was dissolved in 100 mL of deionized water, heated to 40 ° C and stirred to dissolve, 4 mL of glycidyl methacrylate was added, and 2 mL of 5 M NaOH was added. After -3h, the reaction solution was poured into a dialysis bag (MWCO 3500), dialyzed against deionized water for 2-3 d, and freeze-dried to obtain a photosensitive chitosan derivative A-112 (0.88 g) according to the nuclear magnetic resonance spectrum. The calculated double bond content is approximately 32%.
  • component A-114 Two arms of hydroxypolyethylene glycol PEG (10 kDa, 10 g) were dissolved in dry dichloromethane, triethylamine (0.28 mL, 2 mmol) was added, and acryloyl chloride (0.18) was slowly added dropwise. g, 2mmol) of dichloromethane solution in the above solution, stirring reaction for 12h, then the reaction solution was poured into a dialysis bag (MWCO 3500), dialyzed with deionized water for 2-3d, freeze-dried to obtain photosensitive polyethylene
  • the alcohol derivative A-114 (9.8 g), based on the nuclear magnetic resonance spectrum, can be calculated to have a double bond content of about 98%.
  • component A-115 Four-arm hydroxy polyethylene glycol PEG (10 kDa, 10 g) was dissolved in dry dichloromethane, triethylamine (0.56 mL, 4 mmol) was added, and acryloyl chloride (0.36) was slowly added dropwise. g, 4mmol) of dichloromethane solution in the above solution, stirring reaction for 12h, then the reaction solution was poured into a dialysis bag (MWCO 3500), dialyzed with deionized water for 2-3d, freeze-dried to obtain photosensitive polyethylene
  • the alcohol derivative A-115 (9.3 g), based on the nuclear magnetic resonance spectrum, can be calculated to have a double bond content of about 96%.
  • component A-116 Dissolve component A-1 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-116 (0.91g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 54%.
  • component A-117 Dissolve component A-2 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-117 (0.87g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 51%.
  • component A-118 Dissolve component A-8 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-118 (0.86g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 44%.
  • component A-119 Dissolve component A-28 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-119 (0.85g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 43%.
  • component A-120 Dissolve component A-29 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-120 (0.93g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 55%.
  • component A-121 Dissolve component A-30 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-121 (0.85g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 49%.
  • component A-122 Dissolve component A-37 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, and slowly add 2 mL of 5 M NaOH for 24 h, then react the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive carboxymethyl cellulose derivative A-122 (0.91) containing both o-nitrobenzyl and double bond functional groups. g) According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 42%.
  • component A-123 Dissolve component A-43 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dilute with deionized water for 2-3d, freeze-dry to obtain photosensitive chitosan derivative A-123 (0.84g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 56%.
  • component A-124 Dissolve component A-45 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive gelatin derivative A-124 (0.92g) containing both o-nitrobenzyl and double bond functional groups, according to The nuclear magnetic resonance spectrum can be calculated to have a double bond content of about 48%.
  • component A-125 Dissolve component A-49 in 100mL of deionized water, cool to 0-4 ° C, add 4mL of methacrylic anhydride, then slowly add 2mL of 5M NaOH, react for 24h, then transfer the reaction solution Pour into a dialysis bag (MWCO 3500), dialyze with deionized water for 2-3 d, and freeze-dry to obtain a photosensitive polyethylene glycol derivative A-125 (0.94 g) containing both an o-nitrobenzyl group and a double bond functional group. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 24%.
  • component A-126 Dissolve component A-51 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-126 (0.87g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 46%.
  • component A-127 Dissolve component A-52 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-127 (0.85g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 57%.
  • component A-128 Dissolve component A-53 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-128 (0.93g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 47%.
  • component A-129 Dissolve component A-62 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-129 (0.90g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 58%.
  • component A-130 Dissolve component A-63 in 100mL of deionized water, cool to 0-4 ° C, add 4mL of methacrylic anhydride, then slowly add 2mL of 5M NaOH, react for 24h, then transfer the reaction solution Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-130 (0.89g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 46%.
  • component A-131 Dissolve component A-64 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5 M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive hyaluronic acid derivative A-131 (0.87g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 58%.
  • component A-132 Dissolve component A-66 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, then slowly add 2 mL of 5M NaOH, react for 24 h, then transfer the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive carboxymethyl cellulose derivative A-132 containing both o-nitrobenzyl and double bond functional groups (0.92 g) According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 46%.
  • component A-133 Dissolve component A-67 in 100 mL of deionized water, cool to 0-4 ° C, add 4 mL of methacrylic anhydride, and slowly add 2 mL of 5 M NaOH for 24 h, then react the reaction solution. Pour into dialysis bag (MWCO 3500), dialyze with deionized water for 2-3d, freeze-dry to obtain photosensitive chitosan derivative A-133 (0.91g) containing both o-nitrobenzyl and double bond functional groups. According to the nuclear magnetic resonance spectrum, the content of the double bond can be calculated to be about 47%.

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Abstract

光交联水凝胶材料，其制备方法为：将组分A-光敏高分子衍生物溶于生物相容性介质得到光敏高分子溶液A；将组分B-光引发剂溶于生物相容性介质得到光引发剂溶液B；将辅助组分C-其他生物相容性高分子衍生物溶于生物相容性介质得到高分子溶液C；将溶液A和溶液B(或加入溶液C)混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，发生光交联形成水凝胶。该水凝胶体系具备光固化速度快、组织粘附力强、力学性能优异、生物相容性好、临床操作性优异等特点。还涉及制备水凝胶用的试剂盒，以及水凝胶材料在组织工程和再生医学、3D打印及作为细胞、蛋白或药物载体上的应用。

Description

光交联水凝胶材料的制备、原料、产品及应用 技术领域
本发明属于生物材料领域，具体涉及一种光交联水凝胶材料的制备、原料、产品及应用。
背景技术
水凝胶是一类高度含水的具有三维网络交联结构的聚合物材料，由于其具有优异的生物相容性及一定的机械强度，可以高度拟合生物组织的微环境，因此广泛应用于组织工程和再生医学。在临床应用中，原位固化的水凝胶具有优异的组织赋型能力，当前，可原位固化的水凝胶根据成胶机理的不同主要有温敏型、双组份注射型、光敏型等。温敏型主要是通过低温下为液相的凝胶前体，到达体内后在体温作用下发生相转变凝胶化实现原位固化(如LeGoo，羟丁基壳聚糖等)，此类水凝胶通常存在凝胶强度弱，温度响应慢且在体内降解慢等问题。双组份注射型主要是将分别含有活性反应官能团的凝胶前体通过双组份注射器边混合边挤出的方式实现原位固化(如Fibrin Glue，Adherus AutoSpray等)，因此对活性官能团的交联速度具有很高的要求，成胶速度太慢往往导致凝胶前体被体内的血液或渗液稀释或冲走，成胶速度太快则不利于临床操作，易堵针头，同时双组份注射器较为昂贵，大大增加了其应用成本，以上缺陷限制了这类材料的广泛应用。
光敏型水凝胶相对于温敏和双组份水凝胶，由于具有时空精确可控的优势而更具备临床的实际操作性。就当前光交联制备水凝胶的方式而言，通过自由基引发不饱和生物大分子聚合交联是当前最为通用的方法。虽然光引发自由基聚合交联的方式固化速度快(2s左右)，但自由基不可避免会对细胞或生物组织造成损伤，且自由基与生俱来的氧气阻聚使得用该方法原位构筑薄层水凝胶十分困难，同时，该类水凝胶与组织粘附能力缺失也一直是该技术临床转化的壁垒。目前为止，FDA批准了唯一一例光敏水凝胶-FocalSeal，用于防止肺切除术后的疝气形成，就在最近Biomet公司收购了John Hopkins大学的光原位水凝胶构建技术，用于软骨组织修复。虽然以上技术都取得了非常好的临床效果，但它们的使用都必需配合额外底涂，以促进凝胶与组织附着，使得光敏水凝胶的临床使用复杂化。
针对光引发自由基聚合交联制备水凝胶技术的不足，朱麟勇研究组于2014年提出了非自由基光偶合交联技术(Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.；Linyong Zhu et.al.PCT.No.WO2016082725 A1,issued Jun2,2016)，该技术基于邻硝基苄醇受紫外光照产生醛基，进一步交联多胺基高分子衍生物制备水凝胶，完全规避了自由基的产生，能够有效解决自由基的毒性以及氧阻聚，且胶层薄厚可调，同时，邻硝基苄醇受光照产生的醛基也会与组织表面富含的蛋白胺基交联，实现胶层与组织的化学键键连固定，解决传统光敏型水凝胶的组织粘附与整合等难题。但该技术成胶速度较慢，限制了其临床应用。
发明内容
本发明第一个目的是提供环状邻硝基苄基类光扳机，如结构式I-2所示
Figure PCTCN2018080170-appb-000001
Figure PCTCN2018080170-appb-000002
式I-2中，X为O、S或N，X＝O时，为环状邻硝基苄基类光扳机，X＝S时，为环状邻硝基苄硫基类光扳机，X＝N时，为环状邻硝基苄胺基类光扳机；
式Ⅰ-2中，连接键R 1一端与X连接，另一端与R 2，R 3，R 4，R 5中任意的一个基团相连接，构成环状结构；
式I-2中，R’选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基等；
式I-2中，R 1选自氢、醚键类取代基、酯键类取代基、碳酸酯键类取代基、胺基甲酸酯键类取代基、巯基甲酸酯键类取代基或磷酸酯键类取代基等；
式I-2中，R 2，R 3，R 4，R 5可自由的选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、羧基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基等。
对于上述环状邻硝基苄基类光扳机，R 2，R 3，R 4，R 5可以相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环，或形成芳环或芳杂环。
进一步地，所述烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的烷基；
所述亚烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的亚烷基；
所述改性烷基为烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
所述改性亚烷基为亚烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性亚烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
所述醚键类取代基选自以下结构：
-(CH 2) xCH 3、-(CH 2CH 2O) xCH 3、-(CH 2) x(CH 2CH 2O) yCH 3、或
Figure PCTCN2018080170-appb-000003
等，其中x和y≥0且为整数；
所述酯键类取代基选自以下结构：
-CO(CH 2) xCH 3、-CO(CH 2CH 2O) xCH 3、-CO(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述碳酸酯键类取代基选自以下结构：
-COO(CH 2) xCH 3、-COO(CH 2CH 2O) xCH 3、-COO(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述胺基甲酸酯键类取代基选自以下结构：
-CONH(CH 2) xCH 3、-CONH(CH 2CH 2O) xCH 3、-CONH(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述巯基甲酸酯键类取代基选自以下结构：
-COS(CH 2) xCH 3、-COS(CH 2CH 2O) xCH 3、-COS(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述磷酸酯键类取代基选自以下结构：
-POOO(CH 2) xCH 3、-POOO(CH 2CH 2O) xCH 3、-POOO(CH 2) x(CH 2CH 2O) yCH 3等，其中 x和y≥0且为整数；
所述芳基为5～10元芳香单环或芳香稠合双环结构；
所述杂芳基为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环结构；
所述卤原子各自独立地选自F、Cl、Br、I；
所述脂环为饱和或不饱和的3～10元单环或多环脂环；
所述脂杂环为环上含有选自O、S、N或Si中的至少一种杂原子的饱和或不饱和的3-10元单环或多环脂杂环，所述脂杂环上含有S原子时，其任选为-S-、-SO-或-SO 2-；所述脂环或脂杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代；
所述芳环为5～10元芳香单环或芳香稠合双环；
所述芳杂环为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环；所述芳环或芳杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代。
上述环状邻硝基苄基类光扳机优选选自以下环状结构：
Figure PCTCN2018080170-appb-000004
Figure PCTCN2018080170-appb-000005
本发明的第二个目的是提供一系列光敏高分子衍生物。
本发明提供的光敏高分子衍生物，包括三种结构：
1、邻硝基苄基类光扳机修饰的光敏高分子衍生物，简称A 1，具有式A-Ⅰ结构；
2、含双键官能团的光敏高分子衍生物，简称A 2，具有式A-Ⅱ结构；
3、既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物，简称A 3，具有式A-Ⅲ结构。
Figure PCTCN2018080170-appb-000006
其中，邻硝基苄基类光扳机，结构如式I所示，具有两种结构，分别如结构式I-1与结构式I-2。结构式I-1表示不含环状结构的邻硝基苄基类光扳机。结构式I-2表示环状邻硝基苄基类光扳机，符号表示为cNB。
Figure PCTCN2018080170-appb-000007
式I-1、式I-2中，X＝O时，称为邻硝基苄基类光扳机，符号表示为NB，X＝S时，称为邻硝基苄硫基类光扳机，符号表示为sNB，X＝N时，称为邻硝基苄胺基类光扳机，符号表示为nNb。
式A-Ⅰ、式A-Ⅲ、式I、式I-1、式I-2中，R’选自氢、卤原子、羟基、巯基、胺基、 硝基、氰基、醛基、酮基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基等；
式I-1、式I-2中，R 1选自氢、醚键类取代基、酯键类取代基、碳酸酯键类取代基、胺基甲酸酯键类取代基、巯基甲酸酯键类取代基或磷酸酯键类取代基等；
式I-1、式I-2中，R 2，R 3，R 4，R 5可自由的选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、羧基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基等。
对于式I-1、式I-2所示结构，可选地，R 2，R 3，R 4，R 5可相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环，或形成芳环或芳杂环。
式Ⅰ-2中，X为O、S或NH等，连接键R 1一端与X连接，另一端与R 2，R 3，R 4，R 5中任意的一个基团相连接，构成环状结构。
式A-Ⅰ、式A-Ⅲ中，n≥2，即单条P 1高分子链上的邻硝基苄基类光扳机的平均个数大于或等于2。
式A-Ⅰ、式A-Ⅲ中，P 1为一种亲水或水溶性天然高聚物或合成聚合物，或P 1独立的选自多种亲水或水溶性天然高聚物或合成聚合物等。
对于含双键官能团的光敏高分子衍生物，或既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物而言，式A-Ⅱ和式A-Ⅲ中，R’ 1，R’ 2、R’ 3选自氢、烷基、改性烷基或芳基等；R’ 4选自烷基、醚键类取代基、酯键类取代基、酰胺键类取代基等；
可选地，式A-Ⅱ和式A-Ⅲ中，R’ 1，R’ 2、R’ 3可相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环。
式A-Ⅱ和式A-Ⅲ中，n≥2，即单条P 1高分子链上的邻硝基苄基类光扳机的平均个数大于或等于2。P 1为一种亲水或水溶性天然高聚物或合成聚合物，或P 1独立的选自多种亲水或水溶性天然高聚物或合成聚合物等。
以上三种光敏高分子衍生物中的高分子P 1可以是亲水或水溶性天然高聚物，也可以是亲水或水溶性合成聚合物。
亲水或水溶性天然高聚物包括天然多糖类物质及其修饰物或降解物，蛋白及其修饰物、改性物和降解的多肽类物质等；
所述天然多糖类物质包括透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐；
所述蛋白包括各种亲水性或水溶性动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白，所述蛋白降解物包括明胶或多肽；
亲水或水溶性合成聚合物包括两臂或多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮；
所述的以上三种光敏高分子衍生物可以是同时含有一种或一种以上不同基团的亲水或水溶性高分子，或者是一种或一种以上不同基团的亲水或水溶性高分子的混合物。
当组分A为具有式A-Ⅰ结构的邻硝基苄基类光扳机修饰的光敏高分子衍生物时，
当邻硝基苄基类光扳机选择结构式I-1时，
P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，
当邻硝基苄基类光扳机选择结构式I-2时，
P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，或连接到R 1与R 2，R 3，R 4，R 5中任意的一个基团相连接构成的环状链上，
其连接键选自羟基类所获得的连接键P 1-O-；或选自巯基类所获得的连接键P 1-S-；或选自胺基类所获得的连接键P 1-NH-；或选自烷烃类所获得的连接键P 1-；或选自酯键类所获得的连接键P 1-COO-；或选自酰胺键类所获得的连接键P 1-CONH-，该连接键的一端与P 1相连，另一端连接在式A-Ⅰ所示分子的苯环上；
当组分A为具有式A-Ⅲ结构的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物时，
当邻硝基苄基类光扳机选择结构式I-1时，
P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，
P 1另一端与R’ 4连接；
当邻硝基苄基类光扳机选择结构式I-2时，
P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，或连接到R 1与R 2，R 3，R 4，R 5中任意的一个基团相连接构成的环状链上，
P 1另一端与R’ 4连接；
其连接键选自羟基类所获得的连接键-O-P 1-O-；或选自巯基类所获得的连接键-S-P 1-S-；或选自胺基类所获得的连接键-NH-P 1-NH-；或选自烷烃类所获得的连接键-P 1-；或选自酯键类所获得的连接键-COO-P 1-COO-；或选自酰胺键类所获得的连接键-CONH-P 1-CONH-；其连接键也可以选自在P 1两端连接不同种以上所述的羟基类、巯基类、胺基类、烷烃类、酯键类、酰胺键类连接键，该连接键的一端与P 1相连，另一端连接在式A-Ⅲ所示分子的苯环上。
其中，所述式A-Ⅰ为邻硝基苄基类光扳机修饰的光敏高分子衍生物，所述式A-Ⅱ为含双键官能团的光敏高分子衍生物，所述式A-Ⅲ为既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。式A-Ⅲ的结构设计是在式A-Ⅰ和式A-Ⅱ的结构基础上，在同一高分子链上同时接枝邻硝基苄基类光扳机和双键官能团，可以同时实现两种方式的交联，即同时具备光引发自由基聚合交联速度快的优势，以及光偶合反应交联组织粘附力强的优势，并且双重交联的方式，提高了水凝胶的力学性能。因此，分子结构的优化，使得其作为光敏基团修饰得到的高分子衍生物展现出更为优异的材料性能，其交联速度由单纯的醛基-胺基光偶合交联的30s左右提高到了2s以内，组织粘附力提高到80-100kPa左右，力学性能提高到1-2MPa左右，具体数据如实施例一百六十七、一百六十八、一百六十九所示。
进一步地，所述烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的烷基；
所述亚烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的亚烷基；
所述改性烷基为烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
所述改性亚烷基为亚烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性亚烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
所述醚键类取代基选自以下结构：
-(CH 2) xCH 3、-(CH 2CH 2O) xCH 3、-(CH 2) x(CH 2CH 2O) yCH 3、或
Figure PCTCN2018080170-appb-000008
等，其中x和y≥0且为整数；
所述酯键类取代基选自以下结构：
-CO(CH 2) xCH 3、-CO(CH 2CH 2O) xCH 3、-CO(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述碳酸酯键类取代基选自以下结构：
-COO(CH 2) xCH 3、-COO(CH 2CH 2O) xCH 3、-COO(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述胺基甲酸酯键类取代基选自以下结构：
-CONH(CH 2) xCH 3、-CONH(CH 2CH 2O) xCH 3、-CONH(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述巯基甲酸酯键类取代基选自以下结构：
-COS(CH 2) xCH 3、-COS(CH 2CH 2O) xCH 3、-COS(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述磷酸酯键类取代基选自以下结构：
-POOO(CH 2) xCH 3、-POOO(CH 2CH 2O) xCH 3、-POOO(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
所述芳基为5～10元芳香单环或芳香稠合双环结构；
所述杂芳基为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环结构；
所述卤原子各自独立地选自F、Cl、Br、I；
所述脂环为饱和或不饱和的3～10元单环或多环脂环；
所述脂杂环为环上含有选自O、S、N或Si中的至少一种杂原子的饱和或不饱和的3-10元单环或多环脂杂环，所述脂杂环上含有S原子时，其任选为-S-、-SO-或-SO 2-；所述脂环或脂杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代；
所述芳环为5～10元芳香单环或芳香稠合双环；
所述芳杂环为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环；所述芳环或芳杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代。
进一步地，脂环或脂杂环的优选结构包括：
Figure PCTCN2018080170-appb-000009
等；
进一步地，芳环或芳杂环的优选结构包括：
Figure PCTCN2018080170-appb-000010
等；
R’的一些优选结构包括：
-H、-CH 3、-CH 2CH 3、-CH＝CH-CH＝CH-CH 3、-F、-Cl、-Br、-I、-CF 3、-CCl 3、-CBr 3、 -CI 3、-CN、-COOH、-Ph、
Figure PCTCN2018080170-appb-000011
等。
R 2，R 3，R 4，R 5的一些优选结构包括：
-H、-OH、-SH、-NH 2、-F、-Cl、-Br、-I、-CF 3、-CCl 3、-CBr 3、-CI 3、-NO 2、-CN、-CHO、-COOH、-COONH 2、-SO 3H等；
烷基类取代基优选结构，如直链烷基-(CH 2) xCH 3、支链烷基-(CH 2) x(CY’Y”) yCH 3(Y’，Y”为氢、烷基或改性烷基)等，其中x和y≥0且为整数；
醚类取代基优选结构，如-O(CH 2) xCH 3、-O(CH 2CH 2O) xCH 3、-O(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
硫醚类取代基优选结构，如-S(CH 2) xCH 3、-S(CH 2CH 2O) xCH 3、-S(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
胺基类取代基优选结构，如-NH(CH 2) xCH 3、-NH(CH 2) x(CY’Y”) yCH 3、-N(CY’Y”) x(CY’Y”) y、
Figure PCTCN2018080170-appb-000012
(Y，Y’为氢、烷基或改性烷基)等，其中x和y≥0且为整数；
酯类取代基优选结构，如-COO(CH 2) xCH 3、-COO(CH 2CH 2O) xCH 3、-COO(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
酰胺类取代基优选结构，如-CONH(CH 2) xCH 3、-CONH(CH 2CH 2O) xCH 3、-CONH(CH 2) x(CH 2CH 2O) yCH 3等，其中x和y≥0且为整数；
芳香族类取代基优选结构，如-Ph、
Figure PCTCN2018080170-appb-000013
等。
邻硝基苄基类光扳机修饰的高分子衍生物中的高分子P 1可以是亲水或水溶性天然高聚物包括天然多糖类物质及其修饰物或降解物，蛋白及其修饰物或降解物等，所述天然多糖类物质包括透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐等，所述蛋白包括各种亲水性或水溶性动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白，所述蛋白降解物包括明胶或多肽等，亲水或水溶性合成聚合物包括两臂或多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮等。
以上接枝或聚合的水溶或亲水性高分子衍生物中，单条高分子链上的邻硝基苄基类光扳机的平均个数大于或等于2(即n≥2)。
所述邻硝基苄基类光扳机修饰的高分子衍生物可以是同时含有一种或一种以上不同基团的亲水或水溶性高分子，或者是一种或一种以上不同基团的亲水或水溶性高分子的混合物。所述亲水或水溶性高分子指亲水或水溶性天然高聚物，或亲水或水溶性合成聚合物。
可选地，所述式A-Ⅰ的邻硝基苄基类光扳机修饰的高分子衍生物，可选自以下组分A-1～组分A-50中的结构：
Figure PCTCN2018080170-appb-000014
Figure PCTCN2018080170-appb-000015
Figure PCTCN2018080170-appb-000016
Figure PCTCN2018080170-appb-000017
Figure PCTCN2018080170-appb-000018
可选地，所述式A-Ⅰ的邻硝基苄硫基类光扳机修饰的高分子衍生物，可选自以下组分A-51～组分A-69中的结构：
Figure PCTCN2018080170-appb-000019
Figure PCTCN2018080170-appb-000020
可选地，所述式A-Ⅰ的邻硝基苄胺基类光扳机修饰的高分子衍生物，可选自以下组分A-70～组分A-87中的结构：
Figure PCTCN2018080170-appb-000021
Figure PCTCN2018080170-appb-000022
可选地，所述式A-Ⅰ的环状邻硝基苄基类光扳机修饰的高分子衍生物，可选自以下组分A-88～组分A-106中的结构：
Figure PCTCN2018080170-appb-000023
Figure PCTCN2018080170-appb-000024
组分A-1～组分A-106中，n≥2。
可选地，所述式A-Ⅱ的双键修饰的高分子衍生物，可选自以下组分A-107～组分A-115中的结构：
Figure PCTCN2018080170-appb-000025
组分A-107～组分A-115中，n≥2。
可选地，所述式A-Ⅲ的既含邻硝基苄基类光扳机又含双键官能团的高分子衍生物，可选自以下组分A-116～组分A-154中的结构：
Figure PCTCN2018080170-appb-000026
Figure PCTCN2018080170-appb-000027
Figure PCTCN2018080170-appb-000028
组分A-116～组分A-154中，n≥2，HA为透明质酸；CMC为羧甲基纤维素；Alg为海藻酸；CS为硫酸软骨素；PGA为聚谷氨酸；PEG为聚乙二醇；Chitosan为壳聚糖；Gelatin为明胶；PLL为聚赖氨酸；Dex为葡聚糖；Hep为肝素。
结构式I-1、式I-2中，X＝S时，为邻硝基苄硫基类光扳机，所示邻硝基苄硫基类光扳机修饰的高分子衍生物中，用硫原子(S)替代氧原子(O)，因为硫原子的3d空轨道有利于分子内电荷转移，加快了光扳机的光解速率及光解效率，即在光照下能够更快速地、更彻底地释放出醛基/酮基或亚硝基，从而加快了其作为交联位点的交联速度，并且释放的醛基/酮基或亚硝基都能与组织表面的活性基团键连固定，能够大幅度提高材料与组织的粘附力。此外，多种活性官能团的同时释放及交联(单纯的醛基-胺基光偶合交联只是单种活性官能团的释放与交联)，使得交联效率及交联密度大幅度提高，进一步提高材料的力学性能。因此，分子结构的优化，使得其作为光敏基团修饰得到的高分子衍生物展现出更为优异的材料性能，其交联速度由单纯的醛基-胺基光偶合交联的30s左右提高到了2s以内，组织粘附力提高到80-100kPa左右，力学性能提高到1-2MPa左右，具体数据如实施例一百六十七、一百六十八、一百六十九所示。
结构式I-1、式I-2中，X＝N时，为邻硝基苄胺基类光扳机，所示邻硝基苄胺基类光扳机修饰的高分子衍生物中，用氮原子(N)替代氧原子(O)，因为氮原子是强的电子给体，有利于分子内电荷转移，加快了光扳机的光解速率及光解效率，即在光照下能够更快速地、更彻底地释放出醛基/酮基或亚硝基，从而加快了其作为交联位点的交联速度，并且释放的醛基/酮基或亚硝基都能与组织表面的活性基团键连固定，能够大幅度提高材料与组织的粘附力。此外，多种活性官能团的同时释放及交联(单纯的醛基-胺基光偶合交联只是单种活性官能团的释放与交联)，使得交联效率及交联密度大幅度提高，进一步提高材料的力学性能。因此，分子结构的优化，使得其作为光敏基团修饰得到的高分子衍生物展现出更为优异的材料性能，其交联速度由单纯的醛基-胺基光偶合交联的30s左右提 高到了2s以内，组织粘附力提高到80-100kPa左右，力学性能提高到1-2MPa左右，具体数据如实施例一百六十七、一百六十八、一百六十九所示。
结构式I-2中，为环状邻硝基苄基类光扳机，具体为环状邻硝基苄基类光扳机或环状邻硝基苄硫基类光扳机或环状邻硝基苄胺基类光扳机，具有分子内环状结构，其设计目的在于光照下释放的另一活性官能团(如巯基基团等)能够保留在邻硝基苄基的母体上(单纯的醛基-胺基光偶合交联中释放的另一活性官能团会从邻硝基苄基的母体上离去)，从而在同时释放醛基/酮基或亚硝基的基础上，能够额外的释放巯基，进一步增加了有效的交联位点。此外，环状邻硝基苄硫基类光扳机中，硫原子(S)的3d空轨道有利于分子内电荷转移；环状邻硝基苄胺基类光扳机中，氮原子(N)是强的电子给体，有利于分子内电荷转移，加快了光扳机的光解速率及光解效率，即在光照下能够更快速地、更彻底地释放出醛基/酮基或亚硝基，从而加快了其作为交联位点的交联速度，并且释放的醛基/酮基或亚硝基都能与组织表面的活性基团键连固定，能够大幅度提高材料与组织的粘附力。此外，多种活性官能团(醛基/酮基、亚硝基、巯基)的同时释放及交联(单纯的醛基-胺基光偶合交联只是单种活性官能团的释放与交联)，使得交联效率及交联密度大幅度提高，进一步提高材料的力学性能。因此，分子结构的优化，使得其作为光敏基团修饰得到的高分子衍生物展现出更为优异的材料性能，其交联速度由单纯的醛基-胺基光偶合交联的30s左右提高到了2s以内，组织粘附力提高到80-100kPa左右，力学性能提高到1-2MPa左右，具体数据如实施例一百六十七、一百六十八、一百六十九所示。
本发明的第三个目的是提供所述光敏高分子衍生物的制备方法。
2.1、提供邻硝基苄基类光扳机修饰的光敏高分子衍生物(简称A 1)的制备方法。
所述邻硝基苄基类光扳机有两种结构包括：不含环状结构的邻硝基苄基类光扳机、环状邻硝基苄基类光扳机，环状邻硝基苄基类光扳机符号表示为cNB。
另外，所述邻硝基苄基类光扳机包括邻硝基苄基类光扳机、邻硝基苄硫基类光扳机、邻硝基苄胺基类光扳机。邻硝基苄基类光扳机符号表示为NB，邻硝基苄硫基类光扳机符号表示为sNB，邻硝基苄胺基类光扳机符号表示为nNB。
邻硝基苄基类光扳机修饰的光敏高分子衍生物(简称A 1)，制备方法为化学标记法和人工聚合的方法。
其中，化学标记法是利用高分子与邻硝基苄基类光扳机中所含的化学基团间的化学反应而连接，可以是含羧基的高分子与含羟基/巯基/胺基的邻硝基苄基类小分子标记(参考文献O.P.Oommen,S.Wang,M.Kisiel,M.Sloff,J.Hilborn,O.P.Varghese,Adv.Funct.Mater.2013,23,1273.)；也可以是含羟基的高分子与含羧基的或含溴的邻硝基苄基类小分子标记(参考文献K.Peng,I.Tomatsu,A.V.Korobko,A.Kros,Soft Matter 2010,6,85；L.Li,N.Wang,X.Jin,R.Deng,S.Nie,L.Sun,Q.Wu,Y.Wei,C.Gong,Biomaterials 2014,35,3903.)；也可以是含胺基的高分子与含羧基的或含溴的邻硝基苄基类小分子标记(参考文献L.Li,N.Wang,X.Jin,R.Deng,S.Nie,L.Sun,Q.Wu,Y.Wei,C.Gong,Biomaterials 2014,35,3903.)等标记方法。
人工聚合的方法是利用邻硝基苄基衍生物功能单体与其它共单体共聚，可以是无规自由基聚合方法，也可以是控制自由基聚合方法(比如ATRP聚合、RAFT聚合方法)等。
本发明中，邻硝基苄基类光扳机修饰的高分子衍生物的一些可实施的制备方法如下：
第一种可实施的制备方法为：将含有羧基的水溶性聚合物或高分子于蒸馏水中溶解，加入含有活性官能团羟基或巯基或胺基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和活化剂羟基苯并三唑(HOBt)，然后在室温下搅拌24-48h。反应结束后，将反应液加入透析袋中用稀盐酸溶液透析2-3d，然后冷冻干燥，即可得到所述的邻硝基苄基修饰的光敏高分子衍生物。
第二种可实施的制备方法为：将含有羧基的水溶性聚合物或高分子于0.01mol/L 2-(N- 吗啉)乙磺酸MES缓冲溶液(pH＝5.2)中，搅拌至完全溶解，将邻硝基苄基小分子溶于二甲基亚砜后加入上述反应液，将4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM)溶于MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋中，用去离子水透析2-3d，然后冷冻干燥，即可得到所述的邻硝基苄基修饰的光敏高分子衍生物。
第一种可实施方式与第二种可实施方式中，上述含有羧基的水溶性聚合物或高分子可以为聚乙二醇类、含羧基的多糖类(如：透明质酸、羧甲基纤维素、海藻酸等)、含羧基的蛋白或多肽类(如：明胶等)，优选为多臂羧基聚乙二醇、透明质酸、羧甲基纤维素、明胶。进一步优选为透明质酸。
第三种可实施的制备方法为：将含有羟基或胺基的水溶性聚合物于蒸馏水中溶解，加入含有活性官能团羧基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和催化剂对甲苯磺酸吡啶盐(DPTS)，然后在室温下搅拌24-48h。反应结束后，将反应液倒入难溶性溶剂中重沉淀(比如修饰的聚乙二醇衍生物可倒入乙醚中重沉淀，多糖类高分子衍生物可倒入乙醇中重沉淀)，然后溶于水中用透析袋透析2-3d，冷冻干燥后，即可得到所述的邻硝基苄基修饰的光敏高分子衍生物。
第四种可实施的制备方法为：将含有羟基或胺基的水溶性聚合物于蒸馏水中溶解，加入含有活性官能团溴的邻硝基苄基小分子后，加入碳酸钾作为碱，在室温下反应24-48h。反应结束后，将反应液倒入难溶性溶剂(比如修饰的聚乙二醇衍生物可倒入乙醚中，修饰的多糖类高分子衍生物可倒入乙醇中)中重沉淀，然后溶于水中用透析袋透析2-3d，冷冻干燥后，即可得到所述的邻硝基苄基修饰的光敏高分子衍生物。
第三种可实施方式与第四种可实施方式中，上述含有羟基或胺基的水溶性聚合物可以为含羟基或胺基的聚乙二醇类或天然多糖类或蛋白/多肽类，优选为多臂羟基聚乙二醇、多臂胺基聚乙二醇、乙二醇壳聚糖、丙二醇壳聚糖、羧甲基壳聚糖、壳聚糖乳酸盐类或天然多糖类，或聚赖氨酸、明胶等，进一步优选为乙二醇壳聚糖、多臂羟基聚乙二醇。
上述反应中，水溶性聚合物中的羧基、羟基或胺基与小分子邻硝基苄基类衍生物的摩尔比优选为1:0.1-2；胺基修饰的邻硝基苄基类小分子与1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)、活化剂羟基苯并三唑(HOBt)的摩尔比优选为1:2:1.5；胺基修饰的邻硝基苄基类小分子与4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM)的摩尔比优选为1:7.5；羧基修饰的邻硝基苄基类小分子与1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)、催化剂DPTS的摩尔比优选为1:2:1.5；溴代的邻硝基苄基类小分子与碳酸钾的摩尔比优选为1:2。
第五种可实施的制备方法为：将邻硝基苄基可聚合单体衍生物与一种或几种可聚合共单体经过聚合即可得邻硝基苄基修饰的合成共聚物。经过多次溶解-重沉淀的方法将其纯化。
上述邻硝基苄基可聚合单体衍生物可以为丙烯酸酯类化合物、甲基丙烯酸酯类化合物、丙烯酰胺类化合物、甲基丙烯酰胺类化合物，优选为甲基丙烯酸酯类化合物和丙烯酰胺类化合物，进一步优选为甲基丙烯酸酯类化合物。
上述可聚合共单体中至少一种必须是水溶性共单体，可以为甲基丙烯酸聚乙二醇酯(PEG-MA)、丙烯酸聚乙二醇酯、甲基丙烯酸(MAA)、丙烯酸(AA)、丙烯酸羟乙酯、丙烯酰胺(AM)等任意具有水溶性的可聚合单体，优选为甲基丙烯酸聚乙二醇酯(PEG-MA)。其它共单体根据不同的应用而选择。
上述邻硝基苄基可聚合单体衍生物与水溶性共单体的聚合摩尔比可以为1:20-1:2，优选为1:9-1:3，进一步优选为1:4。
上述聚合方法可以是无规自由基聚合、也可以是控制自由基聚合(比如RAFT聚合、ATRP聚合等)。优选为无规自由基聚合。即邻硝基苄基可聚合单体衍生物与共单体共溶 于一定的溶剂中，加入自由基引发剂充分溶解后，经过三次冷冻-抽真空循环操作后，在加热条件下反应过夜。待反应结束后，将反应液倒入无水乙醚中沉淀，经过多次溶解-重沉淀的纯化过程，真空干燥后即可得到含邻硝基苄基的共聚合物。(参考文献G.Delaittre,T.Pauloehrl,M.Bastmeyer,C.Barner-Kowollik,Macromolecules 2012,45,1792-1802.)
2.2、本发明提供含双键官能团的光敏高分子衍生物(简称A 2)的制备方法。
本发明中，双键修饰的光敏高分子衍生物的制备方法包括以下几种：
第一种可实施的制备方法为：将含羟基或胺基的水溶性高分子溶于去离子水，冷却至0-4℃，加入丙烯酸酐或甲基丙烯酸酐，再缓慢滴加5M NaOH，反应24h，然后将反应液倒入透析袋中，用去离子水透析2-3d，然后冷冻干燥，即可得到所述的双键修饰的光敏高分子衍生物。
上述含有羟基或胺基的水溶性聚合物或高分子可以为聚乙二醇类、含羟基或胺基的多糖类(如：透明质酸、海藻酸、羧甲基纤维素、羧甲基壳聚糖、葡聚糖、硫酸软骨素等)、含羟基或胺基的蛋白或多肽类(如：明胶等)，优选为透明质酸、明胶、海藻酸、羧甲基纤维素、硫酸软骨素，进一步优选为透明质酸。
第二种可实施的制备方法为：将含羟基或胺基的水溶性高分子溶于去离子水，加热至40℃搅拌溶解，加入丙烯酸缩水甘油酯或甲基丙烯酸缩水甘油酯，再加入5M NaOH，反应2-3h后，将反应液倒入透析袋中，用去离子水透析2-3d，然后冷冻干燥，即可得到所述的双键修饰的光敏高分子衍生物。
上述含有羟基或胺基的水溶性聚合物或高分子可以为聚乙二醇类、含羟基或胺基的多糖类(如：透明质酸、海藻酸、羧甲基纤维素、羧甲基壳聚糖、葡聚糖、硫酸软骨素等)、含羟基或胺基的蛋白或多肽类(如：明胶等)，优选为透明质酸、明胶、羧甲基壳聚糖，进一步优选为羧甲基壳聚糖。
第三种可实施的制备方法为：将含羟基或胺基的水溶性高分子溶于无水二甲基亚砜中，加入三乙胺，再加入丙烯酰氯或甲基丙烯酰氯(溶于二氯甲烷中)，反应10h，反应结束后，将反应液倒入乙醇中重沉淀，过滤得到的粗产物重新溶于去离子水中，透析2-3d，然后冷冻干燥，即可得到所述的双键修饰的光敏高分子衍生物。
上述含有羟基或胺基的水溶性聚合物或高分子可以为聚乙二醇类、含羟基或胺基的多糖类(如：葡聚糖等)，优选为多臂聚乙二醇、葡聚糖，进一步优选为葡聚糖。
2.3、提供既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物(简称A 3)的制备方法。
所述邻硝基苄基类光扳机有两种结构包括：不含环状结构的邻硝基苄基类光扳机、环状邻硝基苄基类光扳机，环状邻硝基苄基类光扳机符号表示为cNB。
另外，所述邻硝基苄基类光扳机包括邻硝基苄基类光扳机、邻硝基苄硫基类光扳机、邻硝基苄胺基类光扳机。邻硝基苄基类光扳机符号表示为NB，邻硝基苄硫基类光扳机符号表示为sNB，邻硝基苄胺基类光扳机符号表示为nNB。
本发明中，既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物(简称A 3)的制备方法为先标记邻硝基苄基类光扳机后标记双键官能团和先标记双键官能团后标记邻硝基苄基类光扳机，具体标记方法按上述邻硝基苄基类光扳机或双键官能团的标记方法制备。邻硝基苄基类光扳机标记方法是利用高分子与邻硝基苄基类光扳机中所含的化学基团间的化学反应而连接，可以是含羧基的高分子与含羟基/巯基/胺基的邻硝基苄基类小分子标记；也可以是含羟基的高分子与含羧基的或含溴的邻硝基苄基类小分子标记；也可以是含胺基的高分子与含羧基的或含溴的邻硝基苄基类小分子标记等标记方法。双键官能团标记方法是利用丙烯酸酐类分子、甲基丙烯酸酐类分子，或丙烯酸缩水甘油酯类分子、甲基丙烯酸缩水甘油酯类分子，或丙烯酰氯类分子、甲基丙烯酰氯类分子等。
本发明中，既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物(简称A 3) 的制备方法包括以下几种：
第一种可实施的制备方法为：将含邻硝基苄基类光扳机的水溶性高分子溶于去离子水，冷却至0-4℃，加入丙烯酸酐或甲基丙烯酸酐，再缓慢滴加5M NaOH，反应24h，然后将反应液倒入透析袋中，用去离子水透析2-3d，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
第二种可实施的制备方法为：将含邻硝基苄基类光扳机的水溶性高分子溶于去离子水，加热至40℃搅拌溶解，加入丙烯酸缩水甘油酯或甲基丙烯酸缩水甘油酯，再加入5M NaOH，反应2-3h后，将反应液倒入透析袋中，用去离子水透析2-3d，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
第三种可实施的制备方法为：将含邻硝基苄基类光扳机的水溶性高分子溶于无水二甲基亚砜中，加入三乙胺，再加入丙烯酰氯或甲基丙烯酰氯(溶于二氯甲烷中)，反应10h，反应结束后，将反应液倒入乙醇中重沉淀，过滤得到的粗产物重新溶于去离子水中，透析2-3d，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
第四种可实施的制备方法为：将含双键官能团的水溶性聚合物或高分子于蒸馏水中溶解，加入含有活性官能团羟基或巯基或胺基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和活化剂羟基苯并三唑(HOBt)，然后在室温下搅拌24-48h。反应结束后，将反应液加入透析袋中用稀盐酸溶液透析2-3d，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
第五种可实施的制备方法为：将含双键官能团的水溶性聚合物或高分子于0.01mol/L2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)中，搅拌至完全溶解，将邻硝基苄基小分子溶于二甲基亚砜后加入上述反应液，将4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM)溶于MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋中，用去离子水透析2-3d，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
第六种可实施的制备方法为：将含双键官能团的水溶性聚合物溶解后，加入含有活性官能团羧基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和催化剂对甲苯磺酸吡啶盐(DPTS)，然后在室温下搅拌24-48h。反应结束后，将反应液倒入难溶性溶剂中重沉淀(比如修饰的聚乙二醇衍生物可倒入乙醚中重沉淀，多糖类高分子衍生物可倒入乙醇中重沉淀)，然后溶于水中用透析袋透析2-3d，冷冻干燥后，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
第七种可实施的制备方法为：将含双键官能团的水溶性聚合物于蒸馏水中溶解，加入含有活性官能团溴的邻硝基苄基小分子后，加入碳酸钾作为碱，在室温下反应24-48h。反应结束后，将反应液倒入难溶性溶剂(比如修饰的聚乙二醇衍生物可倒入乙醚中，修饰的多糖类高分子衍生物可倒入乙醇中)中重沉淀，然后溶于水中用透析袋透析2-3d，冷冻干燥后，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
本发明的第四个目的是提供光交联水凝胶材料的制备方法。该光交联水凝胶材料是以发明目的二所述光敏高分子衍生物为原料制备的。
光交联水凝胶材料的制备方法，包括以下步骤：
将组分A-光敏高分子衍生物溶于生物相容性介质得到光敏高分子溶液A；
将组分B-光引发剂溶于生物相容性介质得到光引发剂溶液B；
将溶液A和溶液B混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，发生光交联形成水凝胶。其交联方式为：组分A中的邻硝基苄基类光扳机和/或双键官能 团和组分B-光引发剂在光照下，分别发生自由基交联(即邻硝基苄基类光扳机的自由基交联和双键官能团的自由基交联)。
进一步的，另一种光交联水凝胶材料的制备方法，包括以下步骤：
将组分A-光敏高分子衍生物溶于生物相容性介质得到光敏高分子溶液A；
将组分B-光引发剂溶于生物相容性介质得到光引发剂溶液B；
将辅助组分C-其他生物相容性高分子衍生物溶于生物相容性介质得到高分子溶液C，所述辅助组分C-其他生物相容性高分子衍生物为含胺基、联胺、酰肼或羟胺官能团的高分子衍生物，或含巯基官能团的高分子衍生物；
将溶液A、溶液B和溶液C混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，发生光交联形成水凝胶。其交联方式为：组分A中的邻硝基苄基类光扳机和/或双键官能团和组分B-光引发剂在光照下，分别发生自由基交联(即邻硝基苄基类光扳机的自由基交联和双键官能团的自由基交联)，同时组分A中的邻硝基苄基类光扳机在光照下产生的醛基/酮基与组分C中的胺基、联胺、酰肼或羟胺官能团发生光偶合交联，产生的亚硝基与组分C中的巯基官能团发生光致亚硝基交联，是一种复合型光交联的方式。
本发明中，水凝胶前体溶液的配置可根据不同的需要从组分A，组分B，组分C中选择，其中组分A和组分B为必要组分，组分C为辅助组分，因此水凝胶前体溶液可以为组分A/组分B，也可以为组分A/组分B/组分C。组分A的配置可以根据不同的需要从光敏高分子衍生物A 1，A 2，A 3中选择，可以为一种或一种以上光敏高分子衍生物的混合物，但不能为单独的A 2。因此，所有可能涉及的组分方式为A 1/B；A 3/B；A 1、A 2/B；A 1、A 3/B；A 2、A 3/B；A 1、A 2、A 3/B；A 1/B/C；A 3/B/C；A 1、A 2/B/C；A 1、A 3/B/C；A 2、A 3/B/C；A 1、A 2、A 3/B/C。
本发明的制备方法中，生物相容性介质选自蒸馏水、生理盐水、缓冲液和细胞培养基溶液。根据不同的应用，可选取不同的介质。
本发明的制备方法中，混合均匀形成的水凝胶前体溶液中，若为组分A/组分B，则组分A浓度可以为0.1％wt-60％wt，优选为1％wt-10％wt，组分B的浓度可以为0.01％wt-10％wt，优选为0.05％wt-1.0％wt，高分子总浓度可以为0.1％wt-60％wt，优选为1％wt-10％wt；若为组分A/组分B/组分C，则组分A与组分C的质量比可以为1:0.02-50，优选为1:0.1-10，组分B的浓度可以为0.01％wt-10％wt，优选为0.05％wt-1.0％wt，高分子总浓度可以为0.1％wt-60％wt，优选为1％wt-10％wt。
本发明的制备方法中，光源的波长根据邻硝基苄类光扳机及光引发剂的吸收波长来确定，可以为250-500nm，优选为300-450nm，进一步优选为365、375、385、395、405nm。
本发明光交联水凝胶的制备方法采用的技术原理：分A中的邻硝基苄基类光扳机和/或双键官能团和组分B-光引发剂在光照下，分别发生自由基交联，同时组分A中的邻硝基苄基类光扳机在光照下产生的醛基/酮基与组分C中的胺基、联胺、酰肼或羟胺官能团发生光偶合交联，产生的亚硝基与组分C中的巯基官能团发生光致亚硝基交联，从而可以实现在一次光照下的多重交联，是一种复合型光交联的方式。
对于光交联水凝胶材料的制备方法中，
组分B-光引发剂，即光照下能够产生自由基的物质，优选为水溶性光引发剂或可分散在水中的光引发剂，进一步优选为I 2959(组分B-1)，LAP(组分B-2)，Eosin-Y(组分B-3)等及其衍生物。
Figure PCTCN2018080170-appb-000029
组分C-含胺基、联胺、酰肼或羟胺官能团的高分子衍生物，分别具有结构式C-Ⅰ、C-Ⅱ、C-Ⅲ、C-Ⅳ；含巯基官能团的高分子衍生物，具有结构式C-Ⅴ：
Figure PCTCN2018080170-appb-000030
结构式C-Ⅰ、C-Ⅱ、C-Ⅲ、C-Ⅳ、C-Ⅴ中，n≥2，P 2、P 3、P 4、P 5、P 6为亲水或水溶性天然高聚物，也可以是亲水或水溶性合成聚合物等。
亲水或水溶性天然高聚物包括天然多糖类物质及其修饰物或降解物，蛋白及其修饰物、改性物和降解的多肽类物质等。
所述天然多糖类物质包括透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐。
所述蛋白包括各种亲水性或水溶性动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白，所述蛋白降解物包括明胶或多肽。
亲水或水溶性合成聚合物包括两臂或多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚谷氨酸、聚(甲基)丙烯酸、聚(甲基)丙烯酸酯、聚(甲基)丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮。
含胺基、联胺、酰肼、羟胺或巯基基团的高分子衍生物可以是同时含有一种或一种以上不同基团的亲水或水溶性天然高聚物或合成聚合物，或者是一种或一种以上不同基团的亲水或水溶性天然高聚物或合成聚合物。
对于含胺基、联胺、酰肼、羟胺等高分子衍生物，式C-Ⅰ所示结构，代表含n个胺基基团的水溶性或亲水性的高分子。式C-Ⅱ所示结构，代表含n个联胺基基团的水溶性或亲水性的高分子。式C-Ⅲ所示结构，代表含n个酰肼基基团的水溶性或亲水性的高分子。式C-Ⅳ所示结构，代表含n个羟胺基基团的水溶性或亲水性的高分子。式C-Ⅴ所示结构，代表含n个巯基基团的水溶性或亲水性的高分子。
可选地，所述式C-Ⅰ可选自以下组分C-1～组分C-9中的结构；所述式C-Ⅱ可选自以下组分C-10中的结构；所述式C-Ⅲ可选自以下组分C-11～组分C-13中的结构；所述式C-Ⅳ可选自以下组分C-14～组分C-15中的结构；所述式C-Ⅴ选自以下组分C-16～组分C-21中的结构：
Figure PCTCN2018080170-appb-000031
Figure PCTCN2018080170-appb-000032
组分C-1～组分C-21中，n≥2，组分C-1为壳聚糖；组分C-2为乙二醇壳聚糖；组分C-3为羧甲基壳聚糖；组分C-4为明胶；组分C-5为聚赖氨酸；组分C-6为聚乙烯亚胺； 组分C-7为两臂胺基聚乙二醇；组分C-8为四臂胺基聚乙二醇；组分C-9为胺基聚合物；组分C-10为联胺修饰的羧甲基纤维素；组分C-11～组分C-13为酰肼修饰的透明质酸；组分C-14为四臂羟胺聚乙二醇；组分C-15为羟胺修饰的葡聚糖；组分C-16为两臂巯基聚乙二醇；组分C-17为四臂巯基聚乙二醇；组分C-18为巯基修饰的透明质酸；组分C-19为巯基修饰的壳聚糖；组分C-20为巯基修饰的葡聚糖；组分C-21为巯基修饰的肝素。
本发明还提供组分C-含胺基、联胺、酰肼或羟胺基团的高分子衍生物的制备方法。
本发明中，胺基修饰的水溶性聚合物可以是人工合成聚胺类高分子及其修饰物(如聚乙烯亚胺PEI、树枝体PAMAM，两臂或多臂胺基聚乙二醇)，或天然含胺基多糖类亲水或水溶性高分子及其修饰物或降解物(如乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖、壳寡糖等)；也可以是生物或经微生物表达后提取的蛋白及其改性物或降解物(如胶原，血清蛋白及明胶等)；也可以是人工合成或通过微生物表达并提取的含两个或两个胺基以上的亲水或水溶性多肽(如聚赖氨酸等)或丙烯酸酯或甲基丙烯酸酯或丙烯酰胺类或甲基丙烯酰胺类聚合物及其修饰物。优选为明胶、乙二醇壳聚糖。
本发明中，联胺修饰的高分子衍生物的制备方法为：将含有羧基的水溶性聚合物和二联胺于蒸馏水中溶解，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和活化剂羟基苯并三唑(HOBt)，然后在室温下搅拌24-48h。反应结束后，将反应液倒入透析袋中用稀盐酸溶液透析2-3d，然后冷冻干燥，即可得到所述的联胺修饰的高分子衍生物。
上述含有羧基的水溶性聚合物可以为羧基聚乙二醇类、含羧基的多糖类(如壳聚糖乳酸盐、羧甲基壳聚糖、透明质酸、海藻酸、羧甲基纤维素等)，优选为多臂羧基聚乙二醇、透明质酸，进一步优选为透明质酸。
上述反应中，水溶性聚合物中的羧基与小分子二联胺的摩尔比优选为1:0.1-2；二联胺小分子与1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)、活化剂羟基苯并三唑(HOBt)的摩尔比优选为1:2:1.5。
本发明中，酰肼修饰的高分子衍生物的制备方法为：将含有羧基的水溶性聚合物和二酰肼于蒸馏水中溶解，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和活化剂羟基苯并三唑(HOBt)，然后在室温下搅拌24-48h。反应结束后，将反应液倒入透析袋中用稀盐酸溶液透析2-3d，然后冷冻干燥，即可得到所述的酰肼修饰的高分子衍生物。
上述含有羧基的水溶性聚合物可以为羧基聚乙二醇类、含羧基的多糖类(如壳聚糖乳酸盐、羧甲基壳聚糖、透明质酸、海藻酸、羧甲基纤维素等)，优选为多臂羧基聚乙二醇、透明质酸，进一步优选为透明质酸。
上述反应中，小分子二酰肼可以为碳二酰肼、草酸二酰肼、丙二酸二酰肼、丁二酸二酰肼、戊二酸二酰肼、己二酸二酰肼、庚二酸二酰肼等任意二酰肼，优选为碳二酰肼、草酸二酰肼、己二酸二酰肼，进一步优选为碳二酰肼。水溶性聚合物中的羧基与小分子二酰肼的摩尔比优选为1:0.1-2；二酰肼小分子与1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)、活化剂羟基苯并三唑(HOBt)的摩尔比优选为1:2:1.5。
本发明中，羟胺修饰的高分子衍生物的制备方法为：将含有羟基的聚合物与N-羟基邻苯二甲酰亚胺溶于二氯甲烷溶液中，加入三苯基膦后，慢慢滴加二异丙基偶氮二羧酸酯并反应16-24h后，将聚合物在乙醚中沉淀出来，然后重新溶到二氯甲烷溶液中，加入水合肼反应1-3h后，即可得到羟胺修饰的高分子衍生物。
上述含有羟基的聚合物可以为聚乙二醇类，多糖类(如葡聚糖、壳聚糖)，优选为多臂羟基聚乙二醇。
上述反应中，聚合物中的羟基与N-羟基邻苯二甲酰亚胺、三苯基膦、二异丙基偶氮二羧酸酯、水合肼的摩尔比优选为1:10:10:10:10。
本发明还提供组分C-含巯基基团的高分子衍生物的制备方法。
含巯基类基团的高分子衍生物，即巯基修饰的高分子衍生物的制备方法为化学标记法，具体是利用高分子与含巯基的衍生物中所含化学基团间的化学反应而连接，可以是含羧基的高分子与含胺基或含酰肼或含羟胺的小分子标记(参考文献Amy Fu,Kihak Gwon,Julia A.Kornfield,Biomacromolecules.2015,16,497.；Tugba Ozdemir,Swati Pradhan-Bhatt,Xinqiao Jia,ACS Biomater.Sci.Eng.2016,2,2217.)，也可以是含羟基的高分子与含羧基或含溴的小分子标记(参考文献Rayun Choi,Yong-Min Huh,Seungjoo Haam,Langmuir.2010,26,17520.)，也可以是含胺基的高分子与含羧基或含溴的小分子标记(参考文献Hanwei Zhang,Aisha Qadeer,Weiliam Chen,Biomacromolecules.2011,12,1428.)等标记方法。
巯基修饰的高分子衍生物的制备方法包括以下几种：
第一种可实施的制备方法为：将含有羧基的水溶性聚合物或高分子于蒸馏水中溶解，加入含有活性官能团胺基或酰肼或羟胺的带巯基的小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和活化剂羟基苯并三唑(HOBt)，然后在室温下搅拌24-48h。反应结束后，将反应液加入透析袋中用稀盐酸溶液透析2-3d，然后冷冻干燥，即可得到所述的巯基修饰的高分子衍生物。
上述含有羧基的水溶性聚合物或高分子可以为聚乙二醇类、含羧基的多糖类(如：透明质酸、羧甲基纤维素、海藻酸、肝素等)，优选为多臂羧基聚乙二醇、透明质酸、肝素，进一步优选为透明质酸、肝素。
第二种可实施的制备方法为：将含有羟基或胺基的水溶性聚合物或高分子于蒸馏水中溶解，加入含有活性官能团羧基的带巯基的小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)和催化剂4-(二甲胺基)吡啶，然后在室温下搅拌24-48h。反应结束后，将反应液倒入难溶性溶剂中重沉淀(比如修饰的聚乙二醇衍生物可倒入乙醚中重沉淀，多糖类高分子衍生物可倒入乙醇中重沉淀)，然后溶于水中用透析袋透析2-3d，冷冻干燥后，即可得到所述的巯基修饰的高分子衍生物。
上述含有羟基的水溶性聚合物或高分子可以为聚乙二醇类或天然多糖类，优选为多臂聚乙二醇、葡聚糖，进一步优选为葡聚糖。上述含有胺基的水溶性聚合物或高分子可以为聚乙二醇类或天然多糖类或蛋白及多肽类，优选为多臂胺基聚乙二醇、乙二醇壳聚糖、丙二醇壳聚糖、羧甲基壳聚糖、壳聚糖乳酸盐类或蛋白及多肽类，进一步优选为羧甲基壳聚糖。
第三种可实施的制备方法为：将含有羟基或胺基的水溶性聚合物或高分子于蒸馏水中溶解，加入含有活性官能团溴的带巯基保护基的小分子后，加入碳酸钾作为碱，在室温下反应24-48h。反应结束后，将反应液倒入难溶性溶剂(比如修饰的聚乙二醇衍生物可倒入乙醚中，修饰的多糖类高分子衍生物可倒入乙醇中)中重沉淀，然后将粗产物溶于蒸馏水中，加入DTT脱保护，反应一段时间后，将反应液倒入透析袋透析2-3d，冷冻干燥后，即可得到所述的巯基修饰的高分子衍生物。
上述含有羟基的水溶性聚合物或高分子可以为聚乙二醇类或天然多糖类，优选为多臂聚乙二醇、葡聚糖，进一步优选为葡聚糖。上述含有胺基的水溶性聚合物或高分子可以为聚乙二醇类或天然多糖类或蛋白及多肽类，优选为多臂胺基聚乙二醇、乙二醇壳聚糖、丙二醇壳聚糖、羧甲基壳聚糖、壳聚糖乳酸盐类或蛋白及多肽类，进一步优选为羧甲基壳聚糖。
上述反应中，水溶性高分子中的羧基、羟基或胺基与小分子巯基类衍生物的摩尔比优选为1:0.1-2；胺基或酰肼或羟胺修饰的含巯基类小分子与1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)、活化剂羟基苯并三唑(HOBt)的摩尔比优选为1:1.5:1.5，羧基修饰的含巯基类小分子与1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl)、催化剂4-(二甲胺基)吡啶的摩尔比优选为1:1.5:1.5，溴代的含巯基类小分子与碳酸钾的 摩尔比优选为1:2。
本发明的第五个目的是提供利用发明目的四所述光交联水凝胶材料制备方法制得的产品，即光交联水凝胶材料，也可以称为复合型光交联水凝胶材料。
本发明的第六个目的是提供用于本发明方法制备水凝胶的试剂盒。
第一种试剂盒，包含：组分A-光敏高分子衍生物；组分B-光引发剂，及有关水凝胶制备及应用的说明书；
这里组分A-光敏高分子衍生物包括两种结构：
1、邻硝基苄基类光扳机修饰的光敏高分子衍生物，简称A 1，具有上文式A-Ⅰ结构；
2、既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物，简称A 3，具有上文式A-Ⅲ结构。
其中，邻硝基苄基类光扳机，结构如上文式I所示，具有两种结构，分别如上文结构式I-1与上文结构式I-2。结构式I-1表示不含环状结构的邻硝基苄基类光扳机。结构式I-2表示环状邻硝基苄基类光扳机，符号表示为cNB。式I-1或式I-2中，X＝O时，称为邻硝基苄基类光扳机，符号表示为NB，X＝S时，称为邻硝基苄硫基类光扳机，符号表示为sNB，X＝N时，称为邻硝基苄胺基类光扳机，符号表示为nNb。
组分B-光引发剂，即光照下能够产生自由基的物质，优选为水溶性光引发剂或可分散在水中的光引发剂，进一步优选为I 2959(组分B-1)，LAP(组分B-2)，Eosin-Y(组分B-3)等及其衍生物。
第二种试剂盒，除第一种试剂盒内容以外，在第一种试剂盒所述组分A-光敏高分子衍生物中还加入含双键官能团的光敏高分子衍生物，含双键官能团的光敏高分子衍生物，简称A 2，具有上文式A-Ⅱ结构。
第三种试剂盒，在第一种试剂盒的基础上，还包括辅助组分C，所述辅助组分C为其他生物相容性高分子衍生物，包括含胺基、联胺、酰肼、羟胺或巯基官能团的高分子衍生物。辅助组分C的定义与发明目的四所述光交联水凝胶材料制备方法中辅助组分C的定义相同。
第四种试剂盒，在第二种试剂盒的基础上，还包括辅助组分C，所述辅助组分C为其他生物相容性高分子衍生物，包括含胺基、联胺、酰肼、羟胺或巯基官能团的高分子衍生物。辅助组分C的定义与发明目的四所述光交联水凝胶材料制备方法中辅助组分C的定义相同。
对于以上四种试剂盒中还可包含生物相容性介质，如蒸馏水、生理盐水、缓冲液和细胞培养基。
对于以上四种试剂盒中的说明书上记载着水凝胶的应用包括其在术后创面封闭、组织液渗漏封堵、止血材料、组织工程支架材料、3D打印的生物墨水及作为细胞、蛋白或药物载体上的应用。
本发明的第七个目的是提供光交联水凝胶材料制备方法所制得产品，即光交联水凝胶的应用。
本发明提供了上述光交联水凝胶作为制备术后创面封闭-皮肤修复材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备术后创面封闭-术后防黏连材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备术后创面封闭-口腔溃疡材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备组织液渗漏封堵-肠漏封堵材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备组织液渗漏封堵-手术缝合材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备止血材料-肝脏止血材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备止血材料-骨断面止血材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备止血材料-动脉止血材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备止血材料-心脏止血材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备组织工程支架材料-软骨修复材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备组织工程支架材料-骨修复材料或药物的应用。
本发明还提供了上述光交联水凝胶作为制备组织工程支架材料-骨/软骨复合缺损修复材料或药物的应用。
本发明还提供了上述光交联水凝胶在3D打印(FDM)材料-生物墨水的应用。
本发明还提供了上述光交联水凝胶在3D打印(DLP)材料-生物墨水的应用。
本发明还提供了上述光交联水凝胶作为制备细胞、蛋白、药物载体上的应用。
本发明中，所述式A-Ⅰ为邻硝基苄基类光扳机修饰的光敏高分子衍生物，所述式A-Ⅱ为含双键官能团的光敏高分子衍生物，所述式A-Ⅲ为既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。由式A-Ⅰ、式A-Ⅱ、式A-Ⅲ中的一种或多种光敏高分子衍生物构成组分A；将组分A-光敏高分子衍生物溶于生物相容性介质得到光敏高分子溶液A；将组分B-光引发剂溶于生物相容性介质得到光引发剂溶液B；将辅助组分C-其他生物相容性高分子衍生物溶于生物相容性介质得到高分子溶液C。将溶液A和溶液B(或加入溶液C)混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，发生光交联形成水凝胶。其交联方式可以分为以下两种：
方式一：将溶液A和溶液B混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，发生光交联形成水凝胶。其交联方式为：组分A中的邻硝基苄基类光扳机和/或双键官能团和组分B-光引发剂在光照下，分别发生自由基交联(即邻硝基苄基类光扳机的自由基交联和双键官能团的自由基交联)。邻硝基苄基类光扳机的自由基交联是通过邻硝基苄基在光照下产生的亚硝基捕获光引发剂在光照下产生的自由基，形成活性极强的亚硝基自由基，产生的亚硝基自由基可以自身发生二聚交联，也可以与组分A中的其他活性基团(如巯基、羟基、胺基、羧基、磺酸基、羰基、双键等)进行加成交联形成水凝胶。由于亚硝基自由基的反应活性比单纯亚硝基的活性更高，可以进一步提高水凝胶的交联速度及交联效率。双键官能团的自由基交联是通过光引发剂在光照下产生的自由基转移到双键上，进而引发双键的聚合交联。以上两种自由基交联方式可以只进行一种交联，即组分A单独选用式A-Ⅰ或式A-Ⅱ所示的光敏高分子衍生物；也可以在一次光照下同时进行，即组分A单独选用式A-Ⅲ所述的光敏高分子衍生物，或同时选用式A-Ⅰ、式A-Ⅱ、式A-Ⅲ中两种以上光敏高分子衍生物。该类光交联方式可以同时具备光引发自由基聚合交联速度快的优势，以及邻硝基苄基类光扳机交联组织粘附力强的优势，并且多重交联的方式，可以进一步提高水凝胶的力学性能。因此，其交联速度由单纯的醛基-胺基光偶合交联的30s左右提高到了2s以内，组织粘附力提高到80-100kPa左右，力学性能提高到1-2MPa左右，具体数据如实施例一百六十七、一百六十八、一百六十九所示。
方式二：将溶液A、溶液B和溶液C混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，发生光交联形成水凝胶。其交联方式为：组分A中的邻硝基苄基类光扳机和/或双键官能团和组分B-光引发剂在光照下，分别发生自由基交联(即邻硝基苄基类光扳机的自由基交联和双键官能团的自由基交联)。邻硝基苄基类光扳机的自由基交联是通过邻硝基苄基在光照下产生的亚硝基捕获光引发剂在光照下产生的自由基，形成活性极强的亚硝基自由基，产生的亚硝基自由基可以自身发生二聚交联，也可以与组分A中的其他活性基团(如巯基、羟基、胺基、羧基、磺酸基、羰基、双键等)进行加成交联形 成水凝胶。由于亚硝基自由基的反应活性比单纯亚硝基的活性更高，可以进一步提高水凝胶的交联速度及交联效率。双键官能团的自由基交联是通过光引发剂在光照下产生的自由基转移到双键上，进而引发双键的聚合交联。同时组分A中的邻硝基苄基类光扳机在光照下产生的醛基/酮基与组分C中的胺基、联胺、酰肼或羟胺官能团发生席夫碱交联，产生的亚硝基与组分C中的巯基官能团发生光致亚硝基交联。以上两种自由基交联方式可以只进行一种交联，即组分A单独选用式A-Ⅰ或式A-Ⅱ所示的光敏高分子衍生物；也可以在一次光照下同时进行，即组分A单独选用式A-Ⅲ所述的光敏高分子衍生物，或同时选用式A-Ⅰ、式A-Ⅱ、式A-Ⅲ中两种以上光敏高分子衍生物。该类光交联方式可以同时具备光引发自由基聚合交联速度快的优势，以及邻硝基苄基类光扳机交联组织粘附力强的优势，并且多重交联的方式，可以进一步提高水凝胶的力学性能。因此，其交联速度由单纯的醛基-胺基光偶合交联的30s左右提高到了2s以内，组织粘附力提高到80-100kPa左右，力学性能提高到1-2MPa左右，具体数据如实施例一百六十七、一百六十八、一百六十九所示。
下式为该类光交联水凝胶的交联示意图：
Figure PCTCN2018080170-appb-000033
本发明中，该类光交联水凝胶是在现有光交联方式(即单纯的醛基-胺基光偶合交联或光引发自由基聚合交联)的基础上，提出的一种新型光交联凝胶技术。组分B-光引发剂的引入，不仅提高了原有邻硝基苄基类光扳机的交联速度及交联效率(通过产生极强反应活性的亚硝基自由基进行交联)，而且可以将光引发自由基聚合交联的高分子衍生物和光偶合反应交联的高分子衍生物混合后形成复合的光敏高分子溶液，在一次光照下，可以激活引发剂产生自由基，分别进行自由基交联(即邻硝基苄基类光扳机的自由基交联和双键官能团的自由基交联)，也可以发生光偶合反应交联(即邻硝基苄基类光扳机在光照下产生的醛基/酮基与组分C中的胺基、联胺、酰肼或羟胺官能团发生席夫碱交联)及光致亚硝基交联(即邻硝基苄基类光扳机在光照下产生的亚硝基与组分C中的巯基官能团发生光致亚硝基交联)，实现多重光交联制备复合型水凝胶。
本发明与现有技术相比具有下列创新点：
(1)光固化速度快，能在1-2s达到成胶点，10-20s达到最终模量，由于一次实现了多重光交联，其光固化速度优于单纯的光引发自由基聚合交联和光偶合交联；
(2)组织粘附力强，能在组织表面原位凝胶化，同时光照产生的醛基/酮基和亚硝基能与组织表面的巯基、胺基、羧基发生反应，实现水凝胶与周围组织的化学键键连一体化整合，克服了自由基聚合交联需要额外底涂的问题；
(3)力学性能优异，具有较好的延展性和强度，克服了当前大多数水凝胶机械性能 差、柔弱易碎的问题；
(4)生物相容性好，原料主要来源于天然高分子材料，且形成的水凝胶可降解；
(5)临床操作便捷，由于光交联具有优异的时空可控性，使用时可将水凝胶前体溶液涂抹或喷涂于创面组织，在光照下快速成胶同步与组织整合，无需底涂，一步实现创面封闭；
(6)凝胶的化学结构、组成和降解性以及强度、厚薄可调，可以根据不同的应用而灵活地调节凝胶材料的组成和性质，尤其可以在创面原位成薄胶，特别适用于术后创面的封闭和修复，也适用于组织液渗漏封堵，同时可作为止血材料，也可作为组织工程支架材料，也可以用于3D打印的生物墨水，还可以为细胞、蛋白或药物提供一种原位载体，有效应用于再生医学。
因此，该光交联水凝胶体系的技术突破，有望实质性推动光原位凝胶技术的临床应用。
附图说明
注：NB为本发明组分A-1中的邻硝基苄基类光扳机；cNB为本发明组分A-88中的环状邻硝基苄基类光扳机；cNB-MA为本发明组分A-144中的既含环状邻硝基苄基类光扳机又含双键官能团。其中，HA-NB即为组分A-1；HA-cNB即为组分A-88；HA-cNB-MA即为组分A-144。
图1为水凝胶前体溶液(2％HA-NB/6％Gelatin/1％HAMA/0.2％LAP或2％HA-cNB/1％HA-cNB-MA/0.2％LAP)光照成胶的实时流变图。
图2为该水凝胶(2％HA-NB/6％Gelatin/1％HAMA/0.2％LAP或2％HA-cNB/1％HA-cNB-MA/0.2％LAP)的粘附力测试图。
图3为该水凝胶(2％HA-NB/6％Gelatin/1％HAMA/0.2％LAP或2％HA-cNB/1％HA-cNB-MA/0.2％LAP)的压缩测试图。
图4为该水凝胶(HA-NB/Gelatin/HAMA/LAP或HA-cNB/HA-cNB-MA/LAP)的生物相容性测试图。
图5为该水凝胶(组分A-1/组分A-107/组分C-4/组分B-2)的创面封闭的效果直观图。
图6为该水凝胶(组分A-1/组分A-107/组分C-4/组分B-2)作为术后防黏连的效果直观图。
图7为该水凝胶(组分A-1/组分A-107/组分C-4/组分B-2)作为肝脏止血的效果直观图。
图8为该水凝胶(组分A-1/组分A-107/组分C-4/组分B-2)作为骨/软骨组织工程支架材料的效果直观图。
图9为该水凝胶(组分A-1/组分A-107/组分C-4/组分B-2)作为生物墨水的打印效果直观图。
具体实施方式
以下用实施例对本发明作更详细的描述。下面结合附图以及实施例对本发明作进一步描述，但这些实施例仅仅是对本发明最佳实施方式的描述，并不对本发明的范围有任何限制。本领域技术人员在不背离本发明精神和保护范围的情况下作出的其它任何变化和修改，仍包括在本发明保护范围之内。
实施例一：组分A-1的合成
Figure PCTCN2018080170-appb-000034
(1)化合物1的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]328.1507.
(2)组分A-1的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物1(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-1(1.85g)，根据核磁氢谱图，可计算出化合物1的标记率大约为3.42％。
实施例二：组分A-2的合成
Figure PCTCN2018080170-appb-000035
(1)化合物2的合成：按参考文献James F.Cameron.；Jean M.J.Frechet.J.Am.Chem.Soc.1991,113,4303.公开的方法进行合成。
(2)化合物3的合成：将化合物2(1g，3.2mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物3(0.89g，产率82％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.33(d,J＝6.9Hz,3H).MS(ESI):[M+H]342.1624.
(3)组分A-2的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物3(68mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-2(1.92g)，根据核磁氢谱图，可计算出化合物3的标记率大约为3.29％。
实施例三：组分A-3的合成
Figure PCTCN2018080170-appb-000036
(1)化合物4的合成：按参考文献Michael C.Pirrung.；Yong Rok Lee.；Kaapjoo.；James B.Springer.J.Org.Chem.1999,64,5042.公开的方法进行合成。
(2)化合物5的合成：将化合物4(1g，2.7mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物5(0.80g，产率74％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),6.35(dd,J＝10.0,15.0Hz,1H),6.04(m,1H),5.8(m,1H),5.4(m,1H),4.96(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.75(d,J＝6.5Hz,3H).MS(ESI):[M+H]394.1908.
(3)组分A-3的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物5(79mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-3(1.73g)，根据核磁氢谱图，可计算出化合物5的标记率大约为2.97％。
实施例四：组分A-4的合成
Figure PCTCN2018080170-appb-000037
(1)化合物6的合成：按参考文献Isabelle Aujard.；Chouaha Benbrahim.；Ludovic Jullien.Chem.Eur.J.2006,12,6865.公开的方法进行合成。
(2)化合物7的合成：将化合物6(1g，3.1mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物7(0.85g，产率78％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]353.1426.
(3)组分A-4的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物7(70mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-4(1.78g)，根据核磁氢谱图，可计算出化合物7的标记率大约为2.49％。
实施例五：组分A-5的合成
Figure PCTCN2018080170-appb-000038
(1)化合物8的合成：按参考文献Alexander G.Russell.；Dario M.Bassani.；John S.Snaith.J.Org.Chem.2010,75,4648.公开的方法进行合成。
(2)化合物9的合成：将化合物8(1g，2.9mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物9(0.78g，产率72％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]372.1424.
(3)组分A-5的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物9(74mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-5(1.76g)，根据核磁氢谱图，可计算出化合物9的标记率大约为3.08％。
实施例六：组分A-6的合成
Figure PCTCN2018080170-appb-000039
(1)化合物10的合成：按参考文献Alexandre Specht.；Maurice Goeldner.Angew.Chem.Int.Ed.2004,43,2008.公开的方法进行合成。
(2)化合物11的合成：将化合物10(1g，2.7mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物11(0.68g，产率63％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]396.1374.
(3)组分A-6的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物11(79mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-6(1.79g)，根据核磁氢谱图，可计算出化合物11的标记率大约为2.34％。
实施例七：组分A-7的合成
Figure PCTCN2018080170-appb-000040
(1)化合物12的合成：按参考文献Jack E.Baldwin.；Adrian W.McConnaughie.；Sung Bo Shin.Tetrahedron.1990,46,6879.公开的方法进行合成。
(2)化合物13的合成：将化合物12(1g，2.4mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物13(0.61g，产率57％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.75(ddd,J＝8.2,1.4,0.4Hz,1H),7.22(s,1H),7.57(tdd,J＝7.3,1.4,0.7Hz,1H),7.49(dd,J＝7.9,1.4Hz,1H),7.36(ddd,J＝8.1,7.3,1.4Hz,1H),4.96(s,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]449.1618.
(3)组分A-7的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物13(90mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-7(1.72g)，根据核磁氢谱图，可计算出化合物13的标记率大约为2.38％。
实施例八：组分A-8的合成
Figure PCTCN2018080170-appb-000041
(1)化合物14的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000042
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。
(2)化合物15的合成：将化合物14(1g，2.6mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物15(0.90g，产率83％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.63-3.52(m,1H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),2.00-1.34(m,6H).MS(ESI):[M+H]412.2027.
(3)组分A-8的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物15(82mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物 A-8(1.86g)，根据核磁氢谱图，可计算出化合物15的标记率大约为3.43％。
实施例九：组分A-9的合成
Figure PCTCN2018080170-appb-000043
(1)化合物16的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。
(2)化合物17的合成：将化合物16(1g，2.5mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物17(0.80g，产率75％)。 1H NMR(400MHz,CDCl 3):δ＝8.02-7.23(m,5H),7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]432.1713.
(3)组分A-9的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物17(86mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-9(1.82g)，根据核磁氢谱图，可计算出化合物17的标记率大约为3.24％。
实施例十：组分A-10的合成
Figure PCTCN2018080170-appb-000044
(1)化合物18的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。
(2)化合物19的合成：将化合物18(1g，2.7mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物19(0.76g，产率71％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.25(q,J＝6.5Hz,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.32(t,J＝6.5Hz,3H).MS(ESI):[M+H]400.1742.
(3)组分A-10的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物19(80mg，0.2mmoL)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析 袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-10(1.88g)，根据核磁氢谱图，可计算出化合物19的标记率大约为3.01％。
实施例十一：组分A-11的合成
Figure PCTCN2018080170-appb-000045
(1)化合物20的合成：按参考文献Kalbag,S.M.；Roeske,R.W.J.Am.Chem.Soc.1975,97,440.公开的方法进行合成。
(2)化合物21的合成：将化合物20(1g，2.3mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物21(0.84g，产率79％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.63(q,J＝6.9Hz,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.67(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.48(d,J＝6.9Hz,3H).MS(ESI):[M+H]457.1976.
(3)组分A-11的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物21(91mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-11(1.76g)，根据核磁氢谱图，可计算出化合物21的标记率大约为3.15％。
实施例十二：组分A-12的合成
Figure PCTCN2018080170-appb-000046
(1)化合物22的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。
(2)化合物23的合成：将化合物22(1g，2.7mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物23(0.76g，产率71％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.25(q,J＝6.5Hz,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.32(t,J＝6.5Hz,3H).MS(ESI):[M+H]416.1422.
(3)组分A-12的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物 23(80mg，0.2mmoL)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-12(1.88g)，根据核磁氢谱图，可计算出化合物23的标记率大约为3.01％。
实施例十三：组分A-13的合成
Figure PCTCN2018080170-appb-000047
(1)化合物24的合成：按参考文献Engels,J.；Schlaeger,E.J.J.Med.Chem.1977,20,907.公开的方法进行制备化合物24。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.25(q,J＝6.5Hz,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.32(t,J＝6.5Hz,3H).MS(ESI):[M+H]435.1432.
(2)组分A-13的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物24(87mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-13(1.73g)，根据核磁氢谱图，可计算出化合物24的标记率大约为3.08％。
实施例十四：组分A-14的合成
Figure PCTCN2018080170-appb-000048
(1)化合物25的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行制备化合物25。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]362.1124.
(2)组分A-14的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物25(72mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-14(1.72g)，根据核磁氢谱图，可计算出化合物25的标记率大约为3.09％。
实施例十五：组分A-15的合成
Figure PCTCN2018080170-appb-000049
(1)化合物26的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行制备化合物26。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.35(s,3H),2.26-2.17(m,2H).MS(ESI):[M+H]342.1617.
(2)组分A-15的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物26(68mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-15(1.88g)，根据核磁氢谱图，可计算出化合物26的标记率大约为3.28％。
实施例十六：组分A-16的合成
Figure PCTCN2018080170-appb-000050
(1)化合物27的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行制备化合物27。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.76(q,J＝6.5Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.22(t,J＝6.5Hz,3H).MS(ESI):[M+H]388.1554.
(2)组分A-16的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物27(77mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-16(1.68g)，根据核磁氢谱图，可计算出化合物27的标记率大约为2.98％。
实施例十七：组分A-17的合成
Figure PCTCN2018080170-appb-000051
(1)化合物28的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行制备化合物28。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.45(q,J＝7.26Hz,4H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.20(t,J＝7.26Hz,6H).MS(ESI):[M+H]399.2271.
(2)组分A-17的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物28(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-17(1.76g)，根据核磁氢谱图，可计算出化合物28的标记率大约为3.02％。
实施例十八：组分A-18的合成
Figure PCTCN2018080170-appb-000052
(1)化合物29的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行制备化合物29。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),2.08(s,3H).MS(ESI):[M+H]386.1523.
(2)组分A-18的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物29(77mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-18(1.82g)，根据核磁氢谱图，可计算出化合物29的标记率大约为3.15％。
实施例十九：组分A-19的合成
Figure PCTCN2018080170-appb-000053
(1)化合物30的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行制备化合物30。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),2.08(s,3H).MS(ESI):[M+H]385.1712.
(2)组分A-19的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL  0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物30(77mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-19(1.74g)，根据核磁氢谱图，可计算出化合物30的标记率大约为3.12％。
实施例二十：组分A-20的合成
Figure PCTCN2018080170-appb-000054
(1)化合物31的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行制备化合物31。 1H NMR(400MHz,CDCl 3):δ＝8.02-7.23(m,5H),7.71(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]404.1882.
(2)组分A-20的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物31(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-20(1.81g)，根据核磁氢谱图，可计算出化合物31的标记率大约为3.21％。
实施例二十一：组分A-21的合成
Figure PCTCN2018080170-appb-000055
(1)化合物32的合成：按参考文献Emmanuel Riguet.；Christian G.Bochet.Org.Lett.2007,26,5453.公开的方法进行合成。
(2)化合物33的合成：将化合物32(1g，3.4mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物33(0.85g，产率78％)。 1H NMR(400MHz,CDCl 3):δ＝8.05(d,J＝9.54Hz,1H),7.24(d,J＝2.72Hz,1H),6.92(dd,J＝9.54,2.72Hz,1H),4.85(s,2H),3.56-3.68(m,4H),3.49-3.56(m,2H),3.42-3.49(m,2H),3.32(t,J＝5.9Hz,2H),2.82(t,J＝5.9Hz,2H).MS(ESI):[M+H]346.1454.
(3)组分A-21的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物33(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析 袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-21(1.76g)，根据核磁氢谱图，可计算出化合物33的标记率大约为2.84％。
实施例二十二：组分A-22的合成
Figure PCTCN2018080170-appb-000056
(1)化合物34的合成：按参考文献Isabelle Aujard.；Chouaha Benbrahim.；Ludovic Jullien.Chem.Eur.J.2006,12,6865.公开的方法进行合成。
(2)化合物35的合成：将化合物34(1g，3.2mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物35(0.96g，产率88％)。 1H NMR(400MHz,CDCl 3):δ＝8.05(d,J＝9.54Hz,1H),7.28(d,J＝8.00Hz,2H),7.24(d,J＝2.72Hz,1H),6.92(dd,J＝9.54,2.72Hz,1H),6.78(d,8.00Hz,2H),4.96(s,2H),4.83(s,2H),3.32(t,J＝5.9Hz,2H),2.82(t,J＝5.9Hz,2H).MS(ESI):[M+H]346.1454.
(3)组分A-22的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物35(69mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-22(1.83g)，根据核磁氢谱图，可计算出化合物35的标记率大约为3.12％。
实施例二十三：组分A-23的合成
Figure PCTCN2018080170-appb-000057
(1)化合物36的合成：按参考文献Filiz Bley.；Klaus Schaper.；Helmut Gorner.Photochem.Photobiol.2008,84,162.公开的方法进行合成。
(2)化合物37的合成：将化合物36(1g，3.5mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物37(0.83g，产率76％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),5.92(s,2H),4.96(s,2H),4.83(s,2H),3.32(t,J＝5.9Hz,2H),2.82(t,J＝5.9Hz,2H).MS(ESI):[M+H]314.0932.
(3)组分A-23的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物37(63mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-23(1.84g)，根据核磁氢谱图，可计算出化合物37的标记率大约为3.17％。
实施例二十四：组分A-24的合成
Figure PCTCN2018080170-appb-000058
(1)化合物38的合成：按参考文献Filiz Bley.；Klaus Schaper.；Helmut Gorner.Photochem.Photobiol.2008,84,162.公开的方法进行合成。
(2)化合物39的合成：将化合物38(1g，3.0mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物39(0.77g，产率71％)。 1H NMR(400MHz,CDCl 3):δ＝4.96(s,2H),4.83(s,2H),3.32(t,J＝5.9Hz,2H),3.27-3.21(m,4H),2.84(t,J＝6.5Hz,2H),2.82(t,J＝5.9Hz,2H),2.75(t,J＝6.3Hz,2H),2.00-1.91(m,4H).MS(ESI):[M+H]365.1828.
(3)组分A-24的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物39(73mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-24(1.87g)，根据核磁氢谱图，可计算出化合物39的标记率大约为3.06％。
实施例二十五：组分A-25的合成
Figure PCTCN2018080170-appb-000059
(1)化合物40的合成：按参考文献Emmanuel Riguet.；Christian G.Bochet.Org.Lett.2007,26,5453.公开的方法进行合成。
(2)化合物41的合成：将化合物40(1g，3.6mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物41(0.93g，产率85％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.24(s,2H),3.32(t,J＝5.9Hz,2H),3.27-3.21(m,2H),2.82(t,J＝5.9Hz,2H),2.75(t,J＝6.3Hz,2H),2.00-1.91(m,2H).MS(ESI):[M+H]309.1522.
(3)组分A-25的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物41(62mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-25(1.82g)，根据核磁氢谱图，可计算出化合物41的标记率大约为3.12％。
实施例二十六：组分A-26的合成
Figure PCTCN2018080170-appb-000060
(1)化合物42的合成：按参考文献Singh,A.K.；Khade,P.K.Tetrahedron.2005,61,10007.公开的方法进行合成。
(2)化合物43的合成：将化合物42(1g，3.4mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物43(0.90g，产率82％)。 1H NMR(400MHz,CDCl 3):δ＝8.31-7.12(m,5H),4.96(s,2H),4.83(s,2H),3.32(t,J＝5.9Hz,2H),2.82(t,J＝5.9Hz,2H).MS(ESI):[M+H]320.1254.
(3)组分A-26的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物43(64mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-26(1.87g)，根据核磁氢谱图，可计算出化合物43的标记率大约为3.21％。
实施例二十七：组分A-27的合成
Figure PCTCN2018080170-appb-000061
(1)化合物44的合成：按参考文献Felix Friedrich.；Mike Heilemann.；Alexander Heckel.Chem.Commun.2015,51,15382.公开的方法进行合成。
(2)化合物45的合成：将化合物44(1g，3.0mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物45(0.80g，产率74％)。 1H NMR(400MHz,CDCl 3):δ＝8.31-7.12(m,5H),4.96(s,2H),4.83(s,2H),3.32(t,J＝5.9Hz,2H),2.82(t,J＝5.9Hz,2H).MS(ESI):[M+H]360.1254.
(3)组分A-27的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物45(72mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-27(1.78g)，根据核磁氢谱图，可计算出化合物45的标记率大约为2.12％。
实施例二十八：组分A-28的合成
Figure PCTCN2018080170-appb-000062
(1)化合物46的合成：按参考文献Grazyna Groszek.；Agnieszka Nowak-Krol.；Barbara Filipek.Eur.J.Med.Chem.2009,44,5103.公开的方法进行合成。
(2)化合物47的合成：将化合物46(1g，3.3mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物47(0.97g，产率89％)。 1H NMR(400MHz,CDCl 3):δ＝8.04(s,1H),7.42(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]328.1507.
(3)组分A-28的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物47(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-28(1.85g)，根据核磁氢谱图，可计算出化合物47的标记率大约为3.43％。
实施例二十九：组分A-29的合成
Figure PCTCN2018080170-appb-000063
(1)化合物48的合成：按参考文献Thomas F.Greene.；Shu Wang.；Mary J.Meegan.J.Med.Chem.2016,59,90.公开的方法进行合成。
(2)化合物49的合成：将化合物48(1g，3.3mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物49(0.95g，产率87％)。 1H NMR(400MHz,CDCl 3):δ＝7.95(s,1H),7.12(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]328.1507.
(3)组分A-29的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物49(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-29(1.86g)，根据核磁氢谱图，可计算出化合物49的标记率大约为3.52％。
实施例三十：组分A-30的合成
Figure PCTCN2018080170-appb-000064
(1)化合物50的合成：按参考文献Yu-Shan.；Mohane Selvaraj Coumar.；Hsing-Pang Hsieh.J.Med.Chem.2009,52,4941.公开的方法进行合成。
(2)化合物51的合成：将化合物50(1g，3.3mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物51(0.89g，产率81％)。 1H NMR(400MHz,CDCl 3):δ＝7.64(s,1H),7.02(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]328.1507.
(3)组分A-30的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物51(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-30(1.82g)，根据核磁氢谱图，可计算出化合物51的标记率大约为3.39％。
实施例三十一：组分A-31的合成
Figure PCTCN2018080170-appb-000065
(1)化合物52的合成：按参考文献Sarit S.Agasti.；Apiwat Chompoosor.；Vincent M.Rotello.J.Am.Chem.Soc.2009,131,5728.公开的方法进行合成。
(2)化合物53的合成：将化合物52(1g，2.9mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物53(0.91g，产率84％)。 1H NMR(400MHz,CDCl 3):δ＝7.91(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]373.1373.
(3)组分A-31的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物53(75mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-31(1.87g)，根据核磁氢谱图，可计算出化合物53的标记率大约为3.45％。
实施例三十二：组分A-32的合成
Figure PCTCN2018080170-appb-000066
(1)化合物54的合成：按参考文献Chandramouleeswaran Subramani.；Xi Yu.；Vincent M.Rotello.J.Mater.Chem.2011,21,14156.公开的方法进行合成。
(2)化合物55的合成：将化合物54(1g，2.7mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物55(0.84g，产率78％)。 1H NMR(400MHz,CDCl 3):δ＝4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]403.1432.
(3)组分A-32的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物55(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-32(1.81g)，根据核磁氢谱图，可计算出化合物55的标记率大约为3.09％。
实施例三十三：组分A-33的合成
Figure PCTCN2018080170-appb-000067
组分A-33的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取NB混合物(化合物1/化合物55，60mg，重量比1:1)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-33(1.87g)，根据核磁氢谱图，可计算出NB混合物(化合物1/化合物55)的标记率大约为3.52％。
实施例三十四：组分A-34的合成
Figure PCTCN2018080170-appb-000068
(1)化合物56的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000069
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开 的方法进行合成。
(2)化合物57的合成：将化合物56(1g，3.3mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物57(0.93g，产率85％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),3.99(s,3H),3.32(t,J＝5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.55(t,J＝6.1Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]326.1721.
(3)组分A-34的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物57(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-34(1.82g)，根据核磁氢谱图，可计算出化合物57的标记率大约为3.21％。
实施例三十五：组分A-35的合成
Figure PCTCN2018080170-appb-000070
(1)化合物58的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000071
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。
(2)化合物59的合成：将化合物58(1g，3.3mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物59(0.82g，产率75％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.03(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]360.1213.
(3)组分A-35的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物59(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-35(1.87g)，根据核磁氢谱图，可计算出化合物59的标记率大约为2.76％。
实施例三十六：组分A-36的合成
Figure PCTCN2018080170-appb-000072
(1)化合物60的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000073
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。
(2)化合物61的合成：将化合物60(1g，3.3mmol)和乙二胺(1.1mL)溶于甲醇(50mL)中，回流过夜反应后，减压旋蒸，将粗产物溶于甲醇中，在乙酸乙酯中重沉淀。经过多次溶解-重沉淀后，过滤、真空干燥即可得到化合物61(0.80g，产率73％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),3.99(s,3H),3.45(t,J＝6.1Hz,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]327.1625.
(3)组分A-36的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物61(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-36(1.76g)，根据核磁氢谱图，可计算出化合物61的标记率大约为3.21％。
实施例三十七：组分A-37的合成
Figure PCTCN2018080170-appb-000074
组分A-37的合成：将羧甲基纤维素Carboxymethyl cellulose(2g，90kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物1(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏羧甲基纤维素衍生物A-37(1.89g)，根据核磁氢谱图，可计算出化合物1的标记率大约为2.25％。
实施例三十八：组分A-38的合成
Figure PCTCN2018080170-appb-000075
组分A-38的合成：将海藻酸Alginic acid(2g)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物1(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏海藻酸衍生物A-38(1.82g)，根据核磁氢谱图，可计算出化合物1的标记率大约为3.17％。
实施例三十九：组分A-39的合成
Figure PCTCN2018080170-appb-000076
组分A-39的合成：将硫酸软骨素Chondroitin sulfate(2g)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物1(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏硫酸软骨素衍生物A-39(1.73g)，根据核磁氢谱图，可计算出化合物1的标记率大约为2.98％。
实施例四十：组分A-40的合成
Figure PCTCN2018080170-appb-000077
组分A-40的合成：将聚谷氨酸PGA(1g)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，0.3g，2.3mmol)，然后将溶于甲醇中的化合物1(0.5g,1.6mmol)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，0.5g，2.6mmol)加入到上述溶液中室温反应48h后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到光敏聚谷氨酸衍生物A-40(0.92g)，根据其核磁氢谱图，可以计算出化合物1的修饰度大约为21.3％。
实施例四十一：组分A-41的合成
Figure PCTCN2018080170-appb-000078
组分A-41的合成：将四臂聚乙二醇羧酸衍生物4-PEG-COOH(0.5g，10kDa)溶于20mL无水二甲基亚砜DMSO中至完全溶解，取化合物1(130mg，0.4mmoL)溶于5mL无水二甲基亚砜DMSO后加入上述反应液，加入0.2mL三乙胺TEA，再加入六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷PyBop(210mg，0.4mmol)，于室温下反应24h，然后在乙醚中重沉淀，将粗产物溶于水后倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏聚乙二醇衍生物A-41(0.45g)，根据核磁氢谱图，可计算出化合物1的标记率大约为98％。
实施例四十二：组分A-42的合成
Figure PCTCN2018080170-appb-000079
(1)化合物62的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000080
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.79(t,J＝6.1Hz,2H),3.70(t,J＝7.2Hz,2H),3.63-3.52(m,1H),3.56(t,J＝7.2Hz,2H),2.00-1.34(m,6H).MS(ESI):[M+H]372.1627.
(2)组分A-42的合成：将透明质酸Hyaluronic acid(1g，340kDa)溶于50mL水中，将化合物62(0.2g，0.48mmol)、EDC-HCl(0.76g，3.96mmol)和DPTS(0.12g，0.48mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，将反应液倒入冷的乙醇中多次重沉淀纯化，收集到的沉淀干燥后将其溶于无水DMSO中，加入对甲苯磺酸将二氢吡喃保护基团脱掉即可得到光敏透明质酸衍生物A-42(0.86g)。根据其核磁氢谱图，可计算出化合物62的修饰度大约为10％。
实施例四十三：组分A-43的合成
Figure PCTCN2018080170-appb-000081
(1)化合物63的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000082
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.63-3.52(m,1H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),2.00-1.34(m,6H).MS(ESI):[M+H]370.1512.
(2)组分A-43的合成：将1g壳聚糖加入到75mL异丙醇中形成壳聚糖的悬浮液，然后将化合物63(0.2g，0.54mmol)、EDC-HCl(0.76g，3.96mmol)和NHS(0.46g，4.0mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，将混合物溶液过滤，滤液用甲醇/水混合溶剂透析三次、甲醇透析两次后，冷冻干燥即可得到化合物63标记的壳聚糖(0.9g)。将化合物63标记的壳聚糖溶于DMSO中，加入对甲苯磺酸脱除二氢吡喃保护即可得到光敏壳聚糖衍生物A-43，根据其核磁氢谱图，可计算出化合物63的修饰度大约为12.5％。
实施例四十四：组分A-44的合成
Figure PCTCN2018080170-appb-000083
组分A-44的合成：将聚赖氨酸PLL(1g)溶于50mL水中，将化合物63(0.2g，0.54mmol)、EDC-HCl(0.76g，3.96mmol)和NHS(0.46g，4.0mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，将反应液倒入冷的乙醇中多次重沉淀纯化，收集到的沉淀干燥后将其溶于无水DMSO中，加入对甲苯磺酸将二氢吡喃保护基团脱掉即可得到光敏聚赖氨酸衍生物A-44(0.84g)。根据其核磁氢谱图，可计算出化合物63的修饰度大约为15.6％。
实施例四十五：组分A-45的合成
Figure PCTCN2018080170-appb-000084
组分A-45的合成：将明胶Gelatin(1g)溶于50mL蒸馏水中至完全溶解，将化合物63(0.2g，0.54mmol)、EDC-HCl(0.76g，3.96mmol)和NHS(0.46g，4.0mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，将反应液倒入冷的乙醇中多次重沉淀纯化，收集到的沉淀干燥后将其溶于无水DMSO中，加入对甲苯磺酸将二氢吡喃保护基团脱掉即可得到光敏明胶衍生物A-45(0.83g)，根据其核磁氢谱图，可以计算出化合物63的修饰度大约为11.2％。
实施例四十六：组分A-46的合成
Figure PCTCN2018080170-appb-000085
组分A-46的合成：将葡聚糖Dextran(1g)溶于50mL水中，将化合物63(0.23g，0.54mmol)、EDC-HCl(0.76g，3.96mmol)和DPTS(0.12g，0.48mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，将反应液倒入冷的乙醇中多次重沉淀纯化，收集到的沉淀干燥后将其溶于无水DMSO中，加入对甲苯磺酸将二氢吡喃保护基团脱掉即可得到光敏葡聚糖衍生物A-46(0.92g)。根据其核磁氢谱图，可计算出化合物63的修饰度大约为18.2％。
实施例四十七：组分A-47的合成
Figure PCTCN2018080170-appb-000086
(1)化合物64的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000087
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI): [M+H]286.0943.
(2)组分A-47的合成：将巯基修饰的肝素Hep-SH(1g)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，0.3g，2.3mmol)，然后将溶于甲醇中的化合物64(0.5g,1.6mmol)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，0.5g，2.6mmol)加入到上述溶液中室温反应48h后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到光敏肝素衍生物A-47(0.86g)，根据其核磁氢谱图，可以计算出化合物64的修饰度大约为10.2％。
实施例四十八：组分A-48的合成
Figure PCTCN2018080170-appb-000088
(1)化合物65的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000089
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.63-3.52(m,1H),3.04(t,J＝7.2Hz,2H),2.00-1.34(m,6H).MS(ESI):[M+H]391.0518.
(2)组分A-48的合成：将1g壳聚糖加入到75mL异丙醇中形成壳聚糖的悬浮液，25mL的NaOH溶液(10mol/L)分五次慢慢加入到上述壳聚糖的悬浮液中并继续搅拌半小时左右。然后将化合物65(0.2g)加入到上述溶液中并在60℃条件下反应3h。反应结束后，将混合物溶液过滤，滤液用甲醇/水混合溶剂透析三次、甲醇透析两次后，冷冻干燥即可得到化合物65标记的壳聚糖(0.92g)。将化合物65标记的壳聚糖溶于DMSO中，加入对甲苯磺酸脱除二氢吡喃保护即可得到光敏壳聚糖衍生物A-48(0.84g)，根据其核磁氢谱图，可计算出化合物65的修饰度大约为12.4％。
实施例四十九：组分A-49的合成
Figure PCTCN2018080170-appb-000090
组分A-49的合成：将PEG-4OH(1g，0.05mmol)溶于无水乙腈中，加入K 2CO 3(55.3mg，0.4mmol)搅拌30min后，加入化合物65(0.17g，0.4mmol)于室温下继续反应24h。反应结束后，将大部分溶剂除掉，在乙醚中重沉淀，并多次洗涤，然后将化合物65标记的聚乙二醇溶于DMSO中，加入对甲苯磺酸脱除二氢吡喃保护即可得到光敏聚乙二醇衍生物A-49(0.93g)，根据核磁氢谱图，可计算出化合物65的修饰度大约为95％。
实施例五十：组分A-50的合成
Figure PCTCN2018080170-appb-000091
(1)化合物66的合成：将化合物65(0.5g，1.29mmol)和乙二醇(0.24g，3.87mmol)溶于无水乙腈中，加入K 2CO 3(0.5g，3.87mmol)做碱，回流过夜反应。待反应结束后，减压旋蒸掉溶剂，过柱纯化，即可得到化合物66(0.34g，72％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.79(t,J＝6.1Hz,2H),3.70(t,J＝7.2Hz,2H),3.63-3.52(m,1H),3.56(t,J＝7.2Hz,2H),2.00-1.34(m,6H).MS(ESI):[M+H]372.1627.
(2)化合物67的合成：将化合物66(0.64g,1.72mmol)和三乙胺(0.34g，3.44mmol)溶于干燥的二氯甲烷中，冰浴条件下，甲基丙烯酰氯(0.27g，2.58mmol)慢慢逐滴加入到上述溶液中，滴加完后室温条件下过夜反应。反应结束后，减压旋蒸掉溶剂，过柱纯化即可得到化合物67(0.49g，65％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),6.25(s,1H),5.68(s,1H),4.96(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.79(t,J＝6.1Hz,2H),3.70(t,J＝7.2Hz,2H),3.63-3.52(m,1H),3.56(t,J＝7.2Hz,2H),2.00-1.34(m,6H),1.87(s,3H).MS(ESI):[M+H]440.1942.
(3)组分A-50的合成：称取化合物67(0.28g，0.63mmol)、共单体PEG-MA(0.882g，2.52mmol)和引发剂偶氮二异丁腈(11mg)加入到史莱克管中，并加入无水THF溶解，经过多次冷冻-抽真空循环操作处理后，将该反应体系于75℃条件下反应24h。反应结束后，将反应液倒入冷的乙醚中多次重沉淀纯化，收集到的沉淀干燥后将其溶于无水DMSO中，加入对甲苯磺酸将二氢吡喃保护基团脱掉即可得到光敏共聚物衍生物A-50(0.84g)。根据核磁氢谱图，可计算出化合物67在共聚物中的含量大约为15.5％。根据GPC测得合成高分子的分子量在25kDa左右，根据投料比计算可得n为12，x为10，y为40。
实施例五十一：组分A-51的合成
Figure PCTCN2018080170-appb-000092
(1)化合物68的合成：按参考文献Kunihiko Morihiro.；Tetsuya Kodama.；Shohei Mori.；Satoshi Obika.Org.Biomol.Chem.2014,12,2468.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.03(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]344.1207.
(2)组分A-51的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物68(69mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲 溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-51(1.85g)，根据核磁氢谱图，可计算出化合物68的标记率大约为3.34％。
实施例五十二：组分A-52的合成
Figure PCTCN2018080170-appb-000093
(1)化合物69的合成：按参考文献Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.公开的方法进行合成。
(2)化合物70的合成：将化合物69(1g，3.0mmol)溶于50mL四氢呋喃中，分别加入四溴化碳CBr 4(2g，6.0mmol)，和三苯基膦PPh 3(1.6g，6.0mmol)，氩气保护下，室温搅拌反应2h，反应后加入5mL水淬灭反应，旋干溶剂，用乙酸乙酯萃取，柱层析分离(PE：DCM＝4:1)，即可得到化合物70(1.0g，产率84％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.56(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]390.0623.
(3)化合物71的合成：将化合物70(0.5g，1.3mmol)溶于50mL丙酮中，分别加入L-半胱氨酸甲酯盐酸盐(0.45g，2.6mmol)，和氢氧化钠(0.2g，5.2mmol)，氩气保护下，室温搅拌反应2h，反应后加入4M HCl调节PH＝7，旋干溶剂，用乙酸乙酯萃取，柱层析分离(PE：DCM＝4:1)，即可得化合物71(0.7g，产率88％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]545.2219.
(4)组分A-52的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物71(109mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-52(1.92g)，根据核磁氢谱图，可计算出化合物71的标记率大约为3.32％。
实施例五十三：组分A-53的合成
Figure PCTCN2018080170-appb-000094
(1)化合物72的合成：按参考文献James F.Cameron.；Jean M.J.Frechet.J.Am.Chem. Soc.1991,113,4303.公开的方法进行合成。
(2)化合物73的合成：按实施例52的方法，以化合物72为原料制得化合物73(产率73％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.66(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.33(d,J＝6.9Hz,3H).MS(ESI):[M+H]404.0863.
(3)化合物74的合成：按实施例52的方法，以化合物73为原料制得化合物74(产率70％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.86(m,1H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H),1.33(d,J＝6.9Hz,3H).MS(ESI):[M+H]559.2402.
(4)组分A-53的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物74(112mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-53(1.75g)，根据核磁氢谱图，可计算出化合物74的标记率大约为2.34％。
实施例五十四：组分A-54的合成
Figure PCTCN2018080170-appb-000095
(1)化合物75的合成：按参考文献Jack E.Baldwin.；Adrian W.McConnaughie.；Sung Bo Shin.Tetrahedron.1990,46,6879.公开的方法进行合成。
(2)化合物76的合成：按实施例52的方法，以化合物75为原料制得化合物76(产率64％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.75(ddd,J＝8.2,1.4,0.4Hz,1H),7.22(s,1H),7.57(tdd,J＝7.3,1.4,0.7Hz,1H),7.49(dd,J＝7.9,1.4Hz,1H),7.36(ddd,J＝8.1,7.3,1.4Hz,1H),4.66(s,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]511.0881.
(3)化合物77的合成：按实施例52的方法，以化合物76为原料制得化合物77(产率58％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.75(ddd,J＝8.2,1.4,0.4Hz,1H),7.22(s,1H),7.57(tdd,J＝7.3,1.4,0.7Hz,1H),7.49(dd,J＝7.9,1.4Hz,1H),7.36(ddd,J＝8.1,7.3,1.4Hz,1H),4.86(s,1H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]666.2423.
(4)组分A-54的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物77(133mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物 A-54(1.8g)，根据核磁氢谱图，可计算出化合物77的标记率大约为3.35％。
实施例五十五：组分A-55的合成
Figure PCTCN2018080170-appb-000096
(1)化合物78的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000097
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.63-3.52(m,1H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),2.00-1.34(m,6H).MS(ESI):[M+H]428.1831.
(2)组分A-55的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物78(85mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-55(1.89g)，根据核磁氢谱图，可计算出化合物78的标记率大约为3.42％。
实施例五十六：组分A-56的合成
Figure PCTCN2018080170-appb-000098
(1)化合物79的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。1H NMR(400MHz,CDCl3):δ＝8.02-7.23(m,5H),7.71(s,1H),7.22(s,1H),4.76(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]448.1561.
(2)组分A-56的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物79(89mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-56(1.87g)，根据核磁氢谱图，可计算出化合物79的标记率大约为3.21％。
实施例五十七：组分A-57的合成
Figure PCTCN2018080170-appb-000099
(1)化合物80的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.25(q,J＝6.5Hz,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.32(t,J＝6.5Hz,3H).MS(ESI):[M+H]416.1432.
(2)组分A-57的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物80(83mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-57(1.74g)，根据核磁氢谱图，可计算出化合物80的标记率大约为2.34％。
实施例五十八：组分A-58的合成
Figure PCTCN2018080170-appb-000100
(1)化合物81的合成：按参考文献Kalbag,S.M.；Roeske,R.W.J.Am.Chem.Soc.1975,97,440.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.63(q,J＝6.9Hz,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.67(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.48(d,J＝6.9Hz,3H).MS(ESI):[M+H]473.1734.
(2)组分A-58的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物81(94mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-58(1.72g)，根据核磁氢谱图，可计算出化合物81的标记率大约为2.56％。
实施例五十九：组分A-59的合成
Figure PCTCN2018080170-appb-000101
(1)化合物82的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.25(q,J＝6.5Hz,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.32(t,J＝6.5Hz,3H).MS(ESI):[M+H]432.1224.
(2)组分A-59的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物82(83mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-59(1.74g)，根据核磁氢谱图，可计算出化合物82的标记率大约为2.34％。
实施例六十：组分A-60的合成
Figure PCTCN2018080170-appb-000102
(1)化合物83的合成：按参考文献Engels,J.；Schlaeger,E.J.J.Med.Chem.1977,20,907.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.25(q,J＝6.5Hz,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.32(t,J＝6.5Hz,3H).MS(ESI):[M+H]451.1126.
(2)组分A-60的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物83(90mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-60(1.72g)，根据核磁氢谱图，可计算出化合物83的标记率大约为2.36％。
实施例六十一：组分A-61的合成
Figure PCTCN2018080170-appb-000103
(1)化合物84的合成：按实施例52的方法，采用常规化学手段制备化合物84。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.35(s,3H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]559.2452.
(2)组分A-61的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物84(111mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-61(1.73g)，根据核磁氢谱图，可计算出化合物84的标记率大约为3.02％。
实施例六十二：组分A-62的合成
Figure PCTCN2018080170-appb-000104
(1)化合物85的合成：按参考文献Grazyna Groszek.；Agnieszka Nowak-Krol.；Barbara Filipek.Eur.J.Med.Chem.2009,44,5103.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝8.04(s,1H),7.42(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]545.2234.
(2)组分A-62的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物85(109mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-62(1.92g)，根据核磁氢谱图，可计算出化合物85的标记率大约为3.14％。
实施例六十三：组分A-63的合成
Figure PCTCN2018080170-appb-000105
(1)化合物86的合成：按参考文献Thomas F.Greene.；Shu Wang.；Mary J.Meegan.J.Med.Chem.2016,59,90.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.95(s,1H),7.12(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]545.2262.
(2)组分A-63的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物86(109mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-63(1.88g)，根据核磁氢谱图，可计算出化合物86的标记率大约为3.45％。
实施例六十四：组分A-64的合成
Figure PCTCN2018080170-appb-000106
(1)化合物87的合成：按参考文献Yu-Shan.；Mohane Selvaraj Coumar.；Hsing-Pang Hsieh.J.Med.Chem.2009,52,4941.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.64(s,1H),7.02(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]545.2231.
(2)组分A-64的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物87(109mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-64(1.85g)，根据核磁氢谱图，可计算出化合物87的标记率大约为3.32％。
实施例六十五：组分A-65的合成
Figure PCTCN2018080170-appb-000107
组分A-65的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取NB混合物(化合物68/化合物71，60mg，质量比1:1)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-65(1.89g)，根据核磁氢谱图，可计算出NB混合物(化合物68/化合物71)的标记率大约为3.41％。
实施例六十六：组分A-66的合成
Figure PCTCN2018080170-appb-000108
组分A-66的合成：将羧甲基纤维素Carboxymethyl cellulose(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物71(109mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏羧甲基纤维素衍生物A-66(1.74g)，根据核磁氢谱图，可计算出化合物71的标记率大约为2.34％。
实施例六十七：组分A-67的合成
Figure PCTCN2018080170-appb-000109
(1)化合物88的合成：按实施例52的方法，采用常规化学手段制备化合物88。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]503.1732.
(2)组分A-67的合成：将1g壳聚糖加入到75mL异丙醇中形成壳聚糖的悬浮液，然后将化合物88(0.2g，0.40mmol)、EDC-HCl(0.76g，3.96mmol)和NHS(0.46g， 4.0mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到光敏壳聚糖衍生物A-67(0.89g)，根据其核磁氢谱图，可以计算出化合物88的修饰度大约为12.5％。
实施例六十八：组分A-68的合成
Figure PCTCN2018080170-appb-000110
(1)化合物89的合成：按实施例52的方法，采用常规化学手段制备化合物89。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.43(d,J＝5.6,2H),3.04(t,J＝7.2Hz,2H),1.42(s,9H).MS(ESI):[M+H]523.0731.
(2)组分A-68的合成：将PEG-4OH(1g，0.05mmol)溶于无水乙腈中，加入K 2CO 3(55.3mg，0.4mmol)搅拌30min后，加入化合物89(0.20g，0.4mmol)于室温下继续反应24h。反应结束后，将大部分溶剂除掉，在乙醚中重沉淀，并多次洗涤，抽滤烘干后即可得到光敏聚乙二醇衍生物A-68(0.85g)，根据核磁氢谱图，可计算出化合物89的修饰度大约为95％。
实施例六十九：组分A-69的合成
Figure PCTCN2018080170-appb-000111
(1)化合物90的合成：将化合物89(0.5g，1.29mmol)和乙二醇(0.24g，3.87mmol)溶于无水乙腈中，加入K 2CO 3(0.5g，3.87mmol)做碱，回流过夜反应。待反应结束后，减压旋蒸掉溶剂，过柱纯化，即可得到化合物90(0.34g，72％)。
(2)化合物91的合成：将化合物90(0.64g,1.72mmol)和三乙胺(0.34g，3.44mmol)溶于干燥的二氯甲烷中，冰浴条件下，甲基丙烯酰氯(0.27g，2.58mmol)慢慢逐滴加入到上述溶液中，滴加完后室温条件下过夜反应。反应结束后，减压旋蒸掉溶剂，过柱纯化即可得到化合物91(0.49g，65％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),6.25(s,1H),5.68(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.79(t,J＝6.1Hz,2H),3.70(t,J＝7.2Hz,2H),3.56(t,J＝7.2Hz,2H),3.43(d,J＝5.6,2H),1.87(s,3H),1.42(s,9H).MS(ESI):[M+H]573.2125.
(3)组分A-69的合成：称取化合物91(0.28g，0.63mmol)、共单体PEG-MA(0.882g，2.52mmol)和引发剂偶氮二异丁腈(11mg)加入到史莱克管中，并加入无水THF溶解，经过多次冷冻-抽真空循环操作处理后，将该反应体系于75℃条件下反应24h。反应结束后，将反应液倒入冷的乙醚中多次重沉淀纯化，即可得到光敏共聚物衍生物A-69(0.86g)。根据核磁氢谱图，可计算出化合物91在共聚物中的含量大约为15.3％。根据GPC测得合成高分子的分子量在25kDa左右，根据投料比计算可得n为12，x为10，y为40。
实施例七十：组分A-70的合成
Figure PCTCN2018080170-appb-000112
(1)化合物92的合成：按参考文献Takahiro Muraoka.；Honggang Cui.；Samuel I.Stupp.J.Am.Chem.Soc.2008,130,2946.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.35(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]327.1617.
(2)组分A-70的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物92(65mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-70(1.8g)，根据核磁氢谱图，可计算出化合物92的标记率大约为3.26％。
实施例七十一：组分A-71的合成
Figure PCTCN2018080170-appb-000113
(1)化合物93的合成：按参考文献Takahiro Muraoka.；Honggang Cui.；Samuel I.Stupp.J.Am.Chem.Soc.2008,130,2946.公开的方法进行合成。
(2)化合物94的合成：将化合物93(15.4g，36.24mmol)溶于100mL甲醇中，胺基乙酸甲酯(7.0g，78.65mmol)溶于70mL甲醇和NaOH(2M，50mL)水溶液中，然后逐滴加入上述溶液中，室温下搅拌反应30min后，在0℃下缓慢加入NaBH 4(12g，317.2mmol)。反应2h后，旋蒸除去溶剂，然后用2M HCl调节pH至5左右，析出白色固体，用乙醚多次洗涤，得到的粗产物用乙醚重沉淀，即化合物94(17.5g，97％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.42(s,9H).MS(ESI):[M+H]499.2442.
(3)化合物95的合成：将化合物94(15g，30mmol)溶于二氯甲烷/三氟乙酸(3:1)的混合溶液，室温下搅拌反应30min，然后旋蒸除去溶剂，得到的粗产物用乙醚重沉淀，即化合物95(11.4g，95％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]399.1823.
(4)组分A-71的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物 95(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-71(1.87g)，根据核磁氢谱图，可计算出化合物95的标记率大约为3.42％。
实施例七十二：组分A-72的合成
Figure PCTCN2018080170-appb-000114
(1)化合物96的合成：按参考文献James F.Cameron.；Jean M.J.Frechet.J.Am.Chem.Soc.1991,113,4303.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.75(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.33(d,J＝6.9Hz,3H).MS(ESI):[M+H]413.2041.
(2)组分A-72的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物96(82mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-72(1.84g)，根据核磁氢谱图，可计算出化合物96的标记率大约为3.21％。
实施例七十三：组分A-73的合成
Figure PCTCN2018080170-appb-000115
(1)化合物97的合成：按参考文献Jack E.Baldwin.；Adrian W.McConnaughie.；Sung Bo Shin.Tetrahedron.1990,46,6879.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝8.02-7.23(m,5H),7.71(s,1H),7.22(s,1H),4.75(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]475.2125.
(2)组分A-73的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物97(95mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-73(1.78g)，根据核磁氢谱图，可计算出化合物97的标记率大约为3.14％。
实施例七十四：组分A-74的合成
Figure PCTCN2018080170-appb-000116
(1)化合物98的合成：按参考文献Pauloehrl,T.；Delaittre,G.；Bruns,M.；Meiβler,M.；
Figure PCTCN2018080170-appb-000117
H.G.；Bastmeyer,M.；Barner-Kowollik,C.Angew.Chem.Int.Ed.2012,51,9181.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.90-3.80(m,1H),3.63-3.52(m,1H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),2.00-1.34(m,6H).MS(ESI):[M+H]411.2231.
(2)组分A-74的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物98(82mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-74(1.88g)，根据核磁氢谱图，可计算出化合物98的标记率大约为3.38％。
实施例七十五：组分A-75的合成
Figure PCTCN2018080170-appb-000118
(1)化合物99的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝8.02-7.23(m,5H),7.71(s,1H),7.22(s,1H),4.55(m,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]431.1926.
(2)组分A-75的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物99(86mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-75(1.85g)，根据核磁氢谱图，可计算出化合物99的标记率大约为3.21％。
实施例七十六：组分A-76的合成
Figure PCTCN2018080170-appb-000119
(1)化合物100的合成：按参考文献Patchornik Abraham.；Amit B.；Woodward R.B.J.Am.Chem.Soc.1970,92,6333.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.25(q,J＝6.5Hz,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.32(t,J＝6.5Hz,3H).MS(ESI):[M+H]399.1818.
(2)组分A-76的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物100(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-76(1.69g)，根据核磁氢谱图，可计算出化合物100的标记率大约为2.31％。
实施例七十七：组分A-77的合成
Figure PCTCN2018080170-appb-000120
(1)化合物101的合成：按参考文献Kalbag,S.M.；Roeske,R.W.J.Am.Chem.Soc.1975,97,440.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.63(q,J＝6.9Hz,1H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.67(s,3H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H),1.48(d,J＝6.9Hz,3H).MS(ESI):[M+H]456.2036.
(2)组分A-77的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物101(91mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-77(1.82g)，根据核磁氢谱图，可计算出化合物101的标记率大约为3.21％。
实施例七十八：组分A-78的合成
Figure PCTCN2018080170-appb-000121
(1)化合物102的合成：按实施例71的方法，采用常规化学手段制备化合物102。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]433.1426.
(2)组分A-78的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物102(86mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-78(1.74g)，根据核磁氢谱图，可计算出化合物102的标记率大约为3.09％。
实施例七十九：组分A-79的合成
Figure PCTCN2018080170-appb-000122
(1)化合物103的合成：按实施例71的方法，采用常规化学手段制备化合物103。 1H NMR(400MHz,CDCl 3):δ＝8.02-7.23(m,5H),7.71(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]475.2138.
(2)组分A-79的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物103(95mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-79(1.76g)，根据核磁氢谱图，可计算出化合物103的标记率大约为2.45％。
实施例八十：组分A-80的合成
Figure PCTCN2018080170-appb-000123
(1)化合物104的合成：按参考文献Grazyna Groszek.；Agnieszka Nowak-Krol.； Barbara Filipek.Eur.J.Med.Chem.2009,44,5103.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝8.04(s,1H),7.42(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]399.1832.
(2)组分A-80的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物104(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-80(1.86g)，根据核磁氢谱图，可计算出化合物104的标记率大约为3.32％。
实施例八十一：组分A-81的合成
Figure PCTCN2018080170-appb-000124
(1)化合物105的合成：按参考文献Thomas F.Greene.；Shu Wang.；Mary J.Meegan.J.Med.Chem.2016,59,90.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.95(s,1H),7.12(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]399.1832.
(2)组分A-81的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物105(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-81(1.89g)，根据核磁氢谱图，可计算出化合物105的标记率大约为3.28％。
实施例八十二：组分A-82的合成
Figure PCTCN2018080170-appb-000125
(1)化合物106的合成：按参考文献Yu-Shan.；Mohane Selvaraj Coumar.；Hsing-Pang Hsieh.J.Med.Chem.2009,52,4941.公开的方法进行合成。 1H NMR(400MHz,CDCl 3):δ＝7.64(s,1H),7.02(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.32(dd,J＝11.6,5.7Hz,2H),2.82(t,J＝5.9Hz,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]399.1832.
(2)组分A-82的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL  0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物106(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-82(1.91g)，根据核磁氢谱图，可计算出化合物106的标记率大约为3.26％。
实施例八十三：组分A-83的合成
Figure PCTCN2018080170-appb-000126
组分A-83的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取nNB混合物(化合物92/化合物95，60mg，质量比1:1)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-83(1.89g)，根据核磁氢谱图，可计算出nNB混合物(化合物92/化合物95)的标记率大约为3.42％。
实施例八十四：组分A-84的合成
Figure PCTCN2018080170-appb-000127
组分A-84的合成：将羧甲基纤维素Carboxymethyl cellulose(2g，90kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物95(80mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏羧甲基纤维素衍生物A-84(1.72g)，根据核磁氢谱图，可计算出化合物95分子的标记率大约为2.21％。
实施例八十五：组分A-85的合成
Figure PCTCN2018080170-appb-000128
(1)化合物107的合成：按实施例71的方法，采用常规化学手段制备化合物107。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+H]357.1342.
(2)组分A-85的合成：将1g壳聚糖加入到75mL异丙醇中形成壳聚糖的悬浮液，然后将化合物107(0.2g，0.56mmol)、EDC-HCl(0.76g，3.96mmol)和NHS(0.46g，4.0mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到光敏壳聚糖衍生物A-85(0.82g)，根据其核磁氢谱图，可以计算出化合物107的修饰度大约为11.3％。
实施例八十六：组分A-86的合成
Figure PCTCN2018080170-appb-000129
(1)化合物108的合成：按实施例71的方法，采用常规化学手段制备化合物108。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.74(s,2H),3.04(t,J＝7.2Hz,2H).MS(ESI):[M+H]377.0346.
(2)组分A-86的合成：将PEG-4OH(1g，0.05mmol)溶于无水乙腈中，加入K 2CO 3(55.3mg，0.4mmol)搅拌30min后，加入化合物108(0.15g，0.4mmol)于室温下继续反应24h。反应结束后，将大部分溶剂除掉，在乙醚中重沉淀，并多次洗涤，抽滤烘干后即可得到光敏聚乙二醇衍生物A-86(0.93g)，根据核磁氢谱图，可计算出化合物108的修饰度大约为95％。
实施例八十七：组分A-87的合成
Figure PCTCN2018080170-appb-000130
(1)化合物109的合成：将化合物108(0.5g，1.29mmol)和乙二醇(0.24g，3.87mmol)溶于无水乙腈中，加入K 2CO 3(0.5g，3.87mmol)做碱，回流过夜反应。待反应结束后，减压旋蒸掉溶剂，过柱纯化，即可得到化合物109(0.34g，72％)。 1H NMR(400 MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.79(t,J＝6.1Hz,2H),3.74(s,2H),3.70(t,J＝7.2Hz,2H),3.56(t,J＝7.2Hz,2H).MS(ESI):[M+H]359.1462.
(2)化合物110的合成：将化合物109(0.64g,1.72mmol)和三乙胺(0.34g，3.44mmol)溶于干燥的二氯甲烷中，冰浴条件下，甲基丙烯酰氯(0.27g，2.58mmol)慢慢逐滴加入到上述溶液中，滴加完后室温条件下过夜反应。反应结束后，减压旋蒸掉溶剂，过柱纯化即可得到化合物110(0.49g，65％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.22(s,1H),6.25(s,1H),5.68(s,1H),4.55(s,2H),4.13(t,J＝6.1Hz,2H),3.99(s,3H),3.95(s,3H),3.79(t,J＝6.1Hz,2H),3.74(s,2H),3.70(t,J＝7.2Hz,2H),3.56(t,J＝7.2Hz,2H),1.87(s,3H).MS(ESI):[M+H]427.1725.
(3)组分A-87的合成：称取化合物110(0.28g，0.63mmol)、共单体PEG-MA(0.882g，2.52mmol)和引发剂偶氮二异丁腈(11mg)加入到史莱克管中，并加入无水THF溶解，经过多次冷冻-抽真空循环操作处理后，将该反应体系于75℃条件下反应24h。反应结束后，将反应液倒入冷的乙醚中多次重沉淀纯化，即可得到光敏共聚物衍生物A-87(0.85g)。根据核磁氢谱图，可计算出化合物110在共聚物中的含量大约为14.6％。根据GPC测得合成高分子的分子量在25kDa左右，根据投料比计算可得n为12，x为10，y为40。
实施例八十八：组分A-88的合成
Figure PCTCN2018080170-appb-000131
(1)化合物111的合成：将香草醛(25g，165mmol)、和碳酸钾(11.4g，83mmol)溶解在200mL丙酮中，逐滴加入溴化苄(21.2g，181mmol)，在90℃条件下回流反应8h。反应结束后，将反应体系降至室温，然后减压蒸馏除去丙酮，加入100mL水，用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，旋干有机溶剂得到无色液体。然后用100mL乙醇重结晶，得到白色针状产物，即化合物111(36.2g，91％)。 1H NMR(400MHz, CDCl 3):δ＝9.83(s,1H),7.39(ddd,J＝24.2,20.7,7.4Hz,7H),6.98(d,J＝8.2Hz,1H),5.24(s,2H),3.94(d,J＝0.9Hz,3H).MS(ESI):[M+Na]265.0824.
(2)化合物112的合成：将化合物111(10g，41.3mmol)溶解在50mL乙酸酐中，然后在冰浴条件下逐渐滴加50mL的硝酸(65％)。滴加完后，撤去冰浴，在室温条件反应30min，反应结束后，然后将反应体系缓慢倒入600mL冰水中，有黄色固体析出，减压过滤得到黄色固体，然后用乙醇重结晶，得到黄色针状产物，即化合物112(9.72g，82％)。 1H NMR(400MHz,CDCl 3):δ＝10.42(s,1H),7.67(s,1H),7.43-7.39(m,3H),7.37(d,J＝7.0Hz,1H),5.26(s,2H),4.01(s,3H).MS(ESI):[M+Na]310.0689.
(3)化合物113的合成：将化合物112(9g，31.3mmol)溶解在200mL甲醇中，冰浴条件下缓慢加入硼氢化钠(2.37g，62.6mmol)，加完后撤去冰浴，室温条件下反应30min，反应结束后，加入2mol/L的盐酸调节反应的PH＝7，然后减压蒸馏旋去甲醇，加入100mL水，用乙酸乙酯萃取三次，合并有机相，并用无水硫酸钠干燥，旋干溶剂即可得到黄色固体产物，再用乙醇进行重结晶，得到黄色固体产物，即化合物113(9.06g，92％)。 1H NMR(400MHz,CDCl 3):δ＝7.77(s,1H),7.49-7.42(m,2H),7.40(dd,J＝8.1,6.4Hz,3H),7.18(s,1H),5.20(s,2H),4.95(s,2H),4.00(s,3H).MS(ESI):[M+Na]312.0834.
(4)化合物114的合成：将化合物113(3g，10.4mmol)溶解到100mL干燥的四氢呋喃中，换气三次，在冰浴条件下同时加入三苯基膦(4.08g，15.6mmol)和四溴化碳(5.16g，15.6mmol)，然后撤去冰浴，室温条件下反应2h，反应结束后，加入6mL水猝灭反应体系，然后减压旋干四氢呋喃，先用饱和食盐水和乙酸乙酯萃取两次，再用水和乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥有机相，减压旋干溶剂，干法上样柱层析分离(PE:CH 2Cl 2＝4:1)，可得到黄色粉末，即化合物114(3.09g，85％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.46-7.41(m,2H),7.40-7.30(m,3H),6.93(s,1H),5.17-5.13(m,2H),4.8-4.79(m,2H),3.95(s,3H),1.42(s,9H).MS(ESI):[M+Na]374.0003.
(5)化合物115的合成：将化合物114(3g，8.5mmol)溶解到120mL丙酮中，换气三次，在氩气保护下加入L-半胱氨酸甲酯盐酸盐(2.9g，17mmol)和氢氧化钠(0.85g，21.25mmol)，再换气三次，室温条件下反应2h，反应结束后，向反应体系中加入4mol/L的盐酸调节体系PH＝7，减压旋干丙酮，先用饱和食盐水和乙酸乙酯萃取三次，再用水和乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥。干法上样柱层析分离(CH 2Cl 2:CH 3OH＝100:3)，可得到黄色固体，即化合物115(2.71g，78％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.45(d,J＝7.0Hz,2H),7.39(t,J＝7.2Hz,3H),6.95(s,1H),5.18(s,2H),4.13(q,J＝13.6Hz,2H),3.98(s,3H),3.73(s,3H),3.65(m,1H),2.91(dd,J＝13.7,4.6Hz,1H),2.75(dd,J＝13.6,7.5Hz,1H).MS(ESI):[M+H]407.1277.
(6)化合物116的合成：将三缩四乙二醇(22g，113.2mmol)加入到干燥的四氢呋喃中，加入金属钠(40mg，1.74mmol)，有气泡产生，待钠完全溶解后，加入丙烯酸叔丁酯(8g，62.4mmol)，室温下反应20h，反应结束后，用1mol/L的盐酸调节体系的PH＝7，减压旋干四氢呋喃，用饱和食盐水和乙酸乙酯萃取三次，再用水和乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，减压旋干溶剂，无需进一步提纯，得到无色油状液体，即化合物116(16.0g，80％)。 1H NMR(400MHz,CDCl 3):δ＝3.78-3.69(m,4H),3.69-3.54(m,14H),2.52(dd,J＝4.3,2.1Hz,2H),1.45(s,9H).MS(ESI):[M+Na]345.1872.
(7)化合物117的合成：将化合物116(10g，31.2mmol)溶于干燥的二氯甲烷中，加入干燥的三乙胺(5.2mmL，37.4mmol)，然后将对甲基苯磺酰氯(8.9g，46.8mmol)溶解于40mL干燥的二氯甲烷中，冰浴条件下逐渐滴加到上述反应体系中，滴加完后，撤去冰浴，室温下反应6h。反应结束后，直接向体系中加入200mL水，用二氯甲烷萃取三次，合并有机相并用无水硫酸钠干燥，旋干溶剂，柱层析分离(CH 2Cl 2:CH 3OH＝50:1)，得到淡黄色油状液体，即化合物117(12.6g，85％)。 1H NMR(400MHz,CDCl 3):δ＝7.79-7.74 (m,2H),7.32(d,J＝8.5Hz,2H),4.21-3.90(m,2H),3.66(dd,J＝5.7,2.8Hz,4H),3.62-3.35(m,12H),2.47(dd,J＝8.3,4.8Hz,2H),2.42(d,J＝3.2Hz,3H),1.42(d,J＝3.4Hz,9H).MS(ESI):[M+Na]499.1964.
(8)化合物118的合成：将化合物117(10g，21.0mmol)和溴化锂(4.8g，31.5mmol)溶解到30mL N,N-二甲基甲酰胺中，加热到80℃反应1h，反应结束后，减压旋干N,N-二甲基甲酰胺，用水和二氯甲烷萃取三次，合并有机相并用无水硫酸钠干燥，减压旋干溶剂，柱层析分离(CH 2Cl 2)，得到淡黄色液体，即化合物118(7.3g，90％)。 1H NMR(400MHz,CDCl 3):δ＝3.72(t,J＝6.3Hz,2H),3.62(t,J＝6.6Hz,2H),3.58(dd,J＝2.6,1.5Hz,8H),3.54(d,J＝2.2Hz,4H),3.39(t,J＝6.3Hz,2H),2.42(t,J＝6.6Hz,2H),1.36(s,9H).MS(ESI):[M+Na]409.1005.
(9)化合物119的合成：将化合物118(5g，13.0mmol)溶解到30mL干燥的二氯甲烷中，加入10mL三氟乙酸，室温下反应30min，反应结束后，减压旋干溶剂，再分别用二氯甲烷和乙酸乙酯溶解产物，再减压旋干溶剂，以达到完全旋干三氟乙酸的目的，无需进一步纯化，得到黄色油状液体，即化合物119(3.9g，92％)。 1H NMR(400MHz,CDCl 3):δ＝3.72(t,J＝6.3Hz,2H),3.67(t,J＝6.3Hz,2H),3.58(dd,J＝4.1,1.7Hz,4H),3.57(s,4H),3.55(s,4H),3.39(t,J＝6.3Hz,2H),2.54(t,J＝6.3Hz,2H).MS(ESI):[M+Na]353.0414.
(10)化合物120的合成：将化合物115(2.0g，4.9mmol)和化合物119(2.0g，5.9mmol)溶于40mL干燥的二氯甲烷中，加入六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(5.1g，9.8mmol)和干燥的三乙胺(1.4mL，9.8mmol)，室温下反应1h，反应结束后，向体系中加入100mL水，用二氯甲烷和水萃取三次，合并有机相，用无水硫酸钠干燥，减压旋干溶剂，干法上样柱层析分离(CH 2Cl 2:CH 3OH＝100:3)，得到黄色液体，即化合物120(2.2g，62％)。 1H NMR(400MHz,CDCl 3):δ＝7.71(s,1H),7.45(d,J＝7.0Hz,2H),7.39(t,J＝7.2Hz,3H),6.95(s,1H),5.18(s,2H),4.42(m,1H),4.13(q,J＝13.6Hz,2H),3.98(s,3H),3.73(s,3H),3.68-3.63(m,2H),3.62-3.55(m,4H),3.58-3.53(m,12H),3.37(t,J＝6.3Hz,2H),2.43(t,J＝5.8Hz,2H).MS(ESI):[M+Na]741.1529.
(11)化合物121的合成：将化合物120(2g，2.8mmol)溶于20mL的三氟乙酸中，45℃下反应8h，反应结束后，减压旋干三氟乙酸，用二氯甲烷和水萃取三次，合并有机相并用无水硫酸钠干燥，减压旋干溶剂，柱层析分离(CH 2Cl 2:CH 3OH＝25:1)，得到黄色液体，即化合物121(1.4g，82％)。 1H NMR(400MHz,CDCl 3):δ＝7.60(s,1H),6.79(s,1H),4.73-4.66(m,1H),3.99(d,J＝12.9Hz,2H),3.97(s,3H),3.73(s,3H),3.70(d,J＝6.3Hz,2H),3.62-3.55(m,4H),3.58-3.53(m,12H),3.37(t,J＝6.3Hz,2H),2.43(t,J＝5.8Hz,2H).MS(ESI):[M+Na]651.1026.
(12)化合物122的合成：将化合物121(0.5g，0.8mmol)溶于400mL丙酮中，加入(0.2g，1.6mmol)碳酸钾，于75℃下回流反应4h，反应结束后，减压过滤除掉不溶物，然后旋干丙酮，柱层析分离(CH 2Cl 2:CH 3OH＝25:1)，得到黄色固体，即化合物122(0.27g，61％)。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.73(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,4H),3.52-3.39(m,14H),2.49-2.35(m,2H).MS(ESI):[M+Na]569.1782.
(13)化合物123的合成：将化合物122(0.2g，3.7mmol)溶于20mL无水乙二胺中，室温下反应6h，反应结束后，减压旋干乙二胺，干法上样柱层析分离(CH 2Cl 2:CH 3OH:三乙胺＝100:8:0.5)，得到黄色粉末，即化合物123(0.19g，89％)。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]597.2211.
Figure PCTCN2018080170-appb-000132
(14)组分A-88的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物123(115mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-88(1.87g)，根据核磁氢谱图，可计算出化合物123分子的标记率大约为3.49％。
实施例八十九：组分A-89的合成
Figure PCTCN2018080170-appb-000133
(1)化合物124的合成：按实施例88的方法，采用常规化学手段制备化合物124。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.96(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]559.2642.
(2)组分A-89的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物124(111mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-89(1.82g)，根据核磁氢谱图，可计算出化合物124的标记率大约为3.15％。
实施例九十：组分A-90的合成
Figure PCTCN2018080170-appb-000134
(1)化合物125的合成：按实施例88的方法，采用常规化学手段制备化合物125。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.26(s,2H),4.42(m,1H),3.97(s,3H),3.42(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]558.2725.
(2)组分A-90的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物125(111mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6- 二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-90(1.87g)，根据核磁氢谱图，可计算出化合物125的标记率大约为3.27％。
实施例九十一：组分A-91的合成
Figure PCTCN2018080170-appb-000135
(1)化合物126的合成：按实施例88的方法，采用化学手段制备化合物126。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),5.16(m,1H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H),1.33(d,J＝6.9Hz,3H).MS(ESI):[M+Na]589.2517.
(2)组分A-91的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物126(118mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-91(1.73g)，根据核磁氢谱图，可计算出化合物126的标记率大约为3.14％。
实施例九十二：组分A-92的合成
Figure PCTCN2018080170-appb-000136
(1)化合物127的合成：按实施例88的方法，采用化学手段制备化合物127。 1H NMR(400MHz,DMSO):δ＝8.02-7.23(m,5H),7.71(s,1H),7.17(s,1H),5.34(m,1H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]651.2761.
(2)组分A-92的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物127(130mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-92(1.78g)，根据核磁氢谱图，可计算出化合物127的标记率大约为3.09％。
实施例九十三：组分A-93的合成
Figure PCTCN2018080170-appb-000137
(1)化合物128的合成：按实施例88的方法，采用常规化学手段制备化合物128。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),5.82(m,1H),4.76(s,2H),3.97(s,3H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]589.2143.
(2)组分A-93的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物128(118mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-93(1.73g)，根据核磁氢谱图，可计算出化合物128的标记率大约为3.15％。
实施例九十四：组分A-94的合成
Figure PCTCN2018080170-appb-000138
(1)化合物129的合成：按实施例88的方法，采用常规化学手段制备化合物129。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.13(t,J＝7.2Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+Na]575.2332.
(2)组分A-94的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物129(115mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-94(1.84g)，根据核磁氢谱图，可计算出化合物129的标记率大约为2.47％。
实施例九十五：组分A-95的合成
Figure PCTCN2018080170-appb-000139
(1)化合物130的合成：按实施例88的方法，采用常规化学手段制备化合物130。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.13(t,J＝7.2Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.69-2.55(m,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+Na]576.2242.
(2)组分A-95的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物 130(115mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-95(1.75g)，根据核磁氢谱图，可计算出化合物130的标记率大约为3.07％。
实施例九十六：组分A-96的合成
Figure PCTCN2018080170-appb-000140
(1)化合物131的合成：按实施例88的方法，采用常规化学手段制备化合物131。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]609.2053.
(2)组分A-96的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物131(122mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-96(1.76g)，根据核磁氢谱图，可计算出化合物131的标记率大约为3.24％。
实施例九十七：组分A-97的合成
Figure PCTCN2018080170-appb-000141
(1)化合物132的合成：按实施例88的方法，采用常规化学手段制备化合物132。 1H NMR(400MHz,DMSO):δ＝8.02-7.23(m,5H),7.71(s,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]651.2722.
(2)组分A-97的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物132(130mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-97(1.82g)，根据核磁氢谱图，可计算出化合物132的标记率大约为3.05％。
实施例九十八：组分A-98的合成
(1)化合物133的合成：按实施例88的方法，采用常规化学手段制备化合物133。 1H NMR(400MHz,DMSO):δ＝8.11(m,1H),7.27(m,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,12H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]531.2143.
(2)组分A-98的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物133(106mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-98(1.78g)，根据核磁氢谱图，可计算出化合物133的标记率大约为3.31％。
实施例九十九：组分A-99的合成
Figure PCTCN2018080170-appb-000143
(1)化合物134的合成：按实施例88的方法，采用常规化学手段制备化合物134。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]575.2342.
(2)组分A-99的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物134(115mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-99(1.84g)，根据核磁氢谱图，可计算出化合物134的标记率大约为3.06％。
实施例一百：组分A-100的合成
Figure PCTCN2018080170-appb-000144
(1)化合物135的合成：按实施例88的方法，采用常规化学手段制备化合物135。 1H NMR(400MHz,DMSO):δ＝7.54(m,1H),7.03(m,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,20H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]619.2652.
(2)组分A-100的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物135(124mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-100(1.84g)，根据核磁氢谱图，可计算出化合物135的标记率大约为3.16％。
实施例一百零一：组分A-101的合成
Figure PCTCN2018080170-appb-000145
(1)化合物136的合成：按实施例88的方法，采用常规化学手段制备化合物136。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝7.2Hz,2H),3.73(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.86(d,J＝7.6Hz,2H),2.76(d,J＝7.6Hz,2H),2.49-2.35(m,2H),2.44(t,J＝7.2Hz,2H),2.26-2.17(m,2H).MS(ESI):[M+Na]661.2745.
(2)组分A-101的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物136(132mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-101(1.77g)，根据核磁氢谱图，可计算出化合物136的标记率大约为3.21％。
实施例一百零二：组分A-102的合成
Figure PCTCN2018080170-appb-000146
组分A-102的合成：将透明质酸Hyaluronic acid(2g，340kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取cNB混合物(化合物123/化合物136，60mg，质量比1:1)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-102(1.89g)，根据核磁氢谱图，可计算出cNB混合物(化合物123/化合物136)的标记率大约为3.52％。
实施例一百零三：组分A-103的合成
Figure PCTCN2018080170-appb-000147
组分A-103的合成：将羧甲基纤维素Carboxymethyl cellulose(2g，90kDa)溶于100mL 0.01mol/L 2-(N-吗啉)乙磺酸MES缓冲溶液(pH＝5.2)，搅拌至完全溶解，称取化合物123(115mg，0.2mmol)溶于10mL二甲基亚砜DMSO后加入上述反应液，称取4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐DMTMM(0.4g，1.5mmol)溶于3mL MES缓冲溶液，分三次(每隔1h)加入上述反应液中，35℃下反应24h。然后将反应液倒入透析袋(MWCO 7000)中，用去离子水透析2-3d，冷冻干燥即可得到光敏羧甲基纤维素衍生物A-103(1.71g)，根据核磁氢谱图，可计算出化合物123的标记率大约为2.41％。
实施例一百零四：组分A-104的合成
Figure PCTCN2018080170-appb-000148
(1)化合物137的合成：按实施例88的方法，采用常规化学手段制备化合物137。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.42(m,1H),3.97(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),2.49-2.35(m,2H).MS(ESI):[M+Na]533.1845.
(2)组分A-104的合成：将1g壳聚糖加入到75mL异丙醇中形成壳聚糖的悬浮液，然后将化合物137(0.2g，0.35mmol)、EDC-HCl(0.76g，3.96mmol)和NHS(0.46g，4.0mmol)依次加入到上述溶液中，室温下搅拌反应48h。反应结束后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到光敏壳聚糖衍生物A-104(0.82g)，根据其核磁氢谱图，可以计算出化合物137的修饰度大约为12.5％。
实施例一百零五：组分A-105的合成
Figure PCTCN2018080170-appb-000149
(1)化合物138的合成：按实施例88的方法，采用常规化学手段制备化合物138。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.93(s,3H),3.72(d,J＝6.3Hz,2H),3.62-3.55(m,2H),3.52-3.39(m,16H),3.04(t,J＝7.2Hz,2H),2.49-2.35(m,2H).MS(ESI):[M+Na]640.1134.
(2)组分A-105的合成：将PEG-4OH(1g，0.05mmol)溶于无水乙腈中，加入K 2CO 3(55.3mg，0.4mmol)搅拌30min后，加入化合物138(0.23g，0.4mmol)于室温下继续反应24h。反应结束后，将大部分溶剂除掉，在乙醚中重沉淀，并多次洗涤，抽滤烘干后即可得到光敏聚乙二醇衍生物A-105(0.85g)，根据核磁氢谱图，可计算出化合物138的修饰度大约为95.3％。
实施例一百零六：组分A-106的合成
Figure PCTCN2018080170-appb-000150
(1)化合物139的合成：按实施例88的方法，采用常规化学手段制备化合物139。 1H NMR(400MHz,DMSO):δ＝7.71(s,1H),7.17(s,1H),6.25(s,1H),5.68(s,1H),4.76(s,2H),4.42(m,1H),4.13(t,J＝6.1Hz,2H),3.93(s,3H),3.79(t,J＝6.1Hz,2H),3.72(d,J＝6.3Hz,2H),3.70(t,J＝7.2Hz,2H),3.62-3.55(m,2H),3.56(t,J＝7.2Hz,2H),3.52-3.39(m,16H),2.49-2.35(m,2H),1.87(s,3H).MS(ESI):[M+Na]689.2523.
(2)组分A-106的合成：称取化合物139(0.28g，0.63mmol)、共单体PEG-MA(0.882g，2.52mmol)和引发剂偶氮二异丁腈(11mg)加入到史莱克管中，并加入无水THF溶解，经过多次冷冻-抽真空循环操作处理后，将该反应体系于75℃条件下反应24h。反应结束后，将反应液倒入冷的乙醚中多次重沉淀纯化，即可得到光敏共聚物衍生物A-106(0.85g)。根据核磁氢谱图，可计算出化合物139在共聚物中的含量大约为15.4％。根据GPC测得合成高分子的分子量在25kDa左右，根据投料比计算可得n为12，x为10，y为40。
实施例一百零七：组分A-107的合成
Figure PCTCN2018080170-appb-000151
组分A-107的合成：将透明质酸Hyaluronic acid(1g，48kDa)溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏透明质酸衍生物A-107(0.92g)，根据核磁氢谱图，可计算出双键的含量大约为54％。
实施例一百零八：组分A-108的合成
Figure PCTCN2018080170-appb-000152
组分A-108的合成：将羧甲基纤维素Carboxymethyl cellulose(1g，90kDa)溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏羧甲基纤维素衍生物A-108(0.89g)，根据核磁氢谱图，可计算出双键的含量大约为43％。
实施例一百零九：组分A-109的合成
Figure PCTCN2018080170-appb-000153
组分A-109的合成：将海藻酸Alginate(1g，48kDa)溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏海藻酸衍生物A-109(0.87g)，根据核磁氢谱图，可计算出双键的含量大约为57％。
实施例一百十：组分A-110的合成
Figure PCTCN2018080170-appb-000154
组分A-110的合成：将硫酸软骨素Chondroitin sulfate(1g)溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏硫酸软骨素衍生物A-110(0.91g)，根据核磁氢谱图，可计算出双键的含量大约为49％。
实施例一百十一：组分A-111的合成
Figure PCTCN2018080170-appb-000155
组分A-111的合成：将葡聚糖Dextran(6g，70kDa)溶于60mL无水二甲基亚砜DMSO中，加入2mL三乙胺TEA，再加入0.56mL丙烯酰氯(溶于10mL二氯甲烷DCM中)，反应10h，反应结束后，将反应液倒入乙醇中重沉淀，过滤得到的粗产物重新溶于去离子水中，透析2-3d，冷冻干燥即可得到光敏葡聚糖衍生物A-111(5.8g)，根据核磁氢谱图，可计算出双键的含量大约为24％。
实施例一百十二：组分A-112的合成
Figure PCTCN2018080170-appb-000156
组分A-112的合成：将羧甲基壳聚糖Carboxymethylchitosan(1g)溶于100mL去离子水，加热至40℃搅拌溶解，加入4mL甲基丙烯酸缩水甘油酯，再加入2mL 5M NaOH，反应2-3h后，将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏壳聚糖衍生物A-112(0.88g)，根据核磁氢谱图，可计算出双键的含量大约为32％。
实施例一百十三：组分A-113的合成
Figure PCTCN2018080170-appb-000157
组分A-113的合成：将明胶Gelatin(1g)溶于10mL D-PBS中，加热至50℃搅拌至完全溶解，加入0.5mL甲基丙烯酸酐，反应2-3h，反应后用40mL D-PBS稀释反应液，然后倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏明胶衍生物A-113(0.93g)，根据核磁氢谱图，可计算出双键的含量大约为56％。
实施例一百十四：组分A-114的合成
Figure PCTCN2018080170-appb-000158
组分A-114的合成：将两臂羟基聚乙二醇PEG(10kDa，10g)溶于干燥的二氯甲烷中，加入三乙胺(0.28mL，2mmol)，再缓慢滴加丙烯酰氯(0.18g，2mmol)的二氯甲烷溶液于上述溶液中，搅拌反应12h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏聚乙二醇衍生物A-114(9.8g)，根据核磁氢谱图，可计算出双键的含量大约为98％。
实施例一百十五：组分A-115的合成
Figure PCTCN2018080170-appb-000159
组分A-115的合成：将四臂羟基聚乙二醇PEG(10kDa，10g)溶于干燥的二氯甲烷中，加入三乙胺(0.56mL，4mmol)，再缓慢滴加丙烯酰氯(0.36g，4mmol)的二氯甲烷溶液于上述溶液中，搅拌反应12h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到光敏聚乙二醇衍生物A-115(9.3g)，根据核磁氢谱图，可计算出双键的含量大约为96％。
实施例一百十六：组分A-116的合成
Figure PCTCN2018080170-appb-000160
组分A-116的合成：将组分A-1溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-116(0.91g)，根据核磁氢谱图，可计算出双键的含量大约为54％。
实施例一百十七：组分A-117的合成
Figure PCTCN2018080170-appb-000161
组分A-117的合成：将组分A-2溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-117(0.87g)，根据核磁氢谱图，可计算出双键的含量大约为51％。
实施例一百十八：组分A-118的合成
Figure PCTCN2018080170-appb-000162
组分A-118的合成：将组分A-8溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-118(0.86g)，根据核磁氢谱图，可计算出双键的含量大约为44％。
实施例一百十九：组分A-119的合成
Figure PCTCN2018080170-appb-000163
组分A-119的合成：将组分A-28溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-119(0.85g)，根据核磁氢谱图，可计算出双键的含量大约为43％。
实施例一百二十：组分A-120的合成
Figure PCTCN2018080170-appb-000164
组分A-120的合成：将组分A-29溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-120(0.93g)，根据核磁氢谱图，可计算出双键的含量大约为55％。
实施例一百二十一：组分A-121的合成
Figure PCTCN2018080170-appb-000165
组分A-121的合成：将组分A-30溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-121(0.85g)，根据核磁氢谱图，可计算出双键的含量大约为49％。
实施例一百二十二：组分A-122的合成
Figure PCTCN2018080170-appb-000166
组分A-122的合成：将组分A-37溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏羧甲基纤维素衍生物A-122(0.91g)，根据核磁氢谱图，可计算出双键的含量大约为42％。
实施例一百二十三：组分A-123的合成
Figure PCTCN2018080170-appb-000167
组分A-123的合成：将组分A-43溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏壳聚糖衍生物A-123(0.84g)，根据核磁氢谱图，可计算出双键的含量大约为56％。
实施例一百二十四：组分A-124的合成
Figure PCTCN2018080170-appb-000168
组分A-124的合成：将组分A-45溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO  3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏明胶衍生物A-124(0.92g)，根据核磁氢谱图，可计算出双键的含量大约为48％。
实施例一百二十五：组分A-125的合成
Figure PCTCN2018080170-appb-000169
组分A-125的合成：将组分A-49溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏聚乙二醇衍生物A-125(0.94g)，根据核磁氢谱图，可计算出双键的含量大约为24％。
实施例一百二十六：组分A-126的合成
组分A-126的合成：将组分A-51溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-126(0.87g)，根据核磁氢谱图，可计算出双键的含量大约为46％。
实施例一百二十七：组分A-127的合成
Figure PCTCN2018080170-appb-000171
组分A-127的合成：将组分A-52溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-127(0.85g)，根据核磁氢谱图，可计算出双键的含量大约为57％。
实施例一百二十八：组分A-128的合成
Figure PCTCN2018080170-appb-000172
组分A-128的合成：将组分A-53溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-128(0.93g)，根据核磁氢谱图，可计算出双键的含量大约为47％。
实施例一百二十九：组分A-129的合成
Figure PCTCN2018080170-appb-000173
组分A-129的合成：将组分A-62溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-129(0.90g)，根据核磁氢谱图，可计算出双键的含量大约为58％。
实施例一百三十：组分A-130的合成
Figure PCTCN2018080170-appb-000174
组分A-130的合成：将组分A-63溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-130(0.89g)，根据核磁氢谱图，可计算出双键的含量大约为46％。
实施例一百三十一：组分A-131的合成
Figure PCTCN2018080170-appb-000175
组分A-131的合成：将组分A-64溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-131(0.87g)，根据核磁氢谱图，可计算出双键的含量大约为58％。
实施例一百三十二：组分A-132的合成
Figure PCTCN2018080170-appb-000176
组分A-132的合成：将组分A-66溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏羧甲基纤维素衍生物A-132(0.92g)，根据核磁氢谱图，可计算出双键的含量大约为46％。
实施例一百三十三：组分A-133的合成
Figure PCTCN2018080170-appb-000177
组分A-133的合成：将组分A-67溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏壳聚糖衍生物A-133(0.91g)，根据核磁氢谱图，可计算出双键的含量大约为47％。
实施例一百三十四：组分A-134的合成
Figure PCTCN2018080170-appb-000178
组分A-134的合成：将组分A-68溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏聚乙二醇衍生物A-134(0.87g)，根据核磁氢谱图，可计算出双键的含量大约为52％。
实施例一百三十五：组分A-135的合成
Figure PCTCN2018080170-appb-000179
组分A-135的合成：将组分A-70溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-135(0.92g)，根据核磁氢谱图，可计算出双键的含量大约为47％。
实施例一百三十六：组分A-136的合成
Figure PCTCN2018080170-appb-000180
组分A-136的合成：将组分A-71溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-136(0.86g)，根据核磁氢谱图，可计算出双键的含量大约为51％。
实施例一百三十七：组分A-137的合成
Figure PCTCN2018080170-appb-000181
组分A-137的合成：将组分A-72溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-137(0.93g)，根据核磁氢谱图，可计算出双键的含量大约为45％。
实施例一百三十八：组分A-138的合成
Figure PCTCN2018080170-appb-000182
组分A-138的合成：将组分A-80溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-138(0.90g)，根据核磁氢谱图，可计算出双键的含量大约为48％。
实施例一百三十九：组分A-139的合成
Figure PCTCN2018080170-appb-000183
组分A-139的合成：将组分A-81溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-139(0.88g)，根据核磁氢谱图，可计算出双键的含量大约为46％。
实施例一百四十：组分A-140的合成
Figure PCTCN2018080170-appb-000184
组分A-140的合成：将组分A-82溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-140(0.91g)，根据核磁氢谱图，可计算出双键的含量大约为57％。
实施例一百四十一：组分A-141的合成
Figure PCTCN2018080170-appb-000185
组分A-141的合成：将组分A-84溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏羧甲基纤维素衍生物A-141(0.92g)，根据核磁氢谱图，可计算出双键的含量大约为44％。
实施例一百四十二：组分A-142的合成
Figure PCTCN2018080170-appb-000186
组分A-142的合成：将组分A-85溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏壳聚糖衍生物A-142(0.87g)，根据核磁氢谱图，可计算出双键的含量大约为56％。
实施例一百四十三：组分A-143的合成
Figure PCTCN2018080170-appb-000187
组分A-143的合成：将组分A-86溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏聚乙二醇衍生物A-143(0.91g)，根据核磁氢谱图，可计算出双键的含量大约为48％。
实施例一百四十四：组分A-144的合成
Figure PCTCN2018080170-appb-000188
组分A-144的合成：将组分A-88溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-144(0.89g)，根据核磁氢谱图，可计算出双键的含量大约为52％。
实施例一百四十五：组分A-145的合成
Figure PCTCN2018080170-appb-000189
组分A-145的合成：将组分A-89溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的 光敏透明质酸衍生物A-145(0.81g)，根据核磁氢谱图，可计算出双键的含量大约为43％。
实施例一百四十六：组分A-146的合成
Figure PCTCN2018080170-appb-000190
组分A-146的合成：将组分A-90溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-146(0.84g)，根据核磁氢谱图，可计算出双键的含量大约为49％。
实施例一百四十七：组分A-147的合成
Figure PCTCN2018080170-appb-000191
组分A-147的合成：将组分A-91溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-147(0.92g)，根据核磁氢谱图，可计算出双键的含量大约为46％。
实施例一百四十八：组分A-148的合成
Figure PCTCN2018080170-appb-000192
组分A-148的合成：将组分A-98溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-148(0.94g)，根据核磁氢谱图，可计算出双键的含量大约为56％。
实施例一百四十九：组分A-149的合成
Figure PCTCN2018080170-appb-000193
组分A-149的合成：将组分A-99溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-149(0.87g)，根据核磁氢谱图，可计算出双键的含量大约为51％。
实施例一百五十：组分A-150的合成
Figure PCTCN2018080170-appb-000194
组分A-150的合成：将组分A-100溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-150(0.88g)，根据核磁氢谱图，可计算出双键的含量大约为47％。
实施例一百五十一：组分A-151的合成
Figure PCTCN2018080170-appb-000195
组分A-151的合成：将组分A-101溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏透明质酸衍生物A-151(0.91g)，根据核磁氢谱图，可计算出双键的含量大约为45％。
实施例一百五十二：组分A-152的合成
Figure PCTCN2018080170-appb-000196
组分A-152的合成：将组分A-103溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏羧甲基纤维素衍生物A-152(0.84g)，根据核磁氢谱图，可计算出双键的含量大约为43％。
实施例一百五十三：组分A-153的合成
Figure PCTCN2018080170-appb-000197
组分A-153的合成：将组分A-104溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏壳聚糖衍生物A-153(0.89g)，根据核磁氢谱图，可计算出双键的含量大约为50％。
实施例一百五十四：组分A-154的合成
Figure PCTCN2018080170-appb-000198
组分A-154的合成：将组分A-105溶于100mL去离子水，冷却至0-4℃，加入4mL甲基丙烯酸酐，再缓慢滴加2mL 5M NaOH，反应24h，然后将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到既含邻硝基苄基又含双键官能团的光敏聚乙二醇衍生物A-154(0.94g)，根据核磁氢谱图，可计算出双键的含量大约为43％。
实施例一百五十五：光引发剂-LAP的合成
Figure PCTCN2018080170-appb-000199
LAP的合成：将二甲氧基苯膦(3.0g，0.018mol)置于250mL三口烧瓶中，氩气保护，加入2,4,6-三甲基苯甲酰氯(3.2g，0.018mol)，室温下搅拌反应18h，然后将溴化锂(6.1g，0.072mol)溶于100mL2-丁酮中，加入上述反应液中，加热至50℃反应10min后，有沉淀生成，冷却至室温静置4h后，过滤，得到的粗产物用2-丁酮多次洗涤，干燥后即可得白色固体LAP(6.0g)。
实施例一百五十六：组分C-10的合成
Figure PCTCN2018080170-appb-000200
组分C-10的合成：将羧甲基纤维素CMC(400mg)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，153mg)、二联胺(90mg)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，90mg)加入到上述溶液中室温反应48h后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到联胺修饰的羧甲基纤维素(410mg)。TBNS方法测试联胺的接枝率约为10％。
实施例一百五十七：组分C-11的合成
Figure PCTCN2018080170-appb-000201
组分C-11的合成：将透明质酸HA(400mg)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，153mg)、碳二酰肼(CDH，90mg)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，90mg)加入到上述溶液中室温反应48h后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到HA-CDH(410mg)。TBNS方法测试酰肼的接枝率约为10％。
实施例一百五十八：组分C-12的合成
Figure PCTCN2018080170-appb-000202
组分C-12的合成：将透明质酸HA(400mg)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，153mg)、草酸二酰肼(ODH，90mg)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，90mg)加入到上述溶液中室温反应48h后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到HA-ODH(410mg)。TBNS方法测试酰肼的接枝率约为10％。
实施例一百五十九：组分C-13的合成
Figure PCTCN2018080170-appb-000203
组分C-13的合成：将透明质酸HA(400mg)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，153mg)、己二酸二酰肼(ADH，90mg)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，90mg)加入到上述溶液中室温反应48h后，先用含氯化钠的稀盐酸溶液(pH＝3.5)透析1d，再用纯水透析1d后，冷冻干燥即可得到HA-ADH(410mg)。TBNS方法测试酰肼的接枝率约为10％。
实施例一百六十：组分C-14的合成
Figure PCTCN2018080170-appb-000204
组分C-14的合成：称取四臂羟基聚乙二醇(PEG-4OH，2g，97.3μmol)和N-羟基邻苯二甲酰亚胺(634.6mg，3.89mmol)溶于干燥的二氯甲烷中，然后在冰浴条件下慢慢加入三苯基膦(1.02g，3.89mmol)并反应约30min。将偶氮二羧酸二异丙酯(765.9μL，3.89mmol)溶于干燥的二氯甲烷中慢慢滴加到上述溶液中并在室温下反应1d。反应结束后，将N-羟基邻苯二甲酰亚胺修饰的四臂聚乙二醇用乙醚重沉淀。然后将上述物质(0.25g，11.8μmol)重新溶解于乙腈中，加入一水合肼(22.9μL，473μmol)继续搅拌2h。然后向该混合物溶液中加入二氯甲烷并抽滤。将滤液减压旋蒸除掉溶剂，即可得到羟胺修饰的四臂聚乙二醇(PEG-4ONH 2)。
实施例一百六十一：组分C-15的合成
Figure PCTCN2018080170-appb-000205
组分C-15的合成：称取葡聚糖(Dextran，2g，97.3μmol)和N-羟基邻苯二甲酰亚胺(634.6mg，3.89mmol)溶于干燥的二氯甲烷中，然后在冰浴条件下慢慢加入三苯基膦(1.02g，3.89mmol)并反应约30min。将偶氮二羧酸二异丙酯(765.9μL，3.89mmol)溶于干燥的二氯甲烷中慢慢滴加到上述溶液中并在室温下反应1d。反应结束后，将N-羟基邻苯二甲酰亚胺修饰的葡聚糖用乙醚重沉淀。然后将上述物质(0.25g，11.8μmol)重新溶解于乙腈中，加入一水合肼(22.9μL，473μmol)继续搅拌2h。然后向该混合物 溶液中加入二氯甲烷并抽滤。将滤液减压旋蒸除掉溶剂，即可得到羟胺修饰的葡聚糖(Dex-ONH 2)。
实施例一百六十二：组分C-18的合成
Figure PCTCN2018080170-appb-000206
组分C-18的合成：将透明质酸Hyaluronic acid(0.5g，48kDa)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，0.2g)，1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，0.1g),3,3’-二硫代双(丙酰肼)(DTP，0.1g)，用稀盐酸溶液调节PH至4.75，反应24h，然后加入DTT继续反应5h后，将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到HA-SH(0.45g)，根据核磁氢谱图，可计算出巯基的含量大约为20％。
实施例一百六十三：组分C-19的合成
Figure PCTCN2018080170-appb-000207
组分C-19的合成：将羧甲基壳聚糖Carboxymethyl chitosan(1g)溶于100mL去离子水，加入N-乙酰基半胱氨酸(1.77g，10mmol)，再加入1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐EDC-HCl(1.91g，10mmol)，然后用盐酸调节PH至5左右，室温下搅拌反应5h，然后将反应液倒入透析袋(MWCO 3500)中，用5mM HCl溶液透析1d，然后用5mM HCl/1％NaCl溶液透析1d，最后用1mM HCl溶液透析1d，冷冻干燥即可得到CMCh-SH(0.9g)，根据核磁氢谱图，可计算出巯基的含量大约为10％。
实施例一百六十四：组分C-20的合成
Figure PCTCN2018080170-appb-000208
组分C-20的合成：将40kDa葡聚糖Dextran(12g，0.3mmol)溶于50mL DMSO中至完全溶解，加入3-巯基丙酸(636.8mg，6.0mmol)，1,3-二环己基碳二亚胺(910.7mg，9.0mmol),4-(二甲胺基)吡啶(1099.5mg，9.0mmol)，于室温下反应48h，然后在丙酮中重沉淀，将粗产物溶于水后倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到Dex-SH(11.5g)，根据核磁氢谱图，可计算出巯基的含量大约为20％。
实施例一百六十五：组分C-21的合成
Figure PCTCN2018080170-appb-000209
组分C-21的合成：将肝素Heparin(0.5g，12kDa)溶于50mL蒸馏水中至完全溶解，加入羟基苯并三唑(HOBt，0.2g)，1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDC-HCl，0.1g)，巯基乙胺(0.1g)，用稀盐酸溶液调节PH至5-6，反应24h后，将反应液倒入透析袋(MWCO 3500)中，用去离子水透析2-3d，冷冻干燥即可得到Hep-SH(0.45g)，根据核磁氢谱图，可计算出巯基的含量大约为20％。
实施例一百六十六：光交联方法制备水凝胶
按照本发明方法，于37℃下操作，制得不同的水凝胶前体溶液，如表1所示。
表1
Figure PCTCN2018080170-appb-000210
将上述不同凝胶溶液分别在365或395nm(20mW/cm 2)条件下照射一定时间，即可得到不同化学组成的水凝胶。不同的凝胶材料具有不同的生物效应，可以根据不同的应用针对性地选择凝胶材料的组成。
注：组分A…为组分A-2～A-153；组分A……为组分A-1～A-154；组分C…为组分C-1～C-21。
表1中1-20wt％为水凝胶前体溶液优选的质量浓度范围。
实施例一百六十七：光交联水凝胶流变测试
流变分析采用HAAKE MARS流变仪，在37℃的测试平台(φ＝20mm)上进行流变测试。本实例研究了紫外光照时间、光照强度和高分子衍生物的质量浓度对水凝胶成胶时间和储存模量的影响。图1为实施例一制备的组分A-1(即为HA-NB)、实施例一百零七制备的组分A-107(即为HAMA)、组分C-4(即为明胶)、实施例一百五十五制备的组分B-2(即为LAP)；实施例八十八制备的组分A-88(即为HA-cNB)、实施例一百四十四制备的组分A-144(即为HA-cNB-MA)、实施例一百五十五制备的组分B-2(即为LAP)配制的水凝胶前体溶液在光照下的成胶曲线(流变测试中，G’为储存模量，G”为损耗模量，当G’超过G”时即为凝胶点)，因此，无论在成胶速度，还是在凝胶强度上都明显优于单纯的自由基聚合交联和光偶合交联构筑的水凝胶性能。从图1中看出，该溶液在约2s时开始成胶，直至10s左右完全成胶，且完全成胶时的模量可以达到3500-10000Pa。此外，凝胶的强度与凝胶溶液的质量浓度成正比，凝胶的质量浓度越大，所成凝胶的强度越大。其它不同材料组成的水凝胶体系的凝胶点和凝胶强度也有所不同，具体数据如表2所示。
表2
Figure PCTCN2018080170-appb-000211
Figure PCTCN2018080170-appb-000212
Figure PCTCN2018080170-appb-000213
Figure PCTCN2018080170-appb-000214
注：NB 0为文献报道的用于构筑水凝胶的邻硝基苄基类光扳机(Yunlong Yang；Jieyuan Zhang；Zhenzhen Liu；Qiuning Lin；Xiaolin Liu；Chunyan Bao；Yang Wang；Linyong Zhu.Adv.Mater.2016,28,2724.)。HA-NB 0即为NB 0标记的透明质酸高分子衍生物。NB为本发明组分A-1中的邻硝基苄基类光扳机；cNB为本发明组分A-88中的环状邻硝基苄基类光扳机；cNB-MA为本发明组分A-144中的既含环状邻硝基苄基类光扳机又含双键官能团。 其中，HA-NB即为组分A-1；HA-cNB即为组分A-88；HA-cNB-MA即为组分A-144。
实施例一百六十八：光交联水凝胶粘附力测试
取新鲜猪肠衣若干，将其裁剪成3.5cm×2.5cm大小的肠衣片。然后利用502胶水将其固定在6.5cm×2.5cm大小的钢化玻璃片上。取上述钢化玻璃片，在其中一片粘结肠衣面上涂抹150μL的一定组分的水凝胶前体溶液。然后，将另一片玻璃片置于此片玻璃片上方，使上下两片粘附肠衣的位置完全相对。此时，擦去多余的被挤出的水凝胶前体溶液。然后利用395nm LED光源(20mW/cm 2)对肠衣部位进行光照5min，使水凝胶前体溶液在两片肠衣之间原位成胶。成胶完全后，将玻璃片的一端垂直固定，另一端通过细绳连接上能够盛水的容器。随后不断向容器中加入定量水，直到两片玻璃片断开为止。其后，记录下此时水和容器的质量，将其转化成重力也就是玻璃片断裂时的拉力F，利用以下公式计算水凝胶的组织黏附力：
水凝胶组织黏附力＝F/A
其中A为肠衣的粘接面积，测试装置示意图如图2所示。其它不同材料组成的水凝胶体系的组织粘附力也有所不同，具体数据如表3所示。
表3
Figure PCTCN2018080170-appb-000215
Figure PCTCN2018080170-appb-000216
Figure PCTCN2018080170-appb-000217
Figure PCTCN2018080170-appb-000218
实施例一百六十九：光交联水凝胶力学性能测试
力学性能测试(包括拉伸测试和压缩测试)采用GT-TCS-2000拉力机，拉伸测试样品为长20mm，宽3mm，厚2mm的哑铃型试样，测试速度为5mm/min，压缩测试样品为直径10mm，高3mm的圆柱形试样，测试速度为1mm/min，以实施例一制备的组分A-1(即为HA-NB)、实施例一百零七制备的组分A-107(即为HAMA)、组分C-4(即为明胶)、实施例一百五十五制备的组分B-2(即为LAP)；实施例八十八制备的组分A-88(即为HA-cNB)、实施例一百四十四制备的组分A-144(即为HA-cNB-MA)、实施例一百五十五制备的组分B-2(即为LAP)为例，测试该水凝胶的拉伸性能和压缩性能。从图3中看出，水凝胶(HA-NB/HAMA/Gelatin/LAP)能够被压缩到75％左右，压缩强度为2MPa左右；水凝胶(HA-cNB/HA-cNB-MA/LAP)能够被压缩到88％左右，压缩强度为1MPa左右。其它不同材料组成的水凝胶体系的力学性能也有所不同，具体数据如表4所示。
表4
Figure PCTCN2018080170-appb-000219
Figure PCTCN2018080170-appb-000220
Figure PCTCN2018080170-appb-000221
Figure PCTCN2018080170-appb-000222
实施例一百七十：光交联水凝胶生物相容性测试
在本实验中，以实施例一制备的组分A-1(即为HA-NB)、实施例一百零七制备的组分A-107(即为HAMA)、组分C-4(即为明胶)、实施例一百五十五制备的组分B-2(即为LAP)；实施例八十八制备的组分A-88(即为HA-cNB)、实施例一百四十四制备的组分A-144(即为HA-cNB-MA)、实施例一百五十五制备的组分B-2(即为LAP)为例，通过CCK-8试剂盒进行评价。首先，在96孔板中种植成纤维细胞HDFs，细胞密度为5×10 3 细胞/孔，然后加入培养基，在37℃/5％CO 2条件下培养24h。将各组测试样品溶解于细胞培养液中，加入到培养有细胞的孔板中，继续培养24h，然后将孔中的细胞液吸出，向每个孔中加入100μL的培养基和10μL的CCK-8溶液，继续孵育细胞2h。最后，用酶标仪检测每个孔中450nm的吸光度。细胞存活率计算如下：
Cell Viability(％)＝(实验组吸光度的平均值/控制组吸光度的平均值)×100％
从图4中看出，该类光交联水凝胶具有较好的生物相容性。
体内免疫炎症反应测试中，以实施例一制备的组分A-1(即为HA-NB)、实施例一百零七制备的组分A-107(即为HAMA)、组分C-4(即为明胶)、实施例一百五十五制备的组分B-2(即为LAP)；实施例八十八制备的组分A-88(即为HA-cNB)、实施例一百四十四制备的组分A-144(即为HA-cNB-MA)、实施例一百五十五制备的组分B-2(即为LAP)为例，将水凝胶植入兔子皮下，选取不同时间点分别通过组织切片染色分析该类水凝胶对机体产生的炎症反应。
其它不同材料组成的水凝胶体系的生物相容性也有所不同，具体数据如表5所示。
表5
Figure PCTCN2018080170-appb-000223
Figure PCTCN2018080170-appb-000224
以上不同组分的水凝胶材料中组分A与组分B关系均为2％wt：0.2％wt。组分A与组分B与组分C关系均为2％wt：0.2％wt：2％wt。
实施例一百七十一：光交联水凝胶应用于创面封闭-皮肤修复
实验中，在SD大鼠背部皮肤构造直径1.8cm的皮肤完全缺损伤口。然后将400μL水凝胶前体溶液(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)填充到伤口部位。由于该溶液具有良好的流动性，伤口可以被水凝胶前体溶液充分填充和渗透。然 后，在395nm LED光源照射下，在皮肤缺损处原位制备了水凝胶，实现了对创面的封闭(如图5所示)。接下来，对比了原位成型的水凝胶，预先成型的水凝胶和仅用生理盐水清洗处理的SD大鼠背部皮肤伤口在7天内的修复效果。原位成型的水凝胶伤口修复速率要明显快于其他两组，7d时伤口收缩的面积最大，起到了良好的修复效果。而预先成型的水凝胶材料难以充分的填充伤口部位；另外，同组织间不具有共价连接的无缝界面，缺乏良好的组织整合性。新生细胞和组织难以快速的进入到水凝胶材料中，使其充分发挥支架材料的作用。因此，预先成型的水凝胶修复速率和效果要差于原位成型的水凝胶。没有水凝胶填充的伤口修复速率最慢，说明了该光交联水凝胶作为细胞支架材料对伤口修复具有促进作用。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于创面封闭-皮肤修复。
实施例一百七十二：光交联水凝胶应用于创面封闭-术后防黏连
实验中，采用SD大鼠构建腹壁-盲肠刮擦的腹腔黏连模型。由于盲肠是腹腔内最粗、通路最多，血管分布最丰富的肠段，当其对应的腹壁同时发生损伤并且不采取措施的前提下发生腹腔黏连的概率极大，构造的黏连模型稳定。在手术过程中，水凝胶前体溶液(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)可以充分的覆盖盲肠和腹壁的伤口，并且在垂直的组织面上有充足的驻留时间至其光照成胶。在给予30s光照后，得到的水凝胶固定在了创伤部位，利用外科手术刀片对其施加一定的力的情况下并不能将该水凝胶从创伤部位剥离。上述从水凝胶前体溶液的给予到完全成胶的过程在1min内可以结束(如图6所示)。手术后，在无菌的环境下饲养上述SD大鼠14天。14d后，再次打开SD大鼠的腹腔，对其腹腔黏连情况进行了记录。在水凝胶处理的实验组的10只大鼠中，有8只大鼠14d后没有出现任何的肠-腹壁，肠-肠之间的黏连；1只大鼠出现了中等程度的腹壁与盲肠之间的黏连；1只大鼠出现了肠与肠之间一点薄层黏连。另外，上述9只没有发生肠-腹壁黏连的SD大鼠中看不见任何的水凝胶残留，腹壁上的伤口完全愈合。对照组的10只大鼠都发生了严重的腹壁和盲肠的黏连。接下来对实验组和对照组手术中伤口部位的组织切片通过H&E染色的方式进行了组织学分析。实验组中的SD大鼠14d后盲肠和腹壁的损伤基本完全恢复，表层已经再上皮化。而对照组中的SD大鼠14d后盲肠的平滑肌同腹壁的肌肉组织完全融合，成纤维细胞和炎症细胞在黏连处沉积。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于创面封闭-术后防黏连。
实施例一百七十三：光交联水凝胶应用于创面封闭-口腔溃疡
实验中，在SD大鼠口腔构造直径1.0cm的口腔溃疡缺损伤口。然后将200μL水凝胶前体溶液(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)填充到伤口部位。由于该溶液具有良好的流动性，伤口可以被水凝胶前体溶液充分填充和渗透。然后，在395nm LED光源照射下，在口腔缺损处原位制备了水凝胶，实现了对口腔创面的封闭。接下来，对比了原位成型的水凝胶，预先成型的水凝胶和仅用生理盐水清洗处理的SD大鼠口腔伤口在7天内的修复效果。原位成型的水凝胶伤口修复速率要明显快于其他两组，7d时伤口收缩的面积最大，起到了良好的修复效果。而预先成型的水凝胶材料难以充分的填充伤口部位；另外，同组织间不具有共价连接的无缝界面，缺乏良好的组织整合性。新生细胞和组织难以快速的进入到水凝胶材料中，使其充分发挥支架材料的作用。因此，预先成型的水凝胶修复速率和效果要差于原位成型的水凝胶。没有水凝胶填充的伤口修复速率最慢，说明了该光交联水凝胶作为细胞支架材料对口腔溃疡修复具有促进作用。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于创面封闭-口腔溃疡。
实施例一百七十四：光交联水凝胶应用于组织渗液封堵-肠漏封堵
采用新西兰雄性大白兔，分为两组进行盲肠渗漏封堵实验：a：水凝胶处理(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组；b：不做处理的对照组。实验中，在兔子盲肠处制造渗漏的模型，然后将水凝胶前体溶液涂抹到伤口处，待充分渗透后光照原位成胶，成胶后水凝胶能牢固的黏附在缺损处，不需要额外的固定。在手术4周后，通过静脉注射空气的方法处死实验中的兔子，并提取盲肠对实验修复效果进行评价。结果显示，使用水凝胶封堵的盲肠没有发生渗漏的情况，而没用水凝胶处理的盲肠发生了严重的渗漏。经过几周的修复，原来盲肠有缺损的部位经水凝胶处理过后得到了明显的修复，因此，该水凝胶不仅能够有效封堵渗漏，还有利于术后受损组织的修复。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于组织渗液封堵-肠漏封堵。
实施例一百七十五：光交联水凝胶应用于组织渗液封堵-手术缝合
采用新西兰雄性大白兔，分为三组进行手术缝合实验：a：水凝胶处理(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组；b：手术缝合线处理组；c：不做处理的对照组。实验中，在兔子腹部制造伤口缝合的模型，a组是将水凝胶前体溶液涂抹到伤口处，待充分渗透后光照原位成胶，实现对伤口的封堵，由于该水凝胶优异的组织粘附力，能够起到组织缝合的效果；b组是用常规的手术缝合线处理伤口；c组是对伤口不做处理。在手术2周后，通过静脉注射空气的方法处死实验中的兔子，并取样对实验修复效果进行评价。结果显示，使用水凝胶处理的伤口有较好的缝合效果，基本与手术缝合线组的效果差不多，而不做处理的伤口不能有效连接到一起。经过4周的修复，原来伤口缺损部位经水凝胶处理过后组织能够连接到一起，并且得到了明显的修复，因此，该水凝胶不仅能够有效缝合伤口，还有利于术后受损组织的修复。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于组织渗液封堵-手术缝合。
实施例一百七十六：光交联水凝胶应用于止血材料-肝脏止血
采用SD大鼠，对水凝胶的止血效果进行评价，分为三组进行肝脏止血实验：a：明胶海绵组；b：水凝胶处理(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组；c阳性对照组。实验大鼠通过水合氯醛(4％水溶液)腹腔注射进行麻醉，注射计量为0.9ml/100g，深度麻醉后，用剃毛器将大鼠前胸部位毛剃光，碘酒消毒。然后沿着胸腔中线切开大约4cm长切口，打开胸腔，暴露肝脏部位。在肝脏左叶做一约2cm切口。a组用明胶海绵进行止血；b组在切口处加水凝胶前体溶液覆盖切面，395nm LED光照2min成胶止血；c组不做任何处理，让肝脏切口渗血自然凝固，用纱布吸去渗血，通过减重法记录出血量，和出血时间(如图7所示)。实验结束后，a组将粘附在切面的明胶海绵一并留在大鼠体内进行缝合。b组水凝胶在切口原位交联并将切面伤口隔离，将肝脏放回胸腔，缝合。c组不做处理直接缝合。14d后，观察SD大鼠肝脏恢复情况，通过腹腔注射过量麻醉剂水合氯醛(4％水溶液，2.7ml/100g)处死大鼠，沿胸腔中线打开胸腔，观察三组大鼠肝脏恢复情况，并拍照记录。同时对肝脏损伤部位组织取样，标本用4％福尔马林溶液固定2d，脱水处理后，石蜡包埋，在用切片机进行组织切片操作，样片厚度5μm。最后对标本进行H&E染色，用光学显微镜拍照观察记录。实验结果显示，b组肝脏恢复良好，水凝胶降解完全，未发生粘连，肝脏切口长出新生肝脏组织。a组大鼠体内明胶海绵仍未降解，并且大鼠普遍器脏与网膜粘连严重。c组普遍存在肝脏与网膜粘连的情况。H&E染色显示实验组肝脏表面光滑圆润，有丰富的血管分布，肝脏界面清晰。而发生粘连的肝脏经H&E染色发现肝脏界面凹凸不平，肝脏与网膜组织粘连在一起，界面处有沉积的炎症细胞。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于止血材料-肝脏止血。
实施例一百七十七：光交联水凝胶应用于止血材料-骨断面止血
采用新西兰雄性大白兔，分为三组进行骨断面止血实验：a：水凝胶处理(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组；b：骨蜡处理组；c：不做处理的对照组。实验中，在兔子股骨制造骨断面出血模型，a组是将水凝胶前体溶液涂抹到伤口处，待充分渗透后光照原位成胶，实现对骨断面出血的有效封堵，由于该水凝胶优异的组织粘附力及光固化速度，能够起到及时、有效的止血效果；b组是用常规的骨蜡处理出血伤口；c组是对出血伤口不做处理。在手术8周后，通过静脉注射空气的方法处死实验中的兔子，并取样对实验修复效果进行评价。结果显示，使用水凝胶处理的伤口有较好的止血效果，基本与骨蜡组的效果差不多，而不做处理的伤口会有持续的出血状况。经过2周的修复，原来伤口出血部位经水凝胶处理过后组织得到了明显的修复，而经骨蜡处理的伤口没有得到修复，主要是由于骨蜡在体内不降解，因此，该水凝胶不仅能够有效实现骨断面止血，还有利于术后受损组织的修复。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于止血材料-骨断面止血。
实施例一百七十八：光交联水凝胶应用于止血材料-动脉止血
采用新西兰雄性大白兔，分为三组进行动脉止血实验：a：水凝胶处理(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组；b：止血钳处理组；c：不做处理的对照组。实验中，在兔子股动脉制造出血模型，a组是将水凝胶前体溶液涂抹到伤口处，待充分渗透后光照原位成胶，实现对股动脉出血的有效封堵，由于该水凝胶优异的组织粘附力及光固化速度，能够起到及时、有效的止血效果；b组是用常规的止血钳处理出血伤口；c组是对出血伤口不做处理。在手术2周后，通过静脉注射空气的方法处死实验中的兔子，并取样对实验修复效果进行评价。结果显示，使用水凝胶处理的伤口有较好的止血效果，基本与止血钳的效果差不多，而不做处理的伤口会有持续的出血状况。经过2周的修复，原来伤口出血部位经水凝胶处理后组织得到了明显的修复，因此，该水凝胶不仅能够有效实现股动脉止血，还有利于术后受损组织的修复。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于止血材料-动脉止血。
实施例一百七十九：光交联水凝胶应用于止血材料-心脏止血
采用新西兰雄性大白兔，分为三组进行心脏止血实验：a：水凝胶处理(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组；b：明胶海绵处理组；c：不做处理的对照组。实验中，在兔子心脏制造出血模型，a组是将水凝胶前体溶液涂抹到伤口处，待充分渗透后光照原位成胶，实现对心脏出血的有效封堵，由于该水凝胶优异的组织粘附力及光固化速度，能够起到及时、有效的止血效果；b组是用常规的明胶海绵处理出血伤口；c组是对出血伤口不做处理。在手术2周后，通过静脉注射空气的方法处死实验中的兔子，并取样对实验修复效果进行评价。结果显示，使用水凝胶处理的伤口有较好的止血效果，要比明胶海绵的止血效果好，而不做处理的伤口会有持续的出血状况。经过2周的修复，原来伤口出血部位经水凝胶处理后组织得到了明显的修复，并且修复效果比明胶海绵好，因此，该水凝胶不仅能够有效实现心脏止血，还有利于术后受损组织的修复。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于止血材料-心脏止血。
实施例一百八十：光交联水凝胶应用于组织工程支架材料-软骨修复
采用新西兰雄性大白兔，分为三组进行关节软骨的修复实验：a：包裹有软骨细胞的水凝胶(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组，即Gel+软骨细胞组；b：单纯的水凝胶(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组，即Gel组；c：不做处理的对照组，即Control组。在实验中，该水凝胶前体溶液可以充分 的渗透并且填充兔子关节软骨的缺损处，光照成胶后牢固的黏附在缺损处，不需要额外的固定。在手术12周后，通过静脉注射空气的方法处死实验中的兔子，并提取损伤关节对实验修复效果进行评价。兔子关节软骨损伤处大体观照片结果显示，12周后Gel+软骨细胞组在关节缺损处长出了光滑的新生软骨组织，同时和旧的软骨组织进行了良好的整合；在Gel组中软骨也进行了一定的修复，但是还可以看出手术时软骨创伤的轮廓；而在Control组中，软骨组织基本没有修复的情况，损伤处还是明显的空洞。接下来，我们进一步利用H&E染色的方法评价了上述各组软骨的修复情况。H&E染色结果显示，Gel+软骨细胞组和Gel组都有新生的组织生成并且同旧的软骨组织整合良好；但是Gel+软骨细胞组的新生组织的厚度要好于Gel组，并且表面平整；而在Control组中难以找到明显新生组织的迹象。另外，采用番红-O和免疫组化染色的方法对新生软骨的成分进行了分析。在Gel+软骨细胞组和Gel组中，新生的软骨组织都表现出了番红-O染色活性，证明该新生的软骨组织内含有正常软骨的糖蛋白成分。同时，Gel+软骨细胞组和Gel组的新生软骨组织都表现出II型胶原的染色活性，证明该软骨组织中含有大量的II型胶原。上述番红-O和免疫组化染色结果证明利用新型光交联水凝胶材料进行软骨修复时，新生的软骨组织是透明软骨。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于组织工程支架材料-软骨修复。
实施例一百八十一：光交联水凝胶应用于组织工程支架材料-骨修复
采用SD大鼠，进行颅骨修复实验，并将上述SD大鼠随机分成3组：a：水凝胶(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)+羟基磷灰石的实验组；b：水凝胶处理(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组；c：不用材料处理的对照组。实验中，用4％的水合氯醛溶液(0.9mL每克体重)对其进行腹腔麻醉，碘酒消毒。然后，利用外科手术刀片打开大鼠颅骨处头皮。利用牙环钻在老鼠颅骨左右处对称制造直径5mm的完全颅骨缺损模型。在实验组中，取200μL的水凝胶前体溶液填充到SD大鼠颅骨缺损处，使其充分向伤口边缘渗透；用395nm LED光源(20mW/cm 2)光照30s使其完全成胶；最后用缝合线缝合老鼠的头皮。在对照组中，制造好SD大鼠颅骨缺损模型后，直接缝合头皮，不做其他任何处理。上述SD大鼠在无菌，37℃的环境中饲养8周的时间。然后，利用micro-CT扫描成像的方式对各组中SD大鼠颅骨的修复情况进行了评价。结果显示，在没有进行任何处理的对照组中，SD大鼠的颅骨缺损基本没有进行任何的修复，而用水凝胶填充的颅骨缺损处边缘有新生的成骨形成，但是新生骨组织的量较少，大部分缺损处并没有得到良好的修复，而用水凝胶+羟基磷灰石填充的颅骨缺损处基本得到了修复，大量的新生骨组织在缺损处形成。接着利用Van Gieson染色法对颅骨的组织切片进行了组织学染色分析。结果显示，水凝胶+羟基磷灰石处理的SD大鼠的颅骨缺损处都长出了完整的新生骨组织，而只用水凝胶处理的颅骨缺损处只有少量新生骨组织生成，大部分缺损处的骨组织依旧是缺损状态，在对照组中，几乎没有新生的骨组织生成。该组织染色结果进一步证实了包裹有羟基磷灰石的水凝胶对骨缺损有良好的修复效果。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于组织工程支架材料-骨修复。
实施例一百八十二：光交联水凝胶应用于组织工程支架材料-骨/软骨复合缺损修复
采用猪作为动物模型，软骨相材料为水凝胶+软骨细胞，骨相材料为水凝胶+羟基磷灰石+BMSCs，分为三组进行关节骨/软骨复合缺损的修复实验：a：分别包裹有软骨细胞和BMSCs的水凝胶(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组，即 Gel+细胞组；b：单纯的水凝胶(2％组分A-1/1％组分A-107/6％组分C-4/0.2％组分B-2)组，即Gel组。在实验中，先将骨相材料填充至骨相缺损处，并使凝胶前体溶液充分渗透，光照成胶后水凝胶牢固的粘附在骨缺损处，然后将软骨相材料填充至软骨相缺损处，光照成胶后水凝胶牢固的黏附在软骨缺损处(如图8所示)。在手术6个月后，处死实验的猪，并提取损伤关节对实验修复效果进行评价。Gel+细胞组在关节缺损处长出了光滑的新生软骨组织和骨组织，并且和旧的软骨/骨组织进行了良好的整合，同时，软骨组织和骨组织也进行了良好的整合；在Gel组中骨/软骨组织基本没有修复的情况，损伤处还是明显的空洞。接下来，进一步利用H&E染色的方法评价了上述各组软骨的修复情况。H&E染色结果显示，Gel+细胞组有新生的组织生成并且同旧的软骨组织整合良好；但是在Gel组中难以找到明显新生组织的迹象。另外，采用番红-O和免疫组化染色的方法对新生软骨的成分进行了分析。在Gel+细胞组中，新生的软骨组织都表现出了番红-O染色活性，证明该新生的软骨组织内含有正常软骨的糖蛋白成分。同时，Gel+细胞组的新生软骨组织都表现出II型胶原的染色活性，证明该软骨组织中含有大量的II型胶原。上述番红-O和免疫组化染色结果证明利用新型光交联水凝胶材料进行软骨修复时，新生的软骨组织是透明软骨。接着利用Van Gieson染色法对骨的组织切片进行了组织学染色分析。结果显示，Gel+细胞组处理的骨缺损处长出了完整的新生骨组织，而在Gel组中骨缺损处只有少量新生骨组织生成，大部分缺损处的骨组织依旧是缺损状态。该组织染色结果进一步证实了加细胞的水凝胶对骨缺损有良好的修复效果。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于组织工程支架材料-骨/软骨复合缺损修复。
实施例一百八十三：光交联水凝胶应用于3D打印(FDM)的生物墨水
3D打印技术是近些年来迅速发展的一种三维成型技术，已被广泛应用，目前3D打印技术包括熔融沉积式(FDM)、光固化成型(SLA)、激光烧结式(SLS)、连续液面制造式(CLIP)等。但是适用于带细胞打印的方式目前主要是FDM的方式，带细胞打印的材料主要是水凝胶材料，因此，发展3D打印的生物墨水-可打印的水凝胶材料以及提高水凝胶材料打印的分辨率是该领域研究的基本问题。以实施例一制备的组分A-1(即为HA-NB)、实施例一百零七制备的组分A-107(即为HAMA)、组分C-4(即为明胶)、实施例一百五十五制备的组分B-2(即为LAP)；实施例八十八制备的组分A-88(即为HA-cNB)、实施例一百四十四制备的组分A-144(即为HA-cNB-MA)、实施例一百五十五制备的组分B-2(即为LAP)为例，将一定质量浓度的水凝胶前体溶液均匀混合细胞后，装入低温打印桶中，控制打印温度在25℃左右，通过温度来调整生物墨水的粘稠度，以获得最佳的打印状态，然后确定合适的打印压力和打印速度，进行不同结构的生物打印，打印完成后通过光照交联水凝胶(或是边打印边光照)，从而获得带细胞且带结构的水凝胶，进行3D细胞培养(如图9所示)。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于3D打印(FDM)的生物墨水。
实施例一百八十四：光交联水凝胶应用于3D打印(DLP)的生物墨水
DLP(数字光处理)3D打印技术是近来年发展起来的一种新型的光固化打印方式，相比于SLA(立体光固化成型)式的打印机，DLP以其打印速度快、分辨率高而具有大多数打印方式所不可比拟的优势，目前在牙科模型、珠宝设计等领域已经具备一定的应用前景。但是，当前市场上使用的打印墨水仅限于光固化树脂，而水凝胶作为一种新兴的生物墨水还没有得到广泛的关注，主要是由于没有适合DLP打印的水凝胶材料，而本发明提出的复合型光交联水凝胶材料以其快的光固化速度，优异的机械性能非常适合于3D打 印，而且具有更高的打印精度。以实施例一制备的组分A-1(即为HA-NB)、实施例一百零七制备的组分A-107(即为HAMA)、组分C-4(即为明胶)、实施例一百五十五制备的组分B-2(即为LAP)；实施例八十八制备的组分A-88(即为HA-cNB)、实施例一百四十四制备的组分A-144(即为HA-cNB-MA)、实施例一百五十五制备的组分B-2(即为LAP)为例，将一定质量浓度的水凝胶前体溶液均匀混合细胞后，装入液体槽中，通过控制光源的强弱、曝光时间等参数来调整生物墨水的打印情况，以获得最佳的打印状态，从而得到了既带细胞又带结构的水凝胶，可以进行3D细胞培养的研究。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于3D打印(DLP)的生物墨水。
实施例一百八十五：光交联水凝胶应用于药物的包裹与释放
水凝胶是一种能够在水中溶胀但不溶解的交联高分子网络，由于水凝胶大部分由水组成，因此具有非常好的生物相容性，特别适用于药物和生物活性大分子的载体。包裹于水凝胶材料中的药物或生物活性大分子通过分子的扩散作用和材料的降解作用实现药物持续释放的效果。以药物包裹与释放为例具体介绍如下：以实施例一制备的组分A-1(即为HA-NB)、实施例一百零七制备的组分A-107(即为HAMA)、组分C-4(即为明胶)、实施例一百五十五制备的组分B-2(即为LAP)；实施例八十八制备的组分A-88(即为HA-cNB)、实施例一百四十四制备的组分A-144(即为HA-cNB-MA)、实施例一百五十五制备的组分B-2(即为LAP)为例，将其溶于生理盐水中，配成一定质量浓度的水凝胶前体溶液，加入一定量的药物分子，取200μL上述溶液置于圆形模具中光照成水凝胶，接着放入24孔细胞培养板中，加入一定量的生理盐水进行药物释放实验，通过紫外测试分析溶液中药物的释放量，以此来评价该材料对药物的释放效果。
其他不同材料组成的水凝胶体系(组分A：组分A-1～组分A-154；组分B：组分B-1～组分B-3；组分C-1～C-21)属于光交联水凝胶，同样可以应用于药物的包裹与释放。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。

Claims (26)

  1. 环状邻硝基苄基类光扳机，其特征在于，如结构式I-2所示
    Figure PCTCN2018080170-appb-100001
    式I-2中，X为O、S或N，X＝O时，为环状邻硝基苄基类光扳机，X＝S时，为环状邻硝基苄硫基类光扳机，X＝N时，为环状邻硝基苄胺基类光扳机；
    式Ⅰ-2中，连接键R 1一端与X连接，另一端与R 2，R 3，R 4，R 5中任意的一个基团相连接，构成环状结构；
    式I-2中，R’选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式I-2中，R 1选自氢、醚键类取代基、酯键类取代基、碳酸酯键类取代基、胺基甲酸酯键类取代基、巯基甲酸酯键类取代基或磷酸酯键类取代基；
    式I-2中，R 2，R 3，R 4，R 5可自由的选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、羧基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    优选地，R 2，R 3，R 4，R 5相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环，或形成芳环或芳杂环。
  2. 根据权利要求1所述环状邻硝基苄基类光扳机，其特征在于，所述烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的烷基；
    所述亚烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的亚烷基；
    所述改性烷基为烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
    所述改性亚烷基为亚烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性亚烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
    所述醚键类取代基选自以下结构：
    -(CH 2) xCH 3、-(CH 2CH 2O) xCH 3、-(CH 2) x(CH 2CH 2O) yCH 3、或
    Figure PCTCN2018080170-appb-100002
    其中x和y≥0且为整数；
    所述酯键类取代基选自以下结构：
    -CO(CH 2) xCH 3、-CO(CH 2CH 2O) xCH 3、-CO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述碳酸酯键类取代基选自以下结构：
    -COO(CH 2) xCH 3、-COO(CH 2CH 2O) xCH 3、-COO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述胺基甲酸酯键类取代基选自以下结构：
    -CONH(CH 2) xCH 3、-CONH(CH 2CH 2O) xCH 3、-CONH(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述巯基甲酸酯键类取代基选自以下结构：
    -COS(CH 2) xCH 3、-COS(CH 2CH 2O) xCH 3、-COS(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述磷酸酯键类取代基选自以下结构：
    -POOO(CH 2) xCH 3、-POOO(CH 2CH 2O) xCH 3、-POOO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述芳基为5～10元芳香单环或芳香稠合双环结构；
    所述杂芳基为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环结构；
    所述卤原子各自独立地选自F、Cl、Br、I；
    所述脂环为饱和或不饱和的3～10元单环或多环脂环；
    所述脂杂环为环上含有选自O、S、N或Si中的至少一种杂原子的饱和或不饱和的3-10元单环或多环脂杂环，所述脂杂环上含有S原子时，其任选为-S-、-SO-或-SO 2-；所述脂环或脂杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代；
    所述芳环为5～10元芳香单环或芳香稠合双环；
    所述芳杂环为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环；所述芳环或芳杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代。
  3. 根据权利要求1或2所述环状邻硝基苄基类光扳机，其特征在于，选自以下环状结构：
    Figure PCTCN2018080170-appb-100003
    Figure PCTCN2018080170-appb-100004
  4. 光敏高分子衍生物，其特征在于，邻硝基苄基类光扳机修饰的光敏高分子衍生物，具有式A-Ⅰ结构，
    Figure PCTCN2018080170-appb-100005
    其中，邻硝基苄基类光扳机，结构如式I所示，具有两种结构，分别如结构式I-1与结构式I-2，结构式I-2表示环状邻硝基苄基类光扳机；
    Figure PCTCN2018080170-appb-100006
    式I-1、式I-2中，X＝O时，为邻硝基苄基类光扳机，X＝S时，为邻硝基苄硫基类 光扳机，X＝N时，为邻硝基苄胺基类光扳机；
    式A-Ⅰ、式Ⅰ、式I-1、式I-2中，R’选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式I-1、式I-2中，R 1选自氢、醚键类取代基、酯键类取代基、碳酸酯键类取代基、胺基甲酸酯键类取代基、巯基甲酸酯键类取代基或磷酸酯键类取代基；
    式I-1、式I-2中，R 2，R 3，R 4，R 5可自由的选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、羧基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式Ⅰ-2中，X为O、S或NH，连接键R 1一端与X连接，另一端与R 2，R 3，R 4，R 5中任意的一个基团相连接，构成环状结构；
    式A-Ⅰ中，n≥2；
    式A-Ⅰ中，P 1为一种亲水或水溶性天然高聚物或合成聚合物，或P 1独立的选自多种亲水或水溶性天然高聚物或合成聚合物；
    可选地，对于式I-1、式I-2所示结构，R 2，R 3，R 4，R 5相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环，或形成芳环或芳杂环。
  5. 光敏高分子衍生物，其特征在于，既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物，具有式A-Ⅲ结构，
    Figure PCTCN2018080170-appb-100007
    其中，邻硝基苄基类光扳机，结构如式I所示，具有两种结构，分别如结构式I-1与结构式I-2，结构式I-2表示环状邻硝基苄基类光扳机；
    Figure PCTCN2018080170-appb-100008
    式I-1、式I-2中，X＝O时，为邻硝基苄基类光扳机，X＝S时，为邻硝基苄硫基类光扳机，X＝N时，为邻硝基苄胺基类光扳机；
    式A-Ⅲ、式I、式I-1、式I-2中，R’选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式I-1、式I-2中，R 1选自氢、醚键类取代基、酯键类取代基、碳酸酯键类取代基、胺基甲酸酯键类取代基、巯基甲酸酯键类取代基或磷酸酯键类取代基；
    式I-1、式I-2中，R 2，R 3，R 4，R 5可自由的选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、羧基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式Ⅰ-2中，X为O、S或NH，连接键R 1一端与X连接，另一端与R 2，R 3，R 4，R 5中任意的一个基团相连接，构成环状结构；
    式A-Ⅲ中，R’ 1，R’ 2、R’ 3选自氢、烷基、改性烷基或芳基；R’ 4选自烷基、醚键类取代基、酯键类取代基、酰胺键类取代基；
    可选地，式A-Ⅲ中，R’ 1，R’ 2、R’ 3相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环；
    式A-Ⅲ中，n≥2；
    式A-Ⅲ中，P 1为一种亲水或水溶性天然高聚物或合成聚合物，或P 1独立的选自多种亲水或水溶性天然高聚物或合成聚合物；
    可选地，对于式I-1、式I-2所示结构，R 2，R 3，R 4，R 5相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环，或形成芳环或芳杂环。
  6. 根据权利要求4或5所述光敏高分子衍生物，其特征在于，所述烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的烷基；
    所述亚烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的亚烷基；
    所述改性烷基为烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
    所述改性亚烷基为亚烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性亚烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
    所述醚键类取代基选自以下结构：
    -(CH 2) xCH 3、-(CH 2CH 2O) xCH 3、-(CH 2) x(CH 2CH 2O) yCH 3、或
    Figure PCTCN2018080170-appb-100009
    其中x和y≥0且为整数；
    所述酯键类取代基选自以下结构：
    -CO(CH 2) xCH 3、-CO(CH 2CH 2O) xCH 3、-CO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述碳酸酯键类取代基选自以下结构：
    -COO(CH 2) xCH 3、-COO(CH 2CH 2O) xCH 3、-COO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述胺基甲酸酯键类取代基选自以下结构：
    -CONH(CH 2) xCH 3、-CONH(CH 2CH 2O) xCH 3、-CONH(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述巯基甲酸酯键类取代基选自以下结构：
    -COS(CH 2) xCH 3、-COS(CH 2CH 2O) xCH 3、-COS(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述磷酸酯键类取代基选自以下结构：
    -POOO(CH 2) xCH 3、-POOO(CH 2CH 2O) xCH 3、-POOO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述芳基为5～10元芳香单环或芳香稠合双环结构；
    所述杂芳基为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环结构；
    所述卤原子各自独立地选自F、Cl、Br、I；
    所述脂环为饱和或不饱和的3～10元单环或多环脂环；
    所述脂杂环为环上含有选自O、S、N或Si中的至少一种杂原子的饱和或不饱和的3-10元单环或多环脂杂环，所述脂杂环上含有S原子时，其任选为-S-、-SO-或-SO 2-；所述脂环或脂杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代；
    所述芳环为5～10元芳香单环或芳香稠合双环；
    所述芳杂环为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环；所述芳环或芳杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代。
  7. 根据权利要求4所述光敏高分子衍生物，其特征在于，当邻硝基苄基类光扳机选择结构式I-1时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，
    当邻硝基苄基类光扳机选择结构式I-2时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，或连接到R 1与R 2，R 3，R 4，R 5中任意的一个基团相连接构成的环状链上，
    其连接键选自羟基类所获得的连接键P 1-O-；或选自巯基类所获得的连接键P 1-S-；或选自胺基类所获得的连接键P 1-NH-；或选自烷烃类所获得的连接键P 1-；或选自酯键类所获得的连接键P 1-COO-；或选自酰胺键类所获得的连接键P 1-CONH-，该连接键的一端与P 1相连，另一端连接在式A-Ⅰ所示分子的苯环上。
  8. 根据权利要求5所述光敏高分子衍生物，其特征在于，当邻硝基苄基类光扳机选择结构式I-1时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，
    P 1另一端与R’ 4连接；
    当邻硝基苄基类光扳机选择结构式I-2时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，或连接到R 1与R 2，R 3，R 4，R 5中任意的一个基团相连接构成的环状链上，
    P 1另一端与R’ 4连接；
    其连接键选自羟基类所获得的连接键-O-P 1-O-；或选自巯基类所获得的连接键-S-P 1-S-；或选自胺基类所获得的连接键-NH-P 1-NH-；或选自烷烃类所获得的连接键-P 1-；或选自酯键类所获得的连接键-COO-P 1-COO-；或选自酰胺键类所获得的连接键-CONH-P 1-CONH-；其连接键也可以选自在P 1两端连接不同种以上所述的羟基类、巯基类、胺基类、烷烃类、酯键类、酰胺键类连接键，该连接键的一端与P 1相连，另一端连接在式A-Ⅲ所示分子的苯环上。
  9. 根据权利要求4或5所述光敏高分子衍生物，其特征在于，亲水或水溶性天然高聚物包括天然多糖类物质及其修饰物或降解物，蛋白及其修饰物、改性物和降解物；
    所述天然多糖类物质包括透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐；
    所述蛋白包括各种亲水性或水溶性动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白，所述蛋白降解物包括明胶或多肽；
    亲水或水溶性合成聚合物包括两臂或多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯 酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮。
  10. 根据权利要求4所述光敏高分子衍生物，其特征在于，所述式A-Ⅰ的邻硝基苄基类光扳机修饰的高分子衍生物，选自以下组分A-1～组分A-50中的结构：
    Figure PCTCN2018080170-appb-100010
    Figure PCTCN2018080170-appb-100011
    Figure PCTCN2018080170-appb-100012
    Figure PCTCN2018080170-appb-100013
    所述式A-Ⅰ的邻硝基苄硫基类光扳机修饰的高分子衍生物，选自以下组分A-51～组分A-69中的结构：
    Figure PCTCN2018080170-appb-100014
    Figure PCTCN2018080170-appb-100015
    所述式A-Ⅰ的邻硝基苄胺基类光扳机修饰的高分子衍生物，选自以下组分A-70～组分A-87中的结构：
    Figure PCTCN2018080170-appb-100016
    Figure PCTCN2018080170-appb-100017
    所述式A-Ⅰ的环状邻硝基苄基类光扳机修饰的高分子衍生物，选自以下组分A-88～ 组分A-106中的结构：
    Figure PCTCN2018080170-appb-100018
    Figure PCTCN2018080170-appb-100019
    组分A-1～组分A-106中，n≥2，HA为透明质酸；CMC为羧甲基纤维素；Alg为海藻酸；CS为硫酸软骨素；PGA为聚谷氨酸；PEG为聚乙二醇；Chitosan为壳聚糖；Gelatin为明胶；PLL为聚赖氨酸；Dex为葡聚糖；Hep为肝素。
  11. 根据权利要求5所述光敏高分子衍生物，其特征在于，式A-Ⅲ所示既含邻硝基苄基类光扳机又含双键官能团的高分子衍生物，选自以下组分A-116～组分A-154中的结构：
    Figure PCTCN2018080170-appb-100020
    Figure PCTCN2018080170-appb-100021
    Figure PCTCN2018080170-appb-100022
    Figure PCTCN2018080170-appb-100023
    组分A-116～组分A-154中，n≥2，HA为透明质酸；CMC为羧甲基纤维素；Alg为海藻酸；CS为硫酸软骨素；PGA为聚谷氨酸；PEG为聚乙二醇；Chitosan为壳聚糖；Gelatin为明胶；PLL为聚赖氨酸；Dex为葡聚糖；Hep为肝素。
  12. 权利要求4所述光敏高分子衍生物的制备方法，其特征在于，采用化学标记法或人工聚合的方法制备，
    化学标记法是利用高分子与邻硝基苄基类光扳机中所含的化学基团间的化学反应而连接，包括以下标记方法：
    含羧基的高分子与含羟基、巯基或胺基的邻硝基苄基类小分子标记，
    含羟基的高分子与含羧基或含溴的邻硝基苄基类小分子标记，
    含胺基的高分子与含羧基或含溴的邻硝基苄基类小分子标记；
    人工聚合的方法是利用邻硝基苄基衍生物功能单体与其它共单体共聚，聚合方法包括无规自由基聚合方法，也包括控制自由基聚合方法；
    式A-Ⅰ所述邻硝基苄基类光扳机修饰的光敏高分子衍生物的制备方法，优选选择以下方法中的任一种：
    A、将含有羧基的水溶性聚合物或高分子于蒸馏水中溶解，加入含有活性官能团羟基或巯基或胺基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐和活化剂羟基苯并三唑，搅拌反应，反应结束后，将反应液加入透析袋中用稀盐酸溶液透析，然后冷冻干燥，即可得到邻硝基苄基修饰的高分子衍生物；
    B、将含有羧基的水溶性聚合物或高分子于2-(N-吗啉)乙磺酸MES缓冲溶液中，搅拌至完全溶解，将邻硝基苄基小分子溶于二甲基亚砜后加入上述反应液，将4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐溶于MES缓冲溶液加入上述反应液中反应，然后将反应液倒入透析袋中，用去离子水透析，然后冷冻干燥，即可得到邻硝基苄基修饰的高分子衍生物；
    C、将含有羟基或胺基的水溶性聚合物于蒸馏水中溶解，加入含有活性官能团羧基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐和催化剂对甲苯磺酸吡啶盐，然后在室温下搅拌反应，反应结束后，将反应液倒入难溶性溶剂中重沉淀，然后溶于水中用透析袋透析，冷冻干燥后，即可得到邻硝基苄基修饰的高分子衍生物；
    D、将含有羟基或胺基的水溶性聚合物于蒸馏水中溶解，加入含有活性官能团溴的邻硝基苄基小分子后，加入碳酸钾作为碱，反应，反应结束后，将反应液倒入难溶性溶剂中重沉淀，然后溶于水中用透析袋透析，冷冻干燥后，即可得到邻硝基苄基修饰的高分子衍生物；
    E、将邻硝基苄基可聚合单体衍生物与一种或几种可聚合共单体经过聚合即可得邻硝基苄基修饰的合成共聚物；
    所述邻硝基苄基可聚合单体衍生物为丙烯酸酯类化合物、甲基丙烯酸酯类化合物、丙烯酰胺类化合物或甲基丙烯酰胺类化合物，
    所述可聚合共单体中至少一种必须是水溶性共单体，所述可聚合共单体包括甲基丙烯酸聚乙二醇酯、丙烯酸聚乙二醇酯、甲基丙烯酸、丙烯酸、丙烯酸羟乙酯、丙烯酰胺。
  13. 权利要求5所述光敏高分子衍生物的制备方法，其特征在于，采用化学标记法或人工聚合的方法制备，
    化学标记法是利用高分子与邻硝基苄基类光扳机中所含的化学基团间的化学反应而连接，包括以下标记方法：
    含羧基的高分子与含羟基、巯基或胺基的邻硝基苄基类小分子标记，
    含羟基的高分子与含羧基或含溴的邻硝基苄基类小分子标记，
    含胺基的高分子与含羧基或含溴的邻硝基苄基类小分子标记；
    人工聚合的方法是利用邻硝基苄基衍生物功能单体与其它共单体共聚，聚合方法包括无规自由基聚合方法，也包括控制自由基聚合方法；
    优选，式A-Ⅲ所述既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物的制备方法，为先标记邻硝基苄基类光扳机后标记双键官能团，或先标记双键官能团后标记邻硝基苄基类光扳机，
    进一步优选，选择以下方式中的任一种：
    A、将含邻硝基苄基类光扳机的水溶性高分子溶于去离子水，冷却至0-4℃，加入丙烯酸酐或甲基丙烯酸酐，再滴加NaOH，反应，然后将反应液倒入透析袋中，用去离子水透析，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物；
    B、将含邻硝基苄基类光扳机的水溶性高分子溶于去离子水，搅拌溶解，加入丙烯酸缩水甘油酯或甲基丙烯酸缩水甘油酯，再加入NaOH，反应后，将反应液倒入透析袋中，用去离子水透析，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物；
    C、将含邻硝基苄基类光扳机的水溶性高分子溶于无水二甲基亚砜中，加入三乙胺，再加入丙烯酰氯或甲基丙烯酰氯，反应，反应结束后，将反应液倒入乙醇中重沉淀，过滤得到的粗产物重新溶于去离子水中，透析，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物；
    D、将含双键官能团的水溶性聚合物或高分子于蒸馏水中溶解，加入含有活性官能团羟基或巯基或胺基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐和活化剂羟基苯并三唑，然后在室温下搅拌反应，反应结束后，将反应液加入透析袋中用稀盐酸溶液透析，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物；
    E、将含双键官能团的水溶性聚合物或高分子于2-(N-吗啉)乙磺酸MES缓冲溶液中，搅拌至完全溶解，将邻硝基苄基小分子溶于二甲基亚砜后加入上述反应液，将4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐溶于MES缓冲溶液，加入上述反应液中下反应，然后将反应液倒入透析袋中，用去离子水透析，然后冷冻干燥，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物；
    F、将含双键官能团的水溶性聚合物溶解后，加入含有活性官能团羧基的邻硝基苄基小分子后，加入缩合剂1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐和催化剂对甲苯磺酸吡啶盐，然后搅拌反应，反应结束后，将反应液倒入难溶性溶剂中重沉淀，然后溶于水中用透析袋透析，冷冻干燥后，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物；
    G、将含双键官能团的水溶性聚合物于蒸馏水中溶解，加入含有活性官能团溴的邻硝基苄基小分子后，加入碳酸钾作为碱，反应，反应结束后，将反应液倒入难溶性溶剂中重沉淀，然后溶于水中用透析袋透析，冷冻干燥后，即可得到所述的既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物。
  14. 光交联水凝胶材料的制备方法，其特征在于，包括以下步骤：
    将组分A-光敏高分子衍生物溶于生物相容性介质得到光敏高分子溶液A；
    将组分B-光引发剂溶于生物相容性介质得到光引发剂溶液B；
    将溶液A和溶液B混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，组分A中的邻硝基苄基类光扳机和/或双键官能团和组分B-光引发剂在光照下，分别发生自由基交联，形成水凝胶；
    所述组分A-光敏高分子衍生物，选自以下物质中的一种或几种：
    1、邻硝基苄基类光扳机修饰的光敏高分子衍生物，具有式A-Ⅰ结构，
    2、既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物，具有式A-Ⅲ结构，
    Figure PCTCN2018080170-appb-100024
    其中，邻硝基苄基类光扳机，具有两种结构，分别如结构式I-1与结构式I-2，结构式I-2表示环状邻硝基苄基类光扳机；
    Figure PCTCN2018080170-appb-100025
    式I-1、式I-2中，X＝O时，为邻硝基苄基类光扳机，X＝S时，为邻硝基苄硫基类光扳机，X＝N时，为邻硝基苄胺基类光扳机；
    式A-Ⅰ、式A-Ⅲ、式I、式I-1、式I-2中，R’选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式I-1、式I-2中，R 1选自氢、醚键类取代基、酯键类取代基、碳酸酯键类取代基、胺基甲酸酯键类取代基、巯基甲酸酯键类取代基或磷酸酯键类取代基；
    式I-1、式I-2中，R 2，R 3，R 4，R 5可自由的选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、羧基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式Ⅰ-2中，X为O、S或NH，连接键R 1一端与X连接，另一端与R 2，R 3，R 4，R 5中任意的一个基团相连接，构成环状结构；
    式A-Ⅲ中，R’ 1，R’ 2、R’ 3选自氢、烷基、改性烷基或芳基；R’ 4选自烷基、醚键类取代基、酯键类取代基、酰胺键类取代基；
    可选地，式A-Ⅲ中，R’ 1，R’ 2、R’ 3可相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环；
    式A-Ⅰ、式A-Ⅲ中，n≥2，P 1为一种亲水或水溶性天然高聚物或合成聚合物，或P 1独立的选自多种亲水或水溶性天然高聚物或合成聚合物；
    优选地，对于式I-1、式I-2所示结构，R 2，R 3，R 4，R 5相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环，或形成芳环或芳杂环；
    组分B-光引发剂，即光照下能够产生自由基的物质，优选为水溶性光引发剂或可分散在水中的光引发剂，进一步优选为组分B-1、组分B-2或组分B-3，或组分B-1、组分B-2或组分B-3的衍生物，
    Figure PCTCN2018080170-appb-100026
  15. 根据权利要求14所述光交联水凝胶材料的制备方法，其特征在于，在组分A中还加入含双键官能团的光敏高分子衍生物，含双键官能团的光敏高分子衍生物具有式A-Ⅱ结构：
    Figure PCTCN2018080170-appb-100027
    式A-Ⅱ中，R’ 1，R’ 2、R’ 3选自氢、烷基、改性烷基或芳基；R’ 4选自烷基、醚键类取代基、酯键类取代基、酰胺键类取代基；
    可选地，式A-Ⅱ中，R’ 1，R’ 2、R’ 3可相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环；
    式A-Ⅱ中，n≥2，P 1是亲水或水溶性天然高聚物，或是亲水或水溶性合成聚合物。
  16. 根据权利要求14或15所述光交联水凝胶材料的制备方法，其特征在于，包括以下步骤：
    将组分A-光敏高分子衍生物溶于生物相容性介质得到光敏高分子溶液A；
    将组分B-光引发剂溶于生物相容性介质得到光引发剂溶液B；
    将辅助组分C-其他生物相容性高分子衍生物溶于生物相容性介质得到高分子溶液C，所述辅助组分C-其他生物相容性高分子衍生物为含胺基、联胺、酰肼或羟胺官能团的高分子衍生物；
    将溶液A、溶液B和溶液C混合均匀得到水凝胶前体溶液，水凝胶前体溶液在光源照射下，组分A中的邻硝基苄基类光扳机和/或双键官能团和组分B-光引发剂在光照下，分别发生自由基交联，同时组分A中的邻硝基苄基类光扳机在光照下产生的醛基/酮基与组分C中的胺基、联胺、酰肼或羟胺官能团发生光偶合交联，产生的亚硝基与组分C中的巯基官能团发生光致亚硝基交联，形成水凝胶。
  17. 根据权利要求14或15或16所述光交联水凝胶材料的制备方法，其特征在于，所述烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的烷基；
    所述亚烷基为具有1～30个碳原子的饱和或不饱和脂肪族直链或支链的亚烷基；
    所述改性烷基为烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
    所述改性亚烷基为亚烷基的任意碳原子被选自卤原子、-OH、-SH、-NO 2、-CN、-CHO、-COOH、酯基、酰胺基、芳基、亚芳基、-CO-、-O-、-S-、-SO-、-SO 2-、伯胺基、仲胺基、叔胺基、季铵盐基、饱和或不饱和的单环或双环亚环烃基、桥联脂杂环中的至少一种基团置换所得的基团，所述改性亚烷基具有1～30个原子，其碳碳单键可任意地被碳碳双键或碳碳叁键替换；
    所述醚键类取代基选自以下结构：
    -(CH 2) xCH 3、-(CH 2CH 2O) xCH 3、-(CH 2) x(CH 2CH 2O) yCH 3、或
    Figure PCTCN2018080170-appb-100028
    其中x和y≥0且为整数；
    所述酯键类取代基选自以下结构：
    -CO(CH 2) xCH 3、-CO(CH 2CH 2O) xCH 3、-CO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述碳酸酯键类取代基选自以下结构：
    -COO(CH 2) xCH 3、-COO(CH 2CH 2O) xCH 3、-COO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述胺基甲酸酯键类取代基选自以下结构：
    -CONH(CH 2) xCH 3、-CONH(CH 2CH 2O) xCH 3、-CONH(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述巯基甲酸酯键类取代基选自以下结构：
    -COS(CH 2) xCH 3、-COS(CH 2CH 2O) xCH 3、-COS(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述磷酸酯键类取代基选自以下结构：
    -POOO(CH 2) xCH 3、-POOO(CH 2CH 2O) xCH 3、-POOO(CH 2) x(CH 2CH 2O) yCH 3，其中x和y≥0且为整数；
    所述芳基为5～10元芳香单环或芳香稠合双环结构；
    所述杂芳基为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环结构；
    所述卤原子各自独立地选自F、Cl、Br、I；
    所述脂环为饱和或不饱和的3～10元单环或多环脂环；
    所述脂杂环为环上含有选自O、S、N或Si中的至少一种杂原子的饱和或不饱和的3-10元单环或多环脂杂环，所述脂杂环上含有S原子时，其任选为-S-、-SO-或-SO 2-；所述脂环或脂杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代；
    所述芳环为5～10元芳香单环或芳香稠合双环；
    所述芳杂环为环上含有选自O、S、N或Si中的至少一种杂原子的5～10元芳香单环或芳香稠合双环；所述芳环或芳杂环上的H还可任意地被卤原子、硝基、芳基、烷基或改性烷基取代。
  18. 根据权利要求14或15或16所述光交联水凝胶材料的制备方法，其特征在于，
    当组分A为具有式A-Ⅰ结构的邻硝基苄基类光扳机修饰的光敏高分子衍生物时，
    当邻硝基苄基类光扳机选择结构式I-1时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，
    当邻硝基苄基类光扳机选择结构式I-2时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，或连接到R 1与R 2，R 3，R 4，R 5中任意的一个基团相连接构成的环状链上，
    其连接键选自羟基类所获得的连接键P 1-O-；或选自巯基类所获得的连接键P 1-S-；或选自胺基类所获得的连接键P 1-NH-；或选自烷烃类所获得的连接键P 1-；或选自酯键类所获得的连接键P 1-COO-；或选自酰胺键类所获得的连接键P 1-CONH-，该连接键的一端与P 1相连，另一端连接在式A-Ⅰ所示分子的苯环上；
    当组分A为具有式A-Ⅲ结构的既含邻硝基苄基类光扳机又含双键官能团的光敏高分 子衍生物时，
    当邻硝基苄基类光扳机选择结构式I-1时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，
    P 1另一端与R’ 4连接；
    当邻硝基苄基类光扳机选择结构式I-2时，
    P 1一端与R 2，R 3，R 4，R 5中任意的一个或多个基团相连接，或连接于R 2，R 3，R 4，R 5之间形成的饱和或不饱和脂环或脂杂环，或R 2，R 3，R 4，R 5之间形成的芳环或芳杂环，或连接到R 1与R 2，R 3，R 4，R 5中任意的一个基团相连接构成的环状链上，
    P 1另一端与R’ 4连接；
    其连接键选自羟基类所获得的连接键-O-P 1-O-；或选自巯基类所获得的连接键-S-P 1-S-；或选自胺基类所获得的连接键-NH-P 1-NH-；或选自烷烃类所获得的连接键-P 1-；或选自酯键类所获得的连接键-COO-P 1-COO-；或选自酰胺键类所获得的连接键-CONH-P 1-CONH-；其连接键也可以选自在P 1两端连接不同种以上所述的羟基类、巯基类、胺基类、烷烃类、酯键类、酰胺键类连接键，该连接键的一端与P 1相连，另一端连接在式A-Ⅲ所示分子的苯环上。
  19. 根据权利要求14或15或16所述光交联水凝胶材料的制备方法，其特征在于，亲水或水溶性天然高聚物包括天然多糖类物质及其修饰物或降解物，蛋白及其修饰物、改性物和降解物；
    所述天然多糖类物质包括透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐；
    所述蛋白包括各种亲水性或水溶性动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白，所述蛋白降解物包括明胶或多肽；
    亲水或水溶性合成聚合物包括两臂或多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮。
  20. 根据权利要求14或15或16所述光交联水凝胶材料的制备方法，其特征在于，所述式A-Ⅰ中邻硝基苄基类光扳机修饰的高分子衍生物，选自以下组分A-1～组分A-50中的结构：
    Figure PCTCN2018080170-appb-100029
    Figure PCTCN2018080170-appb-100030
    Figure PCTCN2018080170-appb-100031
    Figure PCTCN2018080170-appb-100032
    所述式A-Ⅰ中邻硝基苄硫基类光扳机修饰的高分子衍生物，选自以下组分A-51～组分A-69中的结构：
    Figure PCTCN2018080170-appb-100033
    Figure PCTCN2018080170-appb-100034
    所述式A-Ⅰ中邻硝基苄胺基类光扳机修饰的高分子衍生物，选自以下组分A-70～组分A-87中的结构：
    Figure PCTCN2018080170-appb-100035
    Figure PCTCN2018080170-appb-100036
    所述式A-Ⅰ中环状邻硝基苄基类光扳机修饰的高分子衍生物，选自以下组分A-88～组分A-106中的结构：
    Figure PCTCN2018080170-appb-100037
    Figure PCTCN2018080170-appb-100038
    所述式A-Ⅱ的双键修饰的高分子衍生物，选自以下组分A-107～组分A-115中的结构：
    Figure PCTCN2018080170-appb-100039
    所述既含邻硝基苄基类光扳机又含双键官能团的高分子衍生物，选自以下组分A-116～组分A-154中的结构：
    Figure PCTCN2018080170-appb-100040
    Figure PCTCN2018080170-appb-100041
    Figure PCTCN2018080170-appb-100042
    Figure PCTCN2018080170-appb-100043
    组分A1-组分A-154中，n≥2，HA为透明质酸；CMC为羧甲基纤维素；Alg为海藻酸；CS为硫酸软骨素；PGA为聚谷氨酸；PEG为聚乙二醇；Chitosan为壳聚糖；Gelatin为明胶；PLL为聚赖氨酸；Dex为葡聚糖；Hep为肝素。
  21. 根据权利要求16所述光交联水凝胶材料的制备方法，其特征在于，含胺基、联胺、酰肼或羟胺官能团的高分子衍生物，分别具有结构式C-Ⅰ、C-Ⅱ、C-Ⅲ、C-Ⅳ；含巯基官能团的高分子衍生物，具有结构式C-Ⅴ：
    Figure PCTCN2018080170-appb-100044
    结构式C-Ⅰ、C-Ⅱ、C-Ⅲ、C-Ⅳ、C-Ⅴ中，n≥2，P 2、P 3、P 4、P 5、P 6为亲水或水溶性天然高聚物，或亲水或水溶性合成聚合物；
    亲水或水溶性天然高聚物包括天然多糖类物质及其修饰物或降解物，蛋白及其修饰物、改性物和降解物；
    所述天然多糖类物质包括透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐；
    所述蛋白包括各种亲水性或水溶性动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白，所述蛋白降解物包括明胶或多肽；
    亲水或水溶性合成聚合物包括两臂或多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮；
    所述式C-Ⅰ选自以下组分C-1～组分C-9中的结构；所述式C-Ⅱ选自以下组分C-10中的结构；所述式C-Ⅲ选自以下组分C-11～组分C-13中的结构；所述式C-Ⅳ选自以下组分C-14～组分C-15中的结构；所述式C-Ⅴ选自以下组分C-16～组分C-21中的结构：
    Figure PCTCN2018080170-appb-100045
    Figure PCTCN2018080170-appb-100046
    组分C-1～组分C-21中，n≥2。
  22. 采用权利要求14-21中任一项所述制备方法制备得到的光交联水凝胶材料。
  23. 一种用于权利要求22所述光交联水凝胶材料制备的试剂盒，其特征在于，包含：组分A-光敏高分子衍生物；组分B-光引发剂，及有关水凝胶制备及应用的说明书；
    所述组分A-光敏高分子衍生物，选自以下物质中的一种或几种：
    1、邻硝基苄基类光扳机修饰的光敏高分子衍生物，具有式A-Ⅰ结构，
    2、既含邻硝基苄基类光扳机又含双键官能团的光敏高分子衍生物，具有式A-Ⅲ结构，
    Figure PCTCN2018080170-appb-100047
    Figure PCTCN2018080170-appb-100048
    其中，邻硝基苄基类光扳机，具有两种结构，分别如结构式I-1与结构式I-2，结构式I-2表示环状邻硝基苄基类光扳机；
    Figure PCTCN2018080170-appb-100049
    式I-1、式I-2中，X＝O时，为邻硝基苄基类光扳机，X＝S时，为邻硝基苄硫基类光扳机，X＝N时，为邻硝基苄胺基类光扳机；
    式A-Ⅰ、式A-Ⅲ、式I-1、式I-2中，R’选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式I-1、式I-2中，R 1选自氢、醚键类取代基、酯键类取代基、碳酸酯键类取代基、胺基甲酸酯键类取代基、巯基甲酸酯键类取代基或磷酸酯键类取代基；
    式I-1、式I-2中，R 2，R 3，R 4，R 5可自由的选自氢、卤原子、羟基、巯基、胺基、硝基、氰基、醛基、酮基、羧基、酯基、酰胺基、膦酸基、膦酸酯基、磺酸基、磺酸酯基、砜基、亚砜基、芳基、杂芳基、烷基、亚烷基、改性烷基或改性亚烷基；
    式Ⅰ-2中，X为O、S或NH，连接键R 1一端与X连接，另一端与R 2，R 3，R 4，R 5中任意的一个基团相连接，构成环状结构；
    式A-Ⅲ中，R’ 1，R’ 2、R’ 3选自氢、烷基、改性烷基或芳基；R’ 4选自烷基、醚键类取代基、酯键类取代基、酰胺键类取代基；
    可选地，式A-Ⅲ中，R’ 1，R’ 2、R’ 3可相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环；
    式A-Ⅰ、式A-Ⅲ中，n≥2，P 1为一种亲水或水溶性天然高聚物或合成聚合物，或P 1独立的选自多种亲水或水溶性天然高聚物或合成聚合物；
    组分B-光引发剂，即光照下能够产生自由基的物质，优选为水溶性光引发剂或可分散在水中的光引发剂，进一步优选为组分B-1、组分B-2或组分B-3，或组分B-1、组分B-2或组分B-3的衍生物，
    Figure PCTCN2018080170-appb-100050
  24. 如权利要求23所述的试剂盒，其特征在于，在组分A中还加入含双键官能团的光敏高分子衍生物，含双键官能团的光敏高分子衍生物具有式A-Ⅱ结构；
    Figure PCTCN2018080170-appb-100051
    式A-Ⅱ中，R’ 1，R’ 2、R’ 3选自氢、烷基、改性烷基或芳基；R’ 4选自烷基、醚键类取代基、酯键类取代基、酰胺键类取代基；
    可选地，式A-Ⅱ中，R’ 1，R’ 2、R’ 3可相互连接，与碳原子一起形成饱和或不饱和的脂环或脂杂环；
    P 1是亲水或水溶性天然高聚物，或是亲水或水溶性合成聚合物。
  25. 如权利要求23所述的试剂盒，其特征在于，还包括辅助组分C，所述辅助组分C为其他生物相容性高分子衍生物，包括含胺基、联胺、酰肼或羟胺官能团的高分子衍生物；
    含胺基、联胺、酰肼或羟胺官能团的高分子衍生物，分别具有结构式C-Ⅰ、C-Ⅱ、C-Ⅲ、C-Ⅳ；含巯基官能团的高分子衍生物，具有结构式C-Ⅴ：
    Figure PCTCN2018080170-appb-100052
    结构式C-Ⅰ、C-Ⅱ、C-Ⅲ、C-Ⅳ、C-Ⅴ中，n≥2，P 2、P 3、P 4、P 5、P 6为亲水或水溶性天然高聚物，或亲水或水溶性合成聚合物；
    亲水或水溶性天然高聚物包括天然多糖类物质及其修饰物或降解物，蛋白及其修饰物、改性物和降解物；
    所述天然多糖类物质包括透明质酸、羧甲基纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、海藻酸、葡聚糖、琼脂糖、肝素、硫酸软骨素、乙二醇壳聚糖、丙二醇壳聚糖、壳聚糖乳酸盐、羧甲基壳聚糖或壳聚糖季铵盐；
    所述蛋白包括各种亲水性或水溶性动植物蛋白、胶原蛋白、血清蛋白、丝素蛋白、弹性蛋白，所述蛋白降解物包括明胶或多肽；
    亲水或水溶性合成聚合物包括两臂或多臂聚乙二醇、聚乙烯亚胺、树枝体、合成多肽、聚赖氨酸、聚谷氨酸、聚丙烯酸、聚甲基丙烯酸、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚甲基丙烯酰胺、聚乙烯醇、聚乙烯吡咯烷酮；
    优选地，所述式C-Ⅰ选自以下组分C-1～组分C-9中的结构；所述式C-Ⅱ选自以下组分C-10中的结构；所述式C-Ⅲ选自以下组分C-11～组分C-13中的结构；所述式C-Ⅳ选自以下组分C-14～组分C-15中的结构；所述式C-Ⅴ选自以下组分C-16～组分C-21中的结构：
    Figure PCTCN2018080170-appb-100053
    Figure PCTCN2018080170-appb-100054
    组分C-1～组分C-21中，n≥2。
  26. 如权利要求22所述光交联水凝胶材料的应用，其特征在于，包括以下应用：
    所述光交联水凝胶作为制备术后创面封闭-皮肤修复材料或药物的应用，
    所述光交联水凝胶作为制备术后创面封闭-术后防黏连材料或药物的应用，
    所述光交联水凝胶作为制备术后创面封闭-口腔溃疡材料或药物的应用，
    所述光交联水凝胶作为制备组织液渗漏封堵-肠漏封堵材料或药物的应用，
    所述光交联水凝胶作为制备组织液渗漏封堵-手术缝合材料或药物的应用，
    所述光交联水凝胶作为制备止血材料-肝脏止血材料或药物的应用，
    所述光交联水凝胶作为制备止血材料-骨断面止血材料或药物的应用，
    所述光交联水凝胶作为制备止血材料-动脉止血材料或药物的应用，
    所述光交联水凝胶作为制备止血材料-心脏止血材料或药物的应用，
    所述光交联水凝胶作为制备组织工程支架材料-软骨修复材料或药物的应用，
    所述光交联水凝胶作为制备组织工程支架材料-骨修复材料或药物的应用，
    所述光交联水凝胶作为制备组织工程支架材料-骨/软骨复合缺损修复材料或药物的应用，
    所述光交联水凝胶作为3D打印材料-生物墨水的应用，
    所述光交联水凝胶作为制备细胞、蛋白、药物载体上的应用。
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