CN108546321B - Preparation and application of high-biocompatibility biodegradable bone filling material - Google Patents

Preparation and application of high-biocompatibility biodegradable bone filling material Download PDF

Info

Publication number
CN108546321B
CN108546321B CN201810355227.6A CN201810355227A CN108546321B CN 108546321 B CN108546321 B CN 108546321B CN 201810355227 A CN201810355227 A CN 201810355227A CN 108546321 B CN108546321 B CN 108546321B
Authority
CN
China
Prior art keywords
phosphorylcholine
polyethylene glycol
diisocyanate
polyurethane urea
lysine diisocyanate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201810355227.6A
Other languages
Chinese (zh)
Other versions
CN108546321A (en
Inventor
侯昭升
时玉祥
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jinan Yushi Information Technology Co ltd
Original Assignee
Jinan Yushi Information Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jinan Yushi Information Technology Co ltd filed Critical Jinan Yushi Information Technology Co ltd
Priority to CN201810355227.6A priority Critical patent/CN108546321B/en
Publication of CN108546321A publication Critical patent/CN108546321A/en
Application granted granted Critical
Publication of CN108546321B publication Critical patent/CN108546321B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/50—Polyethers having heteroatoms other than oxygen
    • C08G18/5075—Polyethers having heteroatoms other than oxygen having phosphorus
    • C08G18/5093—Polyethers having heteroatoms other than oxygen having phosphorus having sulfur in addition to phosphorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
    • C08G18/3225—Polyamines
    • C08G18/3228—Polyamines 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/4009—Two or more macromolecular compounds not provided for in one single group of groups C08G18/42 - C08G18/64
    • C08G18/4018—Mixtures of compounds of group C08G18/42 with compounds of group C08G18/48
    • 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4269—Lactones
    • 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
    • C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
    • C08G18/6603—Compounds of groups C08G18/42, C08G18/48, or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38
    • C08G18/6614—Compounds of groups C08G18/42, C08G18/48, or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3225 or C08G18/3271 and/or polyamines of C08G18/38
    • C08G18/6618—Compounds of groups C08G18/42, C08G18/48, or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3225 or C08G18/3271 and/or polyamines of C08G18/38 with compounds of group C08G18/3225 or polyamines of C08G18/38
    • 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
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/73—Polyisocyanates or polyisothiocyanates acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Polyurethanes Or Polyureas (AREA)

Abstract

The invention belongs to the technical field of biological materials, in particular to preparation and application of a biodegradable bone filling material with high biocompatibility, which consists of polyurethane urea with phosphorylcholine positioned at the tail end of a flexible side chain, wherein the raw materials for preparing the polyurethane urea comprise a single-ended dihydroxy polyethylene glycol phosphorylcholine compound, double-ended hydroxy polydioxanone, L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate, phosphorylcholine groups positioned at the tail end of the flexible polyethylene glycol side chain are easy to be enriched on the surface of the material, so that the hydrophilicity of the material is greatly improved, the deposition of platelets and protein is hindered, the generation of thrombus is avoided, the high biocompatibility is realized, the problems that the biocompatibility of the polyurethane which singly takes polyethylene glycol or phosphorylcholine as the side chain is not high and the mechanical property of the material is poor in the biomedical field, particularly as a long-term implant material are solved, the application in the fields of tissue engineering, drug controlled release, gene therapy, cosmetics and the like is widened.

Description

Preparation and application of high-biocompatibility biodegradable bone filling material
Technical Field
The invention belongs to the technical field of biological materials, particularly relates to the field of biocompatibility modification of biomedical polymer materials, and particularly relates to preparation and application of a biodegradable bone filling material with high biocompatibility.
Background
With the rapid development of biotechnology, biomedical materials have become a hot spot in the current scientific research field. However, in clinical application, the existing biomedical materials and devices have problems of infection, blood coagulation, postoperative tissue proliferation and the like to different degrees, and the biocompatibility problems become key factors for restricting the clinical application of the biomedical materials.
Phosphorylcholine (PC) is the main component of the outer membrane of biological cells and is a compound having-PO4 -(CH2)2N+(CH3)3A compound of the group. Phosphorylcholine is an amphiphilic molecule consisting of a hydrophilic head and a hydrophobic tail. Phosphorylcholine plays a very important role in the metabolic processes of organisms. Polymers containing phosphorylcholine groups, such as 2-Methacryloyloxyethyl Phosphorylcholine (MPC) polymeric membranes, 4-hydroxy-2-butylphosphorylcholine (HBPC) polymeric membranes, and the like, can form bilayers resembling cell membranes under certain conditions. The biocompatibility of the material is improved, and the surface of the biological material is not easy to cause protein adsorption, platelet adhesion and the like, so that reactions such as thrombus, inflammation, cell poisoning and the like are obviously reduced.
Polyethylene glycol (PEG) is a high molecular material used in organisms, has good water solubility and biocompatibility, and is widely applied in the field of preparation. Polyethylene glycol (PEG) has high hydrophilicity and flexibility, and on one hand, the PEG can form a hydrated PEG chain with water to form stable steric hindrance and prevent platelets and the like from being adsorbed on the surface of a material; on the other hand, hydrated PEG chains have lower surface energy in water, and the formed water microflows can hinder the adhesion and deformation of proteins. Therefore, the surface of the material can be modified by utilizing the PEG molecules and the derivatives thereof, and the effect of improving the hydrophilicity is achieved.
The polydioxanone (PPDO) is a novel biodegradable material, is the surgical suture material with the greatest development prospect, and can be used for manufacturing bone plates and tissue repair materials and used as a framework material of a drug slow-release system. The PPDO has relatively good comprehensive performance, the molecular chain has good flexibility due to the special ether bond, and the polymer has excellent flexibility, tensile strength and knotting strength, and the strength retention rate in the degradation process is high. Compared with the hard brittle polylactic acid (PLA), the tensile strength of the high molecular weight polylactic acid reaches more than 60MPa, and the elongation at break is lower than 10 percent; however, the tensile strength of high molecular weight polydioxanone can reach more than 30MPa, and the elongation at break can reach more than 300%, which is far higher than that of polylactic acid. Compared with semi-crystalline Polycaprolactone (PCL), the ether bond in PPDO greatly enhances the hydrophilicity, and the period of complete degradation and absorption of the material is about 6 months, which is far faster than that of polycaprolactone.
Patent CN107216435A discloses a novel polyurethane urea with phospholipid polyethylene glycol as side chain and its preparation method. Hydroxyl-terminated polyester is firstly reacted with a certain amount of Lysine Diisocyanate (LDI), and then chain extension is carried out by using chain extender terminated diamino phosphatide polyethylene glycol to obtain the novel poly (urethane-urea) with the side chain being phosphatide polyethylene glycol. The soft polyurethane segment is polyester and the hard segment contains carbamate and carbamide. Although the biocompatibility is high, the material cannot be well applied to the body as an implant material in vivo, particularly as a bone filling material because the mechanical property is not high.
Patents CN106674484A and CN106674486A disclose a polyether containing phosphorylcholine in its side chain and a polyester polyurethane material, respectively, and their preparation methods. The invention firstly uses polyether or polyester diol to react with excessive diisocyanate, and then uses diamino phosphorylcholine compound to carry out chain extension to obtain the phosphorylcholine modified polyurethane. The process is simple and easy to implement, the biocompatibility of the modified material is improved, but the side chain is relatively short and has no flexibility, the phosphorylcholine group is relatively difficult to self-assemble in a water environment, so that the utilization rate of the phosphorylcholine group is low, and the side chain only contains phosphorylcholine, so that the material still has the problem of low biocompatibility when being applied to organisms as a biological material, particularly as a long-term implantable material.
In recent years, research has been conducted on preparing a double-end hydroxyl poly (p-dioxanone) prepolymer (HPPDO) by ring-opening polymerization of p-dioxanone (PDO) with stannous octoate as a catalyst and 1, 4-butanediol as an initiator, and preparing a high-molecular-weight target chain extension product (HPPDO-T or HPPDO-H) by chain extension of the prepolymer with toluene-2, 4-diisocyanate (TDI) or Hexamethylene Diisocyanate (HDI) as a chain extender. Compared with homopolymer, the chain-extended product has better thermal stability, higher tensile strength and better flexibility, and the chain structure has larger influence on the thermal stability and tensile property of the product. After chain extension, the melt viscosity of the product is obviously enhanced, and the shear stress under the same shear rate is also obviously increased. However, in vitro degradation experiments with buffer solutions revealed that the degradation rate of the chain extended product was very close compared to that of the homopolymer, i.e. chain extension did not improve the in vitro degradation performance of PPDO.
In light of the above deficiencies of the prior art, there is a need for a bone filling material that is safe, mechanically functional, biocompatible, less in protein adsorption, degradable, and absorbable.
Disclosure of Invention
In view of the problems in the prior art, a first object of the present invention is to provide a method for preparing a diisocyanate chain extender containing a urea group structure, which comprises the following steps:
1) dropping 1, 4-butanediamine into L-lysine diisocyanate under the protection of dry nitrogen and mechanical stirring, and reacting at room temperature for about 1-3h to obtain a suspension D;
2) adding n-hexane into the suspension D, stirring uniformly, performing suction filtration to obtain a white solid, repeatedly washing with n-hexane until no-NCO absorption peak (2270 cm) is detected in filtrate IR-1) And drying in vacuum to constant weight to obtain white powdery diisocyanate.
The reaction formula is as follows:
Figure BDA0001634516610000021
preferably, L-lysine diisocyanate and 1,4-NH-NCO of butanediamine2The molar ratio of (a) to (b) is 6:1 to 12: 1.
Preferably, the volume of n-hexane in step 2) is 4 times the volume of suspension D.
The prepared diisocyanate is L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate (LBL);
the structural formula of LBL:
Figure BDA0001634516610000031
the diisocyanate is applied as a chain extender for preparing bone filling materials.
The second purpose of the invention is to provide a biodegradable bone filling material with high biocompatibility, a polyurethane urea with phosphorylcholine positioned at the tail end of a flexible side chain, wherein the side chain is flexible polyethylene glycol, phosphorylcholine groups are positioned at the tail end of the side chain polyethylene glycol, and the phosphorylcholine groups positioned at the tail end of the side chain of the flexible polyethylene glycol are easy to be enriched on the surface of the material in the using process of the material, so that the hydrophilicity of the material is greatly improved, the deposition of platelets and proteins is prevented, the generation of thrombus is avoided, the material has high biocompatibility, the problems of low biocompatibility and poor mechanical property of the material of polyurethane which the side chain is independently polyethylene glycol or phosphorylcholine in the biomedical field, particularly as a long-term implanted material, are solved, and the application in the fields of tissue engineering, drug controlled release, gene therapy, cosmetics and the like is widened.
A biodegradable bone filling material with high biocompatibility is composed of the polyurethane urea whose phosphorylcholine is at the end of flexible side chain, the mixture of single-end dihydroxy polyethanediol phosphorylcholine compound and double-end hydroxy polydioxanone, and the chain extension by the diisocyanate chain extender containing carbamido structure, the number-average molecular weight of said polyurethane urea is 1.0X 105～5.0×105The dispersion coefficient is 1.30-1.62; the structural formula of the synthesized polyurethane urea is as follows:
Figure BDA0001634516610000032
wherein:
R1：
Figure BDA0001634516610000033
R2：
Figure BDA0001634516610000034
R3：
Figure BDA0001634516610000035
wherein the PC is a copolymer of a monomer and a monomer,
Figure BDA0001634516610000036
m＝4～50，n1＝4～50，n2＝4～50。
the mass content of the PC group in the polyurethane urea is 0.3-2.0 wt%.
The density of the bone filling material is about 1.0-1.3 g/cm3A hardness of about 150 to 200N/mm2The time taken for degradation (when the bone material is fragmented and loses mechanical properties, degradation is considered complete and is defined as degradation time) is about 105 to 123 days.
The adsorption capacity of the protein of the membrane material prepared by the bone filling material through a solvent volatilization method is less than 0.5 mu g/cm2。
The third purpose of the invention is to provide a preparation method of the high-biocompatibility biodegradable bone filling material, which comprises the following steps:
1) single-end dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2) Mixing with poly (p-dioxanone) (PPDO) with hydroxyl at both ends, and adding LBL to obtain a solution of polyurethane urea;
2) diluting the solution of the polyurethaneurea obtained in the step 1) with DMF (dimethyl formamide) to a concentration of 6-10 g/100mL, adding glacial ethyl ether for sedimentation, and carrying out vacuum drying on the obtained solid until the weight is constant to obtain purified polyurethaneurea;
3) dissolving the polyurethane urea material obtained in the step 2) in an organic solvent, stirring for 12-16h at 40 ℃ to obtain a homogeneous solution, and putting the homogeneous solution into a mold (polytetrafluoroethylene) for freeze drying to obtain the cellular polyurethane urea solid bone material.
Single-end dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2) The number average molecular weight of the compound is 500-2700, and the number average molecular weight of the double-end hydroxyl polydioxanone (PPDO) is 1000-6000.
Preferably, PC- (OH)2The number average molecular weight of (A) is 500 to 2000; the molecular weight distribution is 1.12-1.21;
preferably, the number average molecular weight of PPDO is 2000-5500; the molecular weight distribution is 1.15 to 1.25.
The polyurethane urea bone material can be cut into various dosage forms required by organisms;
wherein, the freezing method is a method in the prior art and comes from Chinese patent CN 201510250602.7;
preferably, in step 1), PC- (OH)2The feeding molar ratio of the PPDO to the PPDO is 0.1: 1-0.3: 1.
Preferably, in step 1), PC- (OH)2Dissolving with PPDO in DMF at concentration of 0.4-0.6 g/mL.
Preferably, the concentration of the DMF solution of LBL in the step 1) is 0.5-1g/mL, and the dropping speed is 10 mL/min.
Preferably, the-NCO of LBL in step 1) is reacted with the-OH and PC- (OH) of PPDO2The molar ratio of the-OH to the-OH is 1.01:1 to 1.05: 1.
Preferably, the chain extension reaction in the step 1) is carried out under dry nitrogen, the reaction temperature is 65-90 ℃, and the reaction time is 3-6 hours.
Preferably, the purification method of the polyurethaneurea in the step 2) is to add DMF (dimethyl formamide) into the system to dilute the system until the concentration is 6-10 g/100mL, 8 times of the volume of the system is settled by using ethyl glacial ether at-10-0 ℃, and the obtained solid is dried in vacuum at the normal temperature of 35-45 ℃ until the weight is constant.
Preferably, the organic solvent is a benign solvent of polyurethane urea with a freezing point of-10 to 10 ℃;
further preferably, the organic solvent is dioxane.
Single-end dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2)，PC-(OH)2The number average molecular weight of the compound is 500-2700, and the compound is prepared by the addition reaction of alpha-thioglycerol and acrylate-terminated phosphorylcholine polyethylene glycol sulfydryl-vinyl; PC- (OH)2The structural formula of (A) is:
Figure BDA0001634516610000041
wherein PC is
Figure BDA0001634516610000042
n1＝4～50。
PC-(OH)2The preparation method comprises the following specific steps:
1) under the protection of dry argon, adding alpha-thioglycerol and acrylate-terminated phosphorylcholine polyethylene glycol into a reaction bottle, adding anhydrous dimethyl sulfoxide with the concentration of 1.0g/mL for dissolving, and uniformly mixing to obtain a mixture B;
2) adding a catalyst of tolidine into the mixture B obtained in the step 2), and obtaining a mixture C after a period of time;
3) the mixture C was precipitated with anhydrous ether, washed and finally dried under vacuum at 70-90 ℃ to constant weight.
The acrylate-terminated phosphorylcholine-based polyethylene glycol used in the preparation method is from Chinese patent CN 201710681598.9.
Preferably, the molar ratio of the alpha-thioglycerol to the acrylate-terminated phosphorylcholine-based polyethylene glycol in the step 1) is 1.05: 1-1.08: 1.
Preferably, the catalyst tolidine in the step 2) is 1-3% of the total mass of the alpha-thioglycerol and the acrylate-terminated phosphorylcholine polyethylene glycol.
Preferably, the reaction time in the step 2) is 24-36 h.
Preferably, the volume of the anhydrous ether in the step 3) is 20-30 times of the volume of the mixture.
The reaction formula is as follows:
Figure BDA0001634516610000051
wherein PC is
Figure BDA0001634516610000052
n1＝4～50。
The fourth purpose of the invention is to provide the application of the high-biocompatibility biodegradable bone filling material in the medical field of long-term implantation materials in human bodies.
Preferably, the hardness of the bone filling material is 150-180N/mm2) The density is 1.024-1.288 g/cm3The degradation time is less than 130d, and the protein adsorption capacity is less than 0.5 mu g/cm2。
The invention has the beneficial effects that:
1. the phosphorylcholine group is positioned at the tail end of the flexible polyethylene glycol side chain, and the phosphorylcholine group positioned at the tail end of the flexible polyethylene glycol chain is easy to enrich on the surface of the material in the using process of the material, so that the hydrophilicity of the material is greatly improved, the deposition of platelets and protein is hindered, the generation of thrombus is avoided, the polyurethane has high biocompatibility, and the problems that the biocompatibility of polyurethane which singly takes polyethylene glycol or phosphorylcholine as the side chain is not high and the mechanical property of the material is poor in the biomedical field, particularly as a long-term implant material are solved.
2. The chain extender used in the invention is multiblock aliphatic diisocyanate containing carbamido, the degradation products are lysine and aliphatic diamine, which are nontoxic and absorbable, meanwhile, the carbamido enhances the microphase separation of the material, and more carbamate groups and carbamido groups in the hard segment can form compact hydrogen bonds, thereby improving the mechanical property of the material. On the other hand, the degradation product is an alkaline substance, and can neutralize acidic substances generated by the degradation of PPDO chain segments, thereby avoiding the generation of acidic inflammation.
3. The single-ended dihydroxypolyethylene glycol phosphorylcholine compound (PC- (OH) used in the present invention2) The hydroxyl groups have similar activity in the end hydroxyl groups of polyether, polyester and polyester ether in the preparation of polyurethane, so that the hydroxyl groups can be mixed in any proportion and then subjected toThe polyurethane is prepared by chain extension, and the content of PC in the product is easy to control. The amino activity of the single-end diamino polyethylene glycol phosphorylcholine compound is higher, and the compound can only be used for preparing a chain extender of polyurethane by a two-step method.
4. The high-biocompatibility biodegradable bone filling material provided by the invention has excellent biodegradability, biocompatibility (particularly blood compatibility) and bioabsorbability.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The invention will be further illustrated by the following examples
Example 1
Preparation of diisocyanate chain extender LBL containing carbamido structure
Under the protection of dry nitrogen and mechanical stirring, 1, 4-butanediamine is added dropwise to L-lysine diisocyanate (-NCO: -NH)21: 8, molar ratio) at room temperature for 2h, adding four times of volume of n-hexane into the reaction product, stirring uniformly, performing suction filtration to obtain a white solid, and repeatedly washing the white solid with n-hexane until no-NCO absorption peak (2270 cm) is detected in filtrate IR-1) And vacuum drying to constant weight to obtain white powdery LBL.
Example 2
Under the protection of dry nitrogen, 6.5g (5mmol) of dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2，Mn1300) with 60.0g (25mmol) polydioxanone (PPDO, M)n2400), adding N, N-Dimethylformamide (DMF) to dissolve (0.5g/mL), heating the reaction system to 80 ℃, dropwise adding LBL (30.6mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 4.0h after the dropwise adding is finished, reducing the temperature to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating by 8 times of volume of glacial ethyl ether, and performing vacuum drying on the obtained solid at 35 ℃ to obtain the high-biocompatibility biodegradable polyurethane urea;
dissolving the polyurethane urea in dioxane, controlling the mass volume concentration to be 60%, stirring the solution at 40 ℃ for 12h to obtain a homogeneous solution, and putting the homogeneous solution into a mold (polytetrafluoroethylene) for freeze drying to obtain the biodegradable bone filling material I with high biocompatibility.
Example 3
Under the protection of dry nitrogen, 6.5g (5mmol) of dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2，Mn1300) with 48.0g (20mmol) polydioxanone (PPDO, M)n2400), adding N, N-Dimethylformamide (DMF) to dissolve (0.5g/mL), heating the reaction system to 85 ℃, dropwise adding LBL (25.8mmol) DMF solution (1.0g/mL), keeping the temperature to continue reacting for 3.5h after the dropwise adding is finished, reducing to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating with 8 times of volume of glacial ethyl ether, and vacuum drying the obtained solid at 35 ℃ to obtain the high-biocompatibility biodegradable polyurethane urea;
dissolving the polyurethane urea in dioxane, controlling the mass volume concentration to be 60%, stirring the solution at 40 ℃ for 12h to obtain a homogeneous solution, and putting the homogeneous solution into a mold (polytetrafluoroethylene) for freeze drying to obtain the biodegradable bone filling material II with high biocompatibility.
Example 4
Under the protection of dry nitrogen, 3.6g (4mmol) of dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2，Mn900) with 27.9g (15.5mmol) polydioxanone (PPDO, M)n1800), adding N, N-Dimethylformamide (DMF), dissolving (0.6g/mL), heating the reaction system to 90 ℃, dropwise adding LBL (20.3mmol) DMF solution (1.0g/mL), and keeping the temperature after dropwise addingContinuing to react for 3.0h, cooling to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating with 8 times of volume of ethyl glacial ether, and vacuum drying the obtained solid at 35 ℃ to obtain the biodegradable polyurethane urea with high biocompatibility;
dissolving the polyurethaneurea in dioxane, controlling the mass volume concentration to be 50%, 60% and 70%, respectively, stirring the solution at 40 ℃ for 12h to obtain a homogeneous solution, putting the homogeneous solution into a mold (polytetrafluoroethylene) for freeze drying to obtain the high-biocompatibility biodegradable bone filling materials III-a, III-b and III-c.
Example 5
Under the protection of dry nitrogen, 4.5g (5mmol) of dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2，Mn900) with 90.00g (25mmol) polydioxanone (PPDO, M)n3600), adding N, N-Dimethylformamide (DMF) to dissolve (0.6g/mL), heating the reaction system to 75 ℃, dropwise adding LBL (30.6mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 4.5h after the dropwise adding is finished, cooling to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating with 8 times of volume of glacial ethyl ether, and vacuum drying the obtained solid at 35 ℃ to obtain the high-biocompatibility biodegradable polyurethane urea;
dissolving the polyurethaneurea in dioxane, controlling the mass volume concentration to be 60%, stirring the solution at 40 ℃ for 12h to obtain a homogeneous solution, and putting the homogeneous solution into a mold (polytetrafluoroethylene) for freeze drying to obtain the biodegradable bone filling material IV with high biocompatibility.
Example 6
9.0g (5mmol) of dihydroxypolyethylene glycol phosphorylcholine compounds (PC- (OH) were added under dry nitrogen2，Mn1800) with 183.60g (34mmol) polydioxanone (PPDO, M)n5400), adding N, N-Dimethylformamide (DMF) to dissolve (0.5g/mL), heating the reaction system to 80 ℃, dropwise adding LBL (39.8mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 3.8h after the dropwise adding is finished, cooling to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating with 8 times of volume of glacial ethyl ether, and vacuum drying the obtained solid at 35 ℃ to obtain the high-biocompatibility biodegradable polyurethane urea;
dissolving the polyurethane urea in dioxane, controlling the mass volume concentration to be 60%, stirring the solution at 40 ℃ for 12h to obtain a homogeneous solution, and putting the homogeneous solution into a mold (polytetrafluoroethylene) for freeze drying to obtain the biodegradable bone filling material V with high biocompatibility.
Example 7
Under the protection of dry nitrogen, 8.1g (4.5mmol) of dihydroxy polyethylene glycol phosphorylcholine compound (PC- (OH)2，Mn1800) with 135.0g (25mmol) polydioxanone (PPDO, M)n5400), adding N, N-Dimethylformamide (DMF) to dissolve (0.5g/mL), heating the reaction system to 85 ℃, dropwise adding LBL (30.1mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 3.2h after the dropwise adding is finished, cooling to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating with 8 times of volume of glacial ethyl ether, and vacuum drying the obtained solid at 35 ℃ to obtain the high-biocompatibility biodegradable polyurethane urea;
the polyurethaneurea is dissolved in dioxane, the mass volume concentration is controlled to be 60%, the solution is stirred for 12 hours at the temperature of 40 ℃ to obtain a homogeneous solution, and the homogeneous solution is put into a mold (polytetrafluoroethylene) for freeze drying to obtain the biodegradable bone filling material VI with high biocompatibility.
Analytical methods the following analytical methods were used in all examples unless otherwise indicated.
Density of bone filling material: the density of the bone filler material was measured using a densitometer model TP655, by new dimension instruments ltd, beijing.
Molecular weight and molecular weight distribution: polyurethaneurea molecular weight and molecular weight distribution were measured using an Alpha gel chromatograph (GPC) from Water corporation, USA, and 4mg of the sample was dissolved in 2mL of tetrahydrofuran, filtered into a dedicated chromatographic flask using a 0.4 μm filter head, and the mobile phase rate was 0.5mL/min, the temperature of the column box was set at 35 ℃, and the standard was monodisperse polystyrene.
And (3) testing mechanical properties: the mechanical property tests of the bone filling material are all carried out on a microcomputer-controlled universal material experiment machine of Shenzhen Rungel instruments Limited. The samples used were 1X 2cm3In the bone filling material of (1), in the measurementBefore testing, the samples were all baked in an oven at 40 ℃ for 4h to eliminate the influence of moisture on the mechanical properties of the samples.
Degradation performance: mixing 1X 1cm3The bone filling material is soaked in physiological saline, the constant temperature of 37 ℃ is maintained, the state of the membrane material is observed in a period of one day, when the bone material generates fragments and loses mechanical property, the degradation is considered to be finished, and the degradation time is determined.
Protein adsorption amount: preparation of membrane material: dissolving bone material in dioxane to obtain 6.5% (g/mL) solution, volatilizing with polytetrafluoroethylene mold at 25 deg.C under normal pressure for 80 hr, taking off the membrane from the mold, and vacuum drying at normal temperature to obtain membrane material with thickness of 0.02 mm. The membrane material was soaked in Phosphate Buffered Saline (PBS) having a pH of 7.4 to sufficiently swell and equilibrate, and after being taken out, it was placed in Bovine Serum Albumin (BSA) solution having a concentration of 0.6g/L, and soaked in a constant-temperature water bath at 37 ℃ for 2 hours. After completion, the membrane was removed and rinsed 3 times thoroughly with PBS buffer. Then ultrasonically cleaning the mixture for 20min by using 1% (w/w) SDS solution (PBS solution), accurately transferring the cleaning solution with the same volume into a test tube with a plug, adding working solution (Pierce Inc., Rockford, 23235) of a Micro-BcATM protein detection kit, fully mixing, sealing, and keeping the temperature of a water bath at 60 ℃ for lh. And finally, naturally cooling to room temperature, measuring absorbance at the wavelength of 562nm by using an ultraviolet-visible spectrophotometer, calculating the adsorption capacity according to a standard curve, and taking the average value of 3 samples.
Hardness of bone filling material: a Brinell hardness test method is adopted, a steel ball with the diameter of D (millimeter) is pressed into the surface of a tested material by a load P (Newton) with a certain size in the test, the load is removed after being kept for a certain time, an indentation with the diameter of D (millimeter) is left on the surface, the surface area F of the indentation is calculated, the Brinell hardness value is obtained according to the following formula and is represented by HB.
Porosity of the bone filler material: the porosity of the bone material was measured in parallel 3 times by mercury intrusion method and the average value was taken.
The properties of one of the highly biocompatible degradable bone filling materials of examples 2 to 7 are shown in Table 1.
TABLE 1 Properties of the polyurethaneureas
Figure BDA0001634516610000091
*PC：
Figure BDA0001634516610000092
As shown in Table 1, the polyurethane urea prepared by the method provided by the patent has high molecular weight, and the hardness of the corresponding film material is 150-180 (N/mm)2) The density is 1.024-1.288 (g/cm)3) And meets the requirements of the scaffold material for organism tissue engineering repair. As the content of the soft segment is increased, the bone hardness is reduced, the degradation time is increased, and the protein adsorption quantity is reduced. The degradation time of the bone material is more than ten weeks, and the longest degradation time is seventeen weeks. The degradation time of the bone filling material is related to the content of phosphorylcholine and the type and porosity of the raw material of polyurethane urea, and the higher the crystallinity of the modified polyurethane urea material is, the slower the degradation is; the higher the porosity, the faster the degradation. The samples in the examples of this patent had a protein adsorption of less than 0.5. mu.g/cm2Even at an adsorption capacity of 0.11. mu.g/cm2The material shows excellent biocompatibility and can be used for organisms for a long time.
Of LBL1H NMR structural characterization:
1H NMR(DMSO-D6,ppm):1.27-1.32(m,10H， 3CHCH2and C 2HCH2CHNCO)，1.52-1.55(m,8H, 2CHCH2NH),1.75(q，4H, 2CHCHNCO),3.12-3.18(t,8H, 2CHNH),4.08-4.15(m,6H, CH-NCO and CH)3C 2H)，5.95-6.04(br,NH)。
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims (21)

1. A preparation method of diisocyanate chain extender containing carbamido structure is characterized in that: the method comprises the following specific steps:
1) dropping 1, 4-butanediamine into L-lysine diisocyanate under the protection of dry nitrogen and mechanical stirring, and reacting at room temperature for 1-3h to obtain a suspension D;
2) adding n-hexane into the suspension D, stirring, vacuum filtering to obtain white solid, repeatedly washing with n-hexane until the IR detection of the filtrate is 2270cm-1no-NCO absorption peak is formed, and the white powdery diisocyanate containing the carbamido structure is obtained after vacuum drying to constant weight;
the diisocyanate containing the carbamido structure is L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate, and the structural formula is as follows:
Figure FDA0002656151030000011
NH is the ratio of-NCO to-NH of L-lysine diisocyanate and 1, 4-butanediamine in the step 1)2The molar ratio of (a) to (b) is 6:1 to 12: 1.
2. Use of the diisocyanate containing a ureido structure obtained by the process according to claim 1 as a chain extender for the preparation of bone filling materials.
3. A high-biocompatibility biodegradable bone filling material is characterized in that: the polyurethane urea consists of phosphorylcholine at the tail end of a flexible side chain, a single-end dihydroxy polyethylene glycol phosphorylcholine compound is mixed with double-end hydroxyl poly (p-dioxanone), and then the chain is extended by using the diisocyanate chain extender containing a carbamido structure in claim 1, wherein the number average molecular weight of the polyurethane urea is 1.0 x 105～5.0×105The dispersion coefficient is 1.30-1.62; the structural formula of the synthesized polyurethane urea is as follows:
Figure FDA0002656151030000012
wherein:
R1：
Figure FDA0002656151030000013
R2：
Figure FDA0002656151030000014
R3：
Figure FDA0002656151030000015
wherein the PC is a copolymer of a monomer and a monomer,
Figure FDA0002656151030000016
m＝4～50，n1＝4～50，n2＝4～50；
the mass content of the PC group in the polyurethane urea is 0.3-2.0 wt%.
4. A method for preparing the highly biocompatible biodegradable bone filling material according to claim 3, wherein: the method comprises the following specific steps:
1) mixing a single-ended dihydroxy polyethylene glycol phosphorylcholine compound with double-ended hydroxy poly (p-dioxanone), and adding an L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate solution to obtain a solution of polyurethaneurea;
2) diluting the solution of the polyurethaneurea obtained in the step 1) with DMF (dimethyl formamide) to a concentration of 6-10 g/100mL, adding glacial ethyl ether for sedimentation, and carrying out vacuum drying on the obtained solid until the weight is constant to obtain purified polyurethaneurea;
3) dissolving the polyurethane urea material obtained in the step 2) in an organic solvent, stirring for 12-16h at 40 ℃ to obtain a homogeneous solution, and putting the homogeneous solution into a polytetrafluoroethylene mold for freeze drying to obtain the cellular polyurethane urea solid bone material.
5. The method of claim 4, wherein: in the step 1), the single-end dihydroxy polyethylene glycol phosphorylcholine compound and the double-end hydroxy poly (p-dioxanone) are dissolved in DMF, and the concentration is 0.4-0.6 g/mL.
6. The method of claim 4, wherein: the concentration of the DMF solution of the L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate in the step 1) is 0.5 to 1g/mL, and the dropping speed is 10 mL/min.
7. The method of claim 4, wherein: the chain extension reaction in the step 1) is carried out under dry nitrogen, the reaction temperature is 65-90 ℃, and the reaction time is 3-6 hours.
8. The method of claim 4, wherein: the purification method of the polyurethaneurea in the step 2) is to add DMF (dimethyl formamide) into the system to dilute the system until the concentration is 6-10 g/100mL, 8 times of volume of glacial ethyl ether is settled, and the obtained solid is dried in vacuum at the normal temperature of 35-45 ℃ until the weight is constant.
9. The method of claim 4, wherein: the organic solvent in the step 3) is a benign solvent of polyurethane urea with a freezing point of-10 to 10 ℃.
10. The method of claim 9, wherein: the organic solvent is dioxane.
11. The method of claim 4, wherein: the feeding molar ratio of the single-end dihydroxy polyethylene glycol phosphorylcholine compound to the double-end hydroxyl poly (p-dioxanone) in the step 1) is 0.1: 1-0.3: 1; the molar ratio of the-NCO of the L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate to the sum of the-OH of the double-end hydroxyl group polydioxanone and the-OH of the single-end dihydroxy polyethylene glycol phosphorylcholine compound is 1.01: 1-1.05: 1.
12. The method of claim 4, wherein: the number average molecular weight of the single-ended dihydroxy polyethylene glycol phosphorylcholine compound is 500-2700, and the number average molecular weight of the double-ended hydroxy poly (p-dioxanone) is 1000-6000.
13. The method of manufacturing according to claim 12, wherein: the number average molecular weight of the single-ended dihydroxy polyethylene glycol phosphorylcholine compound is 500-2000; the molecular weight distribution is 1.12 to 1.21.
14. The method of manufacturing according to claim 12, wherein: the number average molecular weight of the double-end hydroxyl poly (p-dioxanone) is 2000-5500; the molecular weight distribution is 1.15 to 1.25.
15. The bone filler material of claim 3, wherein: the method for preparing the single-ended dihydroxy polyethylene glycol phosphorylcholine compound according to claim 3, comprising the following steps:
1) under the protection of dry argon, adding alpha-thioglycerol and acrylate-terminated phosphorylcholine polyethylene glycol into a reaction bottle, adding anhydrous dimethyl sulfoxide with the concentration of 1.0g/mL for dissolving, and uniformly mixing to obtain a mixture B;
2) adding a catalyst of tolidine into the mixture B obtained in the step 1) to obtain a mixture C after a period of time;
3) and dissolving the mixture C in anhydrous ether, settling, washing, and finally drying at 70-90 ℃ in vacuum to constant weight.
16. The bone filler material of claim 15, wherein: in the step 2), the catalyst tolidine is 1-3% of the total mass of the alpha-thioglycerol and the acrylate-terminated phosphorylcholine-based polyethylene glycol.
17. The bone filler material of claim 15, wherein: the reaction time in the step 2) is 24-36 h.
18. The bone filler material of claim 15, wherein: the volume of the anhydrous ether in the step 3) is 20-30 times of the volume of the mixture.
19. The bone filler material of claim 15, wherein: the molar ratio of the alpha-thioglycerol to the acrylate-terminated phosphorylcholine-based polyethylene glycol in the step 1) is 1.05: 1-1.08: 1.
20. Use of the highly biocompatible biodegradable bone filler material according to claim 3 for the preparation of a long-term implant material for the human body.
21. Use according to claim 20, characterized in that: the hardness of the bone filling material is 150-180N/mm2The density is 1.024-1.288 g/cm3The degradation time is less than 130d, and the protein adsorption capacity is less than 0.5 mu g/cm2。
CN201810355227.6A 2018-04-19 2018-04-19 Preparation and application of high-biocompatibility biodegradable bone filling material Active CN108546321B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810355227.6A CN108546321B (en) 2018-04-19 2018-04-19 Preparation and application of high-biocompatibility biodegradable bone filling material

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810355227.6A CN108546321B (en) 2018-04-19 2018-04-19 Preparation and application of high-biocompatibility biodegradable bone filling material

Publications (2)

Publication Number Publication Date
CN108546321A CN108546321A (en) 2018-09-18
CN108546321B true CN108546321B (en) 2020-11-03

Family

ID=63515624

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810355227.6A Active CN108546321B (en) 2018-04-19 2018-04-19 Preparation and application of high-biocompatibility biodegradable bone filling material

Country Status (1)

Country Link
CN (1) CN108546321B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110627996A (en) * 2019-10-08 2019-12-31 苏州大学 Polyurethane urea, preparation method thereof and super-tough polyurethane urea based on polyurethane urea

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1903383A (en) * 2004-07-26 2007-01-31 株式会社Gc Bioabsorbable polymeric granular porous bone filling material and production method thereof
CN101096415A (en) * 2007-06-26 2008-01-02 四川大学 Poly(P-dioxanone) and preparation method thereof
CN101503501A (en) * 2009-03-02 2009-08-12 四川大学 Biodegradable nontoxic amphipathic multi-block polyurethane material and preparation thereof
CN105601565A (en) * 2014-11-20 2016-05-25 万华化学集团股份有限公司 Method for preparing polyisocyanate containing biuret structure with stable storage
CN106589290A (en) * 2016-12-28 2017-04-26 山东师范大学 High-biocompatibility phosphorylcholine-modified polyurethane material and prepration method thereof
CN107216435A (en) * 2017-06-26 2017-09-29 山东师范大学 A kind of new side chain is the poly- of phosphatide polyethylene glycol（Urethane urea）And preparation method thereof
CN107474239A (en) * 2017-08-10 2017-12-15 山东师范大学 A kind of acrylate ended Phosphorylcholine base polyethylene glycol and preparation method thereof
CN108586293A (en) * 2018-04-19 2018-09-28 济南羽时信息科技有限公司 A kind of biodegradable high intensity polyurethane polyetherester urea foam and preparation method thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9827349B1 (en) * 2013-11-26 2017-11-28 Abyrx Inc. Settable surgical implants and their packaging
US9873805B2 (en) * 2015-06-10 2018-01-23 Flint Group North America Corporation Solvent-based flexible packaging ink composition for high temperature and pressure

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1903383A (en) * 2004-07-26 2007-01-31 株式会社Gc Bioabsorbable polymeric granular porous bone filling material and production method thereof
CN101096415A (en) * 2007-06-26 2008-01-02 四川大学 Poly(P-dioxanone) and preparation method thereof
CN101503501A (en) * 2009-03-02 2009-08-12 四川大学 Biodegradable nontoxic amphipathic multi-block polyurethane material and preparation thereof
CN105601565A (en) * 2014-11-20 2016-05-25 万华化学集团股份有限公司 Method for preparing polyisocyanate containing biuret structure with stable storage
CN106589290A (en) * 2016-12-28 2017-04-26 山东师范大学 High-biocompatibility phosphorylcholine-modified polyurethane material and prepration method thereof
CN107216435A (en) * 2017-06-26 2017-09-29 山东师范大学 A kind of new side chain is the poly- of phosphatide polyethylene glycol（Urethane urea）And preparation method thereof
CN107474239A (en) * 2017-08-10 2017-12-15 山东师范大学 A kind of acrylate ended Phosphorylcholine base polyethylene glycol and preparation method thereof
CN108586293A (en) * 2018-04-19 2018-09-28 济南羽时信息科技有限公司 A kind of biodegradable high intensity polyurethane polyetherester urea foam and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Biodegradable poly(ester urethane)urea elastomers with variable amino content for subsequent functionalization with phosphorylcholine;Jun Fang等;《Acta Biomaterialia》;20141130;第10卷(第11期);第4639-4649页 *
磷酰胆碱改性聚氨酯材料的抗血小板粘附 磷酰胆碱改性聚氨酯材料的抗血小板粘附 磷酰胆碱改性聚氨酯材料的抗血小板粘附 磷酰胆碱改性聚氨酯材料的抗血小板粘附 磷酰胆碱改性聚氨酯材料的抗血小板粘附 磷酰胆碱改性聚氨酯材料的抗血小板粘附性研究;高斌;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20150131(第1期);全文 *

Also Published As

Publication number Publication date
CN108546321A (en) 2018-09-18

Similar Documents

Publication Publication Date Title
JP5600062B2 (en) High modulus polyurethane and polyurethane / urea compositions
Yu et al. Tyrosine–PEG-derived poly (ether carbonate) s as new biomaterials: Part I: synthesis and evaluation
EP0396429B1 (en) Polyurethane-based polymeric materials and biomedical articles and pharmaceutical compositions utilizing the same
US8574311B2 (en) Versatile biodegradable elastic polymers featured with dual crosslinking mechanism for biomedical applications
AU2006321721B2 (en) Biocompatible surgical compositons
US20080140185A1 (en) Biodegradable and Biocompatible Peg-Based Poly(Ester-Urethanes)
CN108421086B (en) Nano-hydroxyapatite modified polyurethane urea bone repair material and preparation method thereof
Bahadur et al. Biocompatible waterborne polyurethane-urea elastomer as intelligent anticancer drug release matrix: a sustained drug release study
EP2629762B1 (en) Pendant hydrophile bearing biodegradable compositions and related devices
Balcioglu et al. Design of xylose-based semisynthetic polyurethane tissue adhesives with enhanced bioactivity properties
Park et al. Catalyst-free synthesis of high elongation degradable polyurethanes containing varying ratios of isosorbide and polycaprolactone: physical properties and biocompatibility
CN107216435B (en) poly (urethane-urea) with side chain of phosphatide polyethylene glycol and preparation method thereof
EP0696605A1 (en) Biocompatible block copolymer
CN109355057A (en) A kind of bionical tissue adhesive of poly-amino acid-based mussel and preparation method thereof
EP3648808A1 (en) Composite material and its method of production
Kobayashi et al. Water‐curable and biodegradable prepolymers
CN111372617A (en) Tissue adhesive sealant device
CN108546321B (en) Preparation and application of high-biocompatibility biodegradable bone filling material
Gorna et al. Novel biodegradable polyurethanes for medical applications
CN110755677B (en) Polyamino acid hydrogel dressing and preparation method and application thereof
EP1353968B1 (en) Linear block copolymer
CN114685753B (en) Tissue regeneration promoting type bi-component medical adhesive as well as preparation method and application thereof
CN108530607B (en) Chitosan oligosaccharide modified polyurethane urea bone repair material and preparation method thereof
JPH0748431A (en) Polyurethaneurea polymer for medical use
CN115068680A (en) Tissue regeneration promoting material with self-adaptability

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant