CN109776778A - A kind of copolymer of the controllable biodegradable with alkaline copolymerization center - Google Patents

A kind of copolymer of the controllable biodegradable with alkaline copolymerization center Download PDF

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Publication number
CN109776778A
CN109776778A CN201910062671.3A CN201910062671A CN109776778A CN 109776778 A CN109776778 A CN 109776778A CN 201910062671 A CN201910062671 A CN 201910062671A CN 109776778 A CN109776778 A CN 109776778A
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copolymer
alkaline
center
copolymer material
lactide
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Inventor
张旗
黄凤洪
陶秀梅
尚丽霞
陈鹏
汤虎
张�浩
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Beijing Nukangda Medicine Polytron Technologies Inc
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Beijing Nukangda Medicine Polytron Technologies Inc
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Priority to CN201910062671.3A priority Critical patent/CN109776778A/en
Priority to CN201910379812.4A priority patent/CN109970957B/en
Publication of CN109776778A publication Critical patent/CN109776778A/en
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/685—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen
    • C08G63/6852—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
    • C08G65/33306—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group acyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2230/00—Compositions for preparing biodegradable polymers

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Materials For Medical Uses (AREA)

Abstract

The present invention provides a kind of copolymers of controllable biodegradable with alkaline copolymerization center；A kind of copolymer prepared by the lactide of different optically-active ratios, caprolactone and alkaline copolymerization center, pH value declines caused by which can improve because of polylactic acid degradation, improves the biocompatibility of copolymer.A kind of biodegradable copolymer provided by the invention has excellent mechanical strength, biocompatibility and pH regulatory function, can be widely applied to carrier used in field of tissue engineering technology or device, is especially applied to prepare nerve trachea.

Description

A kind of copolymer of the controllable biodegradable with alkaline copolymerization center
Technical field
The invention belongs to polymeric material fields, are related to a kind of copolymerization of controllable biodegradable with alkaline copolymerization center Object and its carrier used in preparation field of tissue engineering technology or the application in device.
Background technique
Biodegradable polymer can be divided into natural and synthesis two major classes according to source, and natural degradable polymer includes shell Glycan, chitin and its derivative etc.；Synthesized degradable polymer is divided into artificial synthesized and bacterium and synthesizes two major classes.Bacterium synthesis Degradable polymer include poly- hydroxy alkyl alcohol ester and poly- B2Grape acid esters etc., artificial synthesized degradable polymer include rouge Fat adoption ester, polyaminoacid and poly phosphazene etc., wherein polyesters are currently the only to be approved by the fda in the United States for field of biomedicine A kind of biodegradable material, more common has: polylactic acid, polyhydroxy acid ester, polycaprolactone, polytrimethylene carbonate, Lactic acid-ethylene glycol copolymer etc..
Polylactic acid (PLA) is also referred to as polylactide.Lactide (LA) is the intermediate of synthesizing polylactic acid, can be divided into the friendship of L- third Ester, D- lactide, D, three kinds of L- lactide.PLA not only has preferable chemical inertness, workability, but also has excellent Biological degradability, compatibility and absorbability, so PLA and its copolymer be widely used in biomedical engineering neck Domain, as peripheral nerve repairs conduit, controlled drug delivery system, fracture inside-fixture, tissue repair, cell culture and Medical hand Art suture etc..
Polycaprolactone (PCL) is to make catalyst in metallo-organic compound by 6-caprolactone, and dihydroxy or trihydroxy, which are done, to be drawn It sends out under the conditions of agent made of ring-opening polymerisation, with good biological degradability and biocompatibility, and it is safe and non-toxic.Poly- second Glycol is that a kind of safe, without side-effects synthesis high molecular material has nothing in the intracorporal metabolic process of people clear enough The material of poison, good biocompatibility, the use of PEG can improve the hydrophily of polymer.Patent CN102989044A is disclosed A kind of copolymer prepared using lactide, caprolactone, Lanthanum Isopropoxide, trimethylene carbonate, glycolide as starting material is used In the preparation of degradable medical macromolecule tubing.Patent CN1803204A has opened a kind of nothing by caprolactone and lactide altogether Rule copolymer is blended with polylactic acid, prepares the good Absorbable membranes of toughness.It is referred in patent CN101878048A Lactide and caprolactone are formed by copolymer with flexible performance, can be applied as medical implant and artificial dura mater Deng.But the generally existing disadvantage of the material of the modification by copolymerization of the above disclosure of the invention, that is, improving material elongation at break It will lead to the decline of tensile strength of material simultaneously.
Some researches show that two kinds of optical isomers of left-handed and dextrorotation polylactic acid and its mixture-racemic of polylactic acid are poly- Lactic acid has larger impact to its mechanical property and biodegradability aspect, hands over as patent CN100462387C mentions left-handed third Ester-caprolactone copolymer and different proportion left-hand/right-hand lactide caprolactone copolymer are in terms of degradation cycle and mechanical characteristic There is a big difference, but the caprolactone crystallinity that the copolymer uses is relatively high, and hydrophily is poor, keeps its biodegrade very slow Slowly.
PLA is metabolized in vivo can generate lactic acid, and the accumulation of lactic acid will lead to the pH value decline of PLA implant site tissue, and And the hydrophobicity of PLA will affect cell in the adherency and growth on its surface.It has been reported that using tricalcium phosphate, hydroxyapatite, carbon The alkaline matters such as sour hydrogen sodium, chitosan, lysine are modified PLA and its derivative by way of physical blending.Patent CN103319696A is disclosed to be copolymerized with hydroxyapatite, lactide, glycolide, caprolactone, prepares hydroxyapatite/can Biodegradable polyester composite material, for the recovery support of bone tissue defect, hydroxyapatite is due to its excellent bio-compatible Property and its ingredient properties similar with bone tissue, are conducive to the reparation of bone defect.But the technology is just with simple machinery The method of blending is modified polylactic acid and its derivative, and effective bonding is lacked between basic additive and polymer substrate, Alkaline matter is easy to reunite in a polymer matrix simultaneously, and thereby results in two alternate weak spots, and the power of material is greatly reduced Learn performance.Polypeptide chain arginine-glycine-aspartic acid is introduced polymer terminal group by patent CN 1872355A report, still The polypeptide contains acidic amino acid simultaneously --- and aspartic acid can further decrease the pH value of tissue in degradation process, be unfavorable for Patient health.
Summary of the invention
To solve above-mentioned problems of the prior art, the present invention passes through the ratio for coordinating two kinds of isomers of lactide, A kind of copolymer with more excellent mechanical property is prepared in conjunction with caprolactone and alkaline multi-arm polymeric center；By to lactide- Basic amino acid is introduced in caprolactone copolymerization derivative material, providing one kind can improve under pH value caused by polylactic acid is degraded Drop, improves the copolymer of biocompatibility；By coordinating the ratio of two kinds of isomers of lactide, and combine caprolactone in toughness and Excellent properties in terms of degradation time provide a kind of copolymer with more high tensile and elasticity and degradation property.
The present invention provides a kind of controllable biodegradable copolymer material, and the copolymer material is prepared by A, B, C；
The A is alkaline copolymerization center, is made of alkaline modification object and polyethylene glycol；
The B is one of lactide of levorotatory lactide, dextrorotation lactide or difference L/D value or a variety of；
The C is caprolactone.
Further, the left-handed of lactide, dextrorotation molar ratio are 1:1-19:1 in the copolymer material.
Further, the molar content of the lactide is 45-90 parts；
The molar content of the caprolactone is 10-40 parts；
The molar content at the alkalinity copolymerization center is 5-20 parts.
Further, the inherent viscosity of the copolymer material is 1.0-7.0dl/g, polydispersity≤1.5.
Further, the inherent viscosity of the copolymer material is 2.0-6.0dl/g, polydispersity≤1.3.
Further, the copolymer material be a kind of material with multi-arm structure, by alkaline multi-arm polymeric center, The random or block copolymer that lactide and caprolactone are prepared.
Further, the copolymer material is random to be prepared by alkaline copolymerization center, lactide and caprolactone Or block copolymer.
The alkalinity copolymerization center is prepared by alkaline modification object (AA) and polyethylene glycol (PEG)；The alkaline modification The molar content of object is 2-10 parts, and the molar content of PEG is 5-10 parts.
Further, the AA is selected from arginine, histidine, lysine and its one of dimerization or polymer or more Kind.
The PEG is straight chain or multi-arm PEG, at least contains a carboxyl, and the multi-arm arm number (n) is 2~16, preferably 2-4, average molecular weight 600-5000.
Further, the preparation method at the alkaline copolymerization center comprising the steps of:
(1) carboxy polyethylene glycol dissolves in deionized water；
(2) activated carboxyl in above-mentioned solution is added in carbodiimides；
(3) alkaline modification object is added in the carboxy polyethylene glycol solution after activation, after adjusting pH value, the reaction was continued；
(4) step (3) products therefrom is dialysed, be lyophilized to get.
The present invention also provides a kind of preparation method of controllable biodegradable copolymer material, the preparation method includes following Step:
(1) lactide, caprolactone of different optical activities or alkaline copolymerization center are added separately in reactor, anti-after mixing It is vacuumized again with filling with inert gas at least twice；
(2) ring opening copolymer reacts: ring-opening polymerization catalyst is added into reactor in a nitrogen atmosphere, reactor is heated To 100-220 DEG C, react 6-72 hours；
(3) after reactor is cooling, the product adding into dichloromethane that step (2) obtains is dissolved, is then existed It is precipitated in dehydrated alcohol, the product of precipitation is dried, obtain modified copolymer.
Wherein, the ring opening copolymer temperature is 100-220 DEG C, preferably 120-160 DEG C.
The ring opening copolymer time is 6-72 hours, preferably 12-24 hours.
The ring-opening polymerization catalyst be selected from one of stannous octoate, triethyl aluminum, lactic acid stannous, dibutyl tin or It is a variety of, preferably stannous octoate.
The dosage molar ratio of the comonomer and ring-opening polymerization catalyst is 1:0.00001-0.005；Preferably, two Person's molar ratio is 1:0.0001-0.001；
Further, in controllable biodegradable copolymer material carrier used in field of tissue engineering technology or device Application, especially preparing the application in nerve trachea.
The invention has the benefit that
(1) biodegradable copolymeric material provided by the present invention, relative molecular weight is adjustable, high mechanical strength, flexible Property is strong, dilation is small, can be used for the Regeneration and Repair of tissue；
(2) biodegradable copolymeric material provided by the present invention is by cooperateing with two kinds of optical isomers of lactide Ratio, the content of PEG, realize the mechanical strength and flexibility for improving material, while reducing the expansion rate that material implants；
(3) introducing at multi-arm polymeric center can effectively regulate and control the conformation of lactic acid units and caprolactone units strand, change The crystal property of kind copolymer, improves the mechanical property of material, prepares the controllable copolymer of degradation cycle；
(4) introducing of basic amino acid and its polymer can not only improve the acid intermediate catabolite of copolymer to tissue The influence of pH value improves blending method to the adverse effect of material mechanical performance, while improving the hydrophily and biofacies of material Capacitive.
Detailed description of the invention
Fig. 1 is regenerating nerve dyeing microscope photograph after nerve autograft is repaired rat sciatic nerve 90 days
Fig. 2 is regenerating nerve dyeing microscope photograph after copolymer nerve trachea is repaired rat sciatic nerve 90 days
Fig. 3 is regenerating nerve dyeing microscope after the nerve trachea of comparative example material preparation is repaired rat sciatic nerve 90 days Picture
Specific embodiment
Embodiment of the present invention and the application in the reparation of periphery neurologic defect are carried out below in conjunction with embodiment detailed Thin description it will be appreciated by those skilled in the art that the following example is merely to illustrate the present invention, and is not construed as limitation originally The range of invention.
Embodiment 1-4 has the straight chain or multi-arm copolymer at alkaline copolymerization center
1 embodiment 1-4 of table formula and its reaction condition
The formula at the alkaline copolymerization of table 2 center
Alkaline copolymerization center the preparation method comprises the following steps: by carboxy polyethylene glycol dissolution in deionized water, then EDCI is added Enter in above-mentioned solution and reacts 45min；Amino acid is added in the carboxy polyethylene glycol solution after activation, and uses the HCl tune of 1M PH value is saved to 4, pH value is raised to 6 the reaction was continued 1h after the reaction was continued at room temperature 2h；Product is saturating in 10 DEG C in the hydrochloric acid solution of 1mM Analysis repeats dialysis twice (dialyzate adds 1% sodium chloride), freeze-drying.
The preparation method of copolymer: alkaline copolymerization center, left-handed, dextrorotation lactide, caprolactone are added to anti-after mixing It answers in device, is vacuumized repeatedly after mixing and inflated with nitrogen 20 times；Ring-opening polymerization catalyst is added into reactor in a nitrogen atmosphere, Reactor is heated to relevant temperature, reacts certain time；Adding into dichloromethane after reactor cooling is dissolved, so It is precipitated in dehydrated alcohol afterwards, the product of precipitation is dried.
Comparative example 1
By 42 parts of levorotatory lactides, 42 parts of dextrorotation lactides, 15 parts of caprolactones, vacuumized repeatedly after mixing and inflated with nitrogen 20 It is secondary；0.002 part/mol stannous octoate is added into reactor in a nitrogen atmosphere, reactor is heated to 120 DEG C, reaction 24 is small When；Adding into dichloromethane after reactor cooling is dissolved, is then precipitated in dehydrated alcohol, by the production of precipitation Object is dried.
Comparative example 2
By 4 parts of levorotatory lactides, 40 parts of dextrorotation lactides, 15 parts of caprolactones, vacuumized repeatedly after mixing and inflated with nitrogen 20 It is secondary；0.0001 part/mol stannous octoate is added into reactor in a nitrogen atmosphere, reactor is heated to 120 DEG C, reaction 24 Hour；Adding into dichloromethane after reactor cooling is dissolved, is then precipitated in dehydrated alcohol, by precipitation Product is dried.
Comparative example 3
PEG, 40 parts of levorotatory lactides, 5 parts of dextrorotation lactides, 40 parts of caprolactones by 15 parts of molecular weight for 600, after mixing It vacuumizes repeatedly and inflated with nitrogen 20 times；0.5 part/mol stannous octoate is added into reactor in a nitrogen atmosphere, by reactor plus Heat is reacted 24 hours to 160 DEG C；Adding into dichloromethane after reactor cooling is dissolved, then in dehydrated alcohol It is precipitated, the product of precipitation is dried.
Comparative example 4
By 15 parts of histidines, 76 parts of levorotatory lactides, 4 parts of dextrorotation lactides, 10 parts of caprolactones, vacuumized repeatedly after mixing With inflated with nitrogen 20 times；0.00095 part/mol stannous octoate is added into reactor in a nitrogen atmosphere, reactor is heated to It 220 DEG C, reacts 6 hours；Adding into dichloromethane after reactor cooling is dissolved, is then sunk in dehydrated alcohol It forms sediment, the product of precipitation is dried.
The tensile Properties of 5 copolymer of embodiment
3 performance of copolymer of table and its tensile property comparison
Lactide L/D in upper table refers to feed ratio when levorotatory lactide polymerize with dextrorotation lactide
The detection of polymer intrinsic viscosity is polymerize according to GB/T 1632.1-2008 plastics using detection of capillary tube viscosity Object dilute solution viscosity is tested, and tensile strength and elongation at break are according to the survey of GB/T 1040.3-2006 plastic tensile performance Determine third portion: the experimental condition of thin modeling and thin slice carries out.Dispersion degree is obtained by the detection of GPC.As shown in Table 5, the present invention provides 3 kinds of copolymers in addition multi-arm copolymerization center, PEG compared with un-added copolymer (comparative example 1,3), elongation at break has It obviously increases, illustrates that copolymer high mechanical strength provided by the invention, flexibility are strong.Comparative example 2 is that dextrorotation polylactic acid content is high Polymer, tensile strength and elongation at break are lower.Alkaline modification object is introduced into copolymer (real using chemical bonding mode Apply a 1-4) compared with copolymer (comparative example 4) prepared by simple blend mode, tensile strength and elongation at break are increased Add, illustrates the copolymer provided by the invention containing alkaline copolymerization center, it is limited to avoid alkaline matter in a polymer matrix Reunion, the mechanical property of material greatly improved.
The cell compatibility and degradation solution pH of the alkaline copolymerization of embodiment 6 center copolymer are studied
The cell compatibility of 6.1 copolymers is tested
Copolymer in embodiment 1-4, comparative example 3-4 is hot pressed into thickness under 150 DEG C and 9MPa with compression molding bed For the diaphragm of 0.2mm, be then cut to the disk that diameter is 15mm, according to ethyl alcohol, tap water, tri-distilled water reiteration Washing three times, is then flushed three times with sterilizing tri-distilled water, the hole bottom of tissue culturing plate is fixed in after washing, is gone out through ultraviolet 1mL cell suspension (1 × 10 is added to the every hole of tissue culturing plate after bacterium5A/mL), at 37 DEG C, 5%CO2And the culture of saturated humidity It is cultivated in case after a certain period of time, with micro- sem observation cellular morphology, then removes culture solution, and washed away with buffer nonadherent thin Cell dissociation on copolymer film finally is got off to count by born of the same parents with pancreatin, calculates cell adherence rate.
6.2 degradation solution pH measurement
Table 4 has the copolymer degradation pH value of different basic amino acids and cell adherence rate compares for 24 hours
Comparative example 3 Comparative example 4 Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4
10 weeks degradation solution pH value 4.15 5.36 6.26 6.77 6.55 6.49
Cell adherence rate (%) for 24 hours 45 50 67 63 72 68
Note: the detection of pH value is detected according to " Chinese Pharmacopoeia " 2015 editions the 4th 0631pH value measuring methods
As shown in Table 4, compared with the copolymer (comparative example 3) without alkaline modification object, the copolymerization containing alkaline modification object Object can effectively increase degradation solution pH, have significant difference, illustrate that alkaline modification object has neutralized the degradation such as lactide caprolactone The acidic materials that process generates can further decrease the copolymer probability that implant site inflammation occurs in vivo.Contain alkalinity Cell adhesion rate of the copolymer of modifier when for 24 hours is significantly higher than the copolymer without alkaline modification object, has conspicuousness poor It is different, illustrate that the cell compatibility of copolymer can be improved in alkaline modification object and PEG.
In comparative example 4, the simple blend of alkaline modification object and polymeric material can increase the pH of degradation solution to a certain extent With cell adhesion rate, but effect is poor, and alkaline modification object is introduced into copolymer by bonding pattern, can more efficient raising material The biocompatibility of material.
The degradation cycle of 7 copolymer of embodiment is studied
5 copolymer of table and its performance comparison
Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Comparative example 3 Comparative example 4
Degradation cycle (week) 55 57 51 53 49 52
Note: degradation test is tried according to YY/T 0473-2004 surgical implant polyactide copolymer and blend external degradation Test progress
As shown in Table 5, the polymer containing alkaline modification object is longer than the copolymer degradation period be free of, by adjusting alkalinity The degradation time of polymer is adjusted in the content of object.
8 copolymer of embodiment prepares nerve trachea effect disquisition in repairing nerve
The preparation of nerve trachea:
Copolymer material prepared by embodiment 2 and comparative example 3 is dissolved in methylene chloride, is centrifuged off bubble, it will be molten In liquid dip-coating to the glass bar of 1.5mm diameter.After dip-coating, glass bar is horizontal positioned, and constantly rotation is to guarantee pipe thickness phase Together.It repeats the above steps, until the thickness needed for obtaining.Glass bar with copolymer layer is placed on 80% ethanol-water solution Middle immersion 20min.Shell is removed from glass bar, and is cut into length appropriate.The pipe of preparation is put immersion 12h in ethanol to remove Remaining organic solvent is removed, is then dried in vacuo at 40 DEG C.
Rat sciatic nerve reparative experiment:
12 wistar rats are randomly divided into nerve autograft group (A), copolymer nerve trachea group (B), comparative example Nerve trachea group (C), every group 4.10% chloraldurate is fixed with 0.4mL/100g intraperitoneal injection of anesthesia, prone position.It is left back Leg preserved skin, iodophor disinfection cut skin, and muscle sufficiently exposes sciatic nerve, and detachment sciatic nerve 6-7mm makes it bounce back naturally To 10mm defect.Under XTS-4A surgical microscope, sciatic nerve is cut and carries out shifting in situ with outer membrane sewing by A group It plants.B, two broken ends of fractured bone of C group is inserted into 2mm row outer membrane and conduit in conduit respectively and sutures, and retains neurologic defect gap 10mm, 11-0 nothing Wound suture is sewed up the incision, sub-cage rearing.
Histological observation:
Conduit cuts Sciatic position distal section regenerating nerve after transplanting 90 days, 10% formalin it is fixed for 24 hours with On, HE dyeing, optical microphotograph sem observation.As a result as shown in Figure 1-3, nerve fibre has no aobvious in nerve autograft group nerve tract Exception is write, the visible thin vessels being dispersed between nerve fibre have no bleeding, essentially normal neuronal growth conditions.Copolymer It is with minimal amount of lymphocyte outside conduit group neuron membrane, bleeding is had no, a large amount of schwann cells is seen in nerve tract, are shown The repairing effect and nerve autograft of conduit group are close.The lymphocyte of volume and a small amount of is seen between comparative example group nerve cell Thick liquid cell has no bleeding, and the quantity of nerve fibre is reduced compared with nerve autograft group and self-control nerve trachea group in nerve tract, small Increased vascularization.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, the embodiment not to The scope of the patents of the invention is limited, all equivalence enforcements or change without departing from carried out by the present invention are intended to be limited solely by the technology of the present invention In the range of scheme.

Claims (10)

1. a kind of alkalinity copolymerization center, is prepared by alkaline modification object and polyethylene glycol, the alkaline modification object is selected from smart ammonia Acid, histidine, lysine and its one of dimerization or polymer are a variety of；The molar content of the alkaline modification object is 2-10 Part, the molar content of polyethylene glycol is 5-10 parts.
2. a kind of copolymer material comprising alkaline copolymerization center, which is characterized in that it include A, B, C ingredient,
The A is alkaline copolymerization center described in claim 1, is made of alkaline modification object and polyethylene glycol；
The B is one of lactide of levorotatory lactide, dextrorotation lactide or difference L/D value or a variety of；
The C is caprolactone.
3. copolymer material as claimed in claim 2, which is characterized in that the copolymer material also includes multi-arm polymeric center.
4. copolymer material according to claim 1, which is characterized in that difference L/D value third is handed in the copolymer material The left-handed of ester, dextrorotation molar ratio are 1:1-19:1；The molar content of lactide is 45-90 parts, and the molar content of caprolactone is 10- 40 parts, the molar content at alkaline copolymerization center is 5-20 parts.
5. controllable biodegradable copolymer material according to claim 1, which is characterized in that the spy of the copolymer material Property viscosity be 1.0-7.0dl/g, polydispersity≤1.5, preferred intrinsic viscosity be 2.0-6.0dl/g, polydispersity≤ 1.3。
6. controllable biodegradable copolymer material according to claim 1-3, which is characterized in that the copolymer Material is the random or block copolymer being prepared by alkaline copolymerization center, lactide and caprolactone.
7. copolymer material according to claim 2, which is characterized in that alkaline modification object is selected from arginine, histidine, relies Propylhomoserin and its one of dimerization or polymer are a variety of.
8. controllable biodegradable copolymer material according to claim 2, which is characterized in that the polyethylene glycol is straight chain Or multi-arm polyethylene glycol, at least contain a carboxyl, the multi-arm arm number is 2~16, average molecular weight 600-5000.
9. the preparation method of controllable biodegradable copolymer material described in -8 according to claim 1, which is characterized in that under including State step:
(1) lactide, caprolactone of different optical activities and alkaline copolymerization center are added separately in reactor, are taken out repeatedly after mixing Vacuum and filling with inert gas are at least twice；
(2) catalyst is added into reactor in a nitrogen atmosphere, reactor heating is reacted；
(3) after reactor is cooling, the product adding into dichloromethane that step (2) obtains is dissolved, then anhydrous It is precipitated in ethyl alcohol, the product of precipitation is dried, obtain modified copolymer.
10. application of the described in any item controllable biodegradable copolymer materials of claim 1-8 in preparation organizational project, excellent The carrier or device of choosing are that peripheral nerve injury repairs conduit, artificial blood vessel, blood vessel ligation clamp, medical anti-adhesive film, angiocarpy Bracket, sustained-release micro-spheres, embolism microball (particle) etc..
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CN101787119A (en) * 2010-03-25 2010-07-28 复旦大学 Polymer with tumor organization pH responsiveness and micelle thereof
CN103992475A (en) * 2014-05-06 2014-08-20 成都市绿科华通科技有限公司 Biocompatible degradable porous polyethylene glycol material
WO2017139212A1 (en) * 2016-02-08 2017-08-17 Cyta Therapeutics, Inc. Particle delivery of rapamycin to the liver
CN106822921B (en) * 2016-12-30 2019-12-20 中国科学院苏州生物医学工程技术研究所 Nano drug-loading system and preparation and application thereof

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