CN1424115A - Tissue engineering stent material and preparation thereof - Google Patents
Tissue engineering stent material and preparation thereof Download PDFInfo
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- CN1424115A CN1424115A CN 02152164 CN02152164A CN1424115A CN 1424115 A CN1424115 A CN 1424115A CN 02152164 CN02152164 CN 02152164 CN 02152164 A CN02152164 A CN 02152164A CN 1424115 A CN1424115 A CN 1424115A
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Abstract
A scaffold material for tissue engineering is prepared by the cross-linking reaction between a novel biodegradable cross-linking agent and the biocompatibile and water-soluble high-molecular material, such as N-vinyl pyrrolidone (NVP) and hydroxyethyl methylacrylate (HEMA) or its copolymer. It can make cells grow adhesively, adjustable degradation speed, and no inflammation reaction.
Description
Technical Field
The invention relates to a biodegradable medical material, in particular to a method for preparing a tissue engineering scaffold material by using a biodegradable cross-linking agent, N-vinyl pyrrolidone, hydroxyethyl methacrylate and a copolymer thereof.
The invention also relates to a tissue engineering scaffold material prepared by the method.
Background
The tissue engineering scaffold material is the key oftissue engineering, is an indispensable material condition for tissue engineering, and is also the key point of biological material research. The importance of which is apparent. The scaffold material provides a living three-dimensional space for cells, which is beneficial for the cells to obtain enough nutrient substances, perform nutrient exchange and discharge waste so as to enable the cells to grow on the pre-designed three-dimensional scaffold. Since cells must rely on the presence of extracellular matrix to perform their function, the choice of extracellular matrix substitutes, i.e., seeded matrix scaffolds, is an important aspect in tissue engineering. The scaffold material not only affects the biological behavior and culture efficiency of cells, but also determines whether the scaffold material can be well applied to organisms after transplantation, and the combination and repair effect is a bottleneck for limiting the clinical application of the scaffold material. As an emerging field, scaffold materials are new biomaterials following an inert biomaterial phase (replacement repair), a biomaterial biochemical phase. The currently researched stent materials comprise two main types of natural and synthetic stent materials, and both the two main types have the advantages and the disadvantages, and are rarely used independently, and modification or compounding of a plurality of materials is generally carried out to enable the physicochemical property and the biological property of the stent material to be most reasonable and optimized.
The tissue engineering scaffold material has good biocompatibility, and cells are degraded under the action of body fluid, enzyme, cells and the like while being adhered and proliferated on the surface of the cells to form tissues after being implanted into a body, so that the cells are changed into small molecular substances to be absorbed or discharged out of the body through metabolism. The existing biodegradable materials comprise natural materials, such as collagen, natural coral, fibrin, chitin and derivatives thereof, and also comprise high molecular materials, ceramic materials, composite materials and the like. The most used natural materials include chitin and its derivatives, collagen and other protein substances, the former is difficult to process due to poor solubility, and the latter is difficult to achieve ideal strength. The ceramic material is mostly applied to hydroxyapatite, tricalcium phosphate and other biomedical porous ceramic materials, the hydroxyapatite has better strength but poorer degradation performance, the tricalcium phosphate has better degradation performance but poorer mechanical property, and the ceramic material particularly shows brittleness in the aspect of tension, so the ceramic material has greater difficulty in being used as a biodegradable material. The biomedical material with biodegradation and absorption performance is mainly a high molecular material and a composite material formed by the high molecular material and other materials. The biodegradable polymer material is mainly aliphatic polyester such as polylactic acid (PLA), polyglycolic acid (PGA), PLA/PGA copolymer, etc. However, in the clinical process, the degradation speed of the material is too high, the reaction rate of nonspecific aseptic inflammation of a patient is high, and the reason for aseptic inflammation is considered to be that the material is degraded into small molecular fragments to cause aggregation and phagocytosis of macrophages in vivo.
The existing biodegradable material has the following disadvantages:
1. the degradation rate of the biodegradable material is not matched to the growth of the cellular tissue.
2. Toxic side effects of the biodegradable material itself and its degradation products include chemical toxicity and biological toxicity.
3. Some materials, although havinggood biocompatibility, are difficult to adapt to practical requirements due to their water solubility and their inability to degrade after ordinary crosslinking, such as PVP, PEG, PVA, PEO, etc.
4. As a scaffold material for tissue engineering, polylactic acid and chitin have the biggest defects that the acid-base property of a degradation product has certain toxicity to cells, and the most obvious defects of the two materials are that the degradation rate of the material is difficult to match with the formation rate of tissues.
In short, the most obvious disadvantages of biodegradable materials to date are that the degradation rate is difficult to control and the side effects of the degradation products are difficult to eliminate.
In general, the ideal biodegradable material for extracellular scaffolds should have the following conditions: (1) good biocompatibility; (2) good biodegradability, and the material can be completely replaced by the tissue of the implanted bed; (3) easy to machine and form, and have certain intensity, can keep the original shape after certain time after transplanting; (4) the surface of the material is easy for cell adhesion and does not influence or promote the proliferation and differentiation of the material; (5) can be compounded with other active molecules such as Bone Morphogenetic Protein (BMP) and the like to jointly induce the formation of tissues and the like; (6) the material should provide maximum space and area to accommodate maximum cell attachment, which requires a high porosity of more than 90% while maintaining the strength of the material. In addition, the vascularization problem of the neogenetic tissue is also related to the pore size and porosity of the material.
Disclosure of Invention
The invention aims to provide a tissue engineeringscaffold material which can enable cells to adhere and grow, does not cause inflammatory reaction after being implanted, has adjustable degradation and is matched with the growth rate of tissues.
The invention also aims to provide a preparation method of the tissue engineering scaffold material.
The invention prepares the tissue engineering scaffold material by using a novel biodegradable cross-linking agent and some water-soluble high molecular materials with good biocompatibility, such as N-vinyl pyrrolidone (NVP), hydroxyethyl methacrylate (HEMA) and copolymers thereof, and through a cross-linking reaction.
Polyvinyl pyrrolidone (PVP) is a polymer compound obtained by homopolymerizing NVP, and its application fields are very wide, and its commercial products are in many fields. Such as cosmetics, surfactants, paper, textiles, glass industry, medicine, etc. In addition, because of its excellent biocompatibility, physiological inertia, film forming property, crosslinking property, colloid protection capability and other properties, it is gradually paid attention to in the field of biological materials and has been studied and applied. PVP is very soluble in water, even though high molecular weight PVP such as K-90 is soluble in water, its solution viscosity increases with the molecular weight of PVP and the concentration of the solution, and is soluble in a variety of alcohols, amines, halogenated hydrocarbons, nitroalkanes, and low molecular weight fatty acids, in addition to small amounts of non-polar solvents. The PVP is stable in dissolving state in dilute acid and dilute alkali solution. In addition, PVP is compatible with anionic and cationic substances, so that the PVP has wide compatibility, can be mutually dissolved with a plurality of high molecular substances, such as dextrin, cellulose and derivatives thereof, gum arabic, polyvinyl alcohol, sodium alginate, PVC and the like, and can form a film uniformly. PVP is capable of forming complexes with many substances, both soluble complexes with water insoluble substances, such as iodophors; the use of a water-insoluble complex with water-soluble materials, such as a precipitant, also makes PVP a very effective complexing agent. PVP and its solutions are storage stable under normal use conditions, PVP is also widely used as a pharmaceutical excipient, a film-forming agent for tablets, sugar coatings, a stabilizer and a suspending agent for certain pharmaceutical solutions. The earliest medical application of PVP was as a plasma substitute during the second war. PVP was the first synthetic polymer used for vitreous substitutes. In the nineties, PVP hydrogels made by Goldberg were patented as a vitreous substitute, as viscoelastic material in ophthalmic surgery, and as artificial vitreous material. PVP cannot be degraded in human body, but because it is water soluble, small molecular weight can be discharged out of body by renal tubule filtration, and large molecule can be phagocytized by macrophage.
The preparation method of the tissue engineering scaffold material comprises the following steps:
(1) connecting degradable segments to the polyhydroxy micromolecules through chemical reaction by using the polyhydroxy micromolecules as a matrix to form degradable star-shaped molecules with hydroxyl at the tail ends, and finally activating the hydroxyl at the tail ends to introduce double bonds to finally obtain degradable cross-linking agent molecules with various controllable molecular weights; wherein the small polyhydroxy molecules are ethylene glycol, glycerol, pentaerythritol or polycondensates thereof; the degradable segment is polylactic acid, polyglycolic acid, polyhydroxy butyric acid or polycaprolactone and binary and ternary copolymers thereof;
(2) dissolving the degradable cross-linking agent molecule in (1) in organic solvent to prepare solution with mass concentration of 0.02-5g/ml, wherein the molar concentration of active group vinyl is 1 x 10-4-1×10-1mol/ml; the organic solvent is acetone or absolute ethyl alcohol;
(3) mixing the cross-linking agent solution of (2) with N-vinyl pyrrolidone monomer with the molar ratio of 0-100 and hydroxyethyl methacrylate monomer with the molar ratio of 0-100 according to the mass ratio of 100-1: 1-100, adding initiator accounting for 0-1% of the mass of the reactants, adding photosensitizer accounting for 0-1% of the mass of the reactants, heating at 60-150 ℃ for 1 minute to 6 hours for cross-linking reaction, adding pore-forming agent, and pouring into various forming molds to obtain the support material; the initiator used is Azobisisobutyronitrile (AIBN) or dibenzoyl peroxide (BPO); the photosensitizer is 2, 2-dimethyl-2-phenylacetophenone;
(4) the resulting scaffold material was extracted with an organic solvent for 3-6 hours.
And (3) adding a pore-foaming agent to form pores by adopting a water-soluble pore-foaming method, using sodium salt, calcium salt or magnesium salt as the pore-foaming agent, enabling the particle size range to be 40-80 meshes, enabling the weight to be 1.5-2.5 times of the mass of the reactant, leaching the pore-foaming agent by using sterile distilled water after reaction, and drying in vacuum to obtain the porous scaffold material. The porosity of the porous support material is 80-100%, and the pore size is 100-300 microns. For hydrogel-based scaffold materials, the water absorption may range from 50-500% and the expansion may range from 1-5 times.
The step (3) of crosslinking may be carried out by heating, irradiating with an infrared lamp, irradiating with an ultraviolet lamp, or the like,60Co radiation, microwave radiation, ultrasonic radiation and supercritical fluidreaction; the reaction is carried out for 1 minute to 6 hours under the irradiation of an infrared lamp with the power of 40 to 200 watts and the voltage range of 150 and 250 volts, or the reaction is carried out for 10 minutes to 6 hours under the irradiation of an ultraviolet lamp with the power of 20 to 120 watts.
The above crosslinking reaction equation is as follows:
the structural formula of the cross-linking agent is shown as the following figure:
the structural formula of N-vinyl pyrrolidone: hydroxyethyl methacrylate structural formula:
the tissue engineering scaffold material obtained by the method is a cross-linked reticular macromolecule, is insoluble in water and various common organic solvents, and is not melted when heated. The physical state of the scaffold material can also be changed from a hydrogel with poor strength but high water absorption to a plastic state with high strength according to the difference of crosslinking density and the difference of crosslinking agent molecules. The water absorption range is 50% -500%; the volume expansion can range from 1 to 5 times; the strength ranges from a few Mpa to 200 Mpa.
Compared with the existing research, the invention has the following advantages:
1. the degradable cross-linking agent is used for cross-linking some water-soluble macromolecules (NVP, HEMA) with good biocompatibility, the defect that the original polymers are not degraded after cross-linking or have large brittleness after cross-linking is overcome, the application fields of the NVP and HEMA are expanded, and a new way is opened up for the application of the tissue engineering scaffold material.
2. The degradation rate of the stent material can be easily adjusted by the length of the degradable ester segment of the cross-linking agent and the difference of the proportion and the cross-linking density of the cross-linking agent, NVP and HEMA, and can be matched with the growth rate of various tissues; solves a big defect in the application of the tissue engineering scaffold material.
3. The synthesized material has good biocompatibility and strong water absorption, and is beneficial to tissue culture and cell adhesion.
4. The PVP segment in the scaffold material has stronger complexation, can be combined with various cell growth factors to regulate the growth, differentiation and proliferation of cells, and is the key in the research of the scaffold material for tissue engineering.
5. The method is simple and easy to implement, and can be used for preparing scaffold materials with different shapes, and the scaffold materials prepared by the method have the strength ranging from poor (hydrogel) to strong (plastic) tissue engineering scaffold materials, and are suitable for the growth requirements of different tissue cells.
6. The degradation product of the stent material is hydroxyl acid which is formed by hydrolyzing polyesters into single molecules, PVP and HEMA can be changed into water-soluble fragments by controlling the molecular weight of the PVP and HEMA, finally the hydroxyl acid is metabolized into carbon dioxide and water by the organism to be discharged out of the body, and the water-soluble fragments of the PVP and HEMA are discharged out of the body by the filtration of renal tubules.
Detailed Description
Example 1
Theselected cross-linking agent is ethylene glycol 2000 as matrix, degradable polylactic acid segment is arranged at two ends, the lactic acid unit is 3, and the tail end is double bond. Preparing a tetrahydrofuran solution with the weight percentage of 20 percent. Adding 1ml of cross-linking agent solution and 1ml of NVP into a clean 5ml small beaker, adding 0.003g of AIBN, uniformly stirring, volatilizing the solvent in a fume hood for 5 minutes, pouring into a culture dish with the diameter of 3cm, putting on a hot table in a vacuum drying oven, heating at 80 ℃, reacting for 3 hours, vacuumizing again, removing the solvent, extracting with absolute ethyl alcohol in a Soxhlet extractor, removing small molecular homopolymers and other small molecular substances of the NVP, soaking and washing for 3 times by using sterile physiological saline to obtain the hydrogel material with certain shape and better strength. The in vitro degradation time of this material was 7 days. The material can be compounded with growth factors (basic fibroblast growth factor b FGF and bone morphogenetic protein BNP) to prepare a slow-release material for bone defect replacement.
Example 2
The cross-linking agent is selected from glycerol as matrix, degradable polylactic acid segments are arranged at two ends, the lactic acid unit is 6, and the tail end is a double bond. Preparing a tetrahydrofuran solution with the weight percentage of 20 percent. Adding 1.5ml of cross-linking agent solution and 1ml of NVP into a clean 5ml small beaker, adding 0.003g of AIBN, uniformly stirring, volatilizing the solvent in a fume hood for 5 minutes, pouring the solution on a flat PET film for casting to form a film, irradiating the film for 5 minutes by using an infrared lamp (40W, 220V), reacting for 3 hours at 80 ℃ to obtain a colorless and transparent film with the thickness of 0.8mm, vacuumizing, removing the solvent, and measuring that the contact angle is 32 degrees, the water absorption rate is 72 percent and the in-vitro degradation time is 30 days. The material can be used as a corneal scaffold material, and preliminary animal experiments show that the material has better histocompatibility.
Example 3
The cross-linking agent is selected from glycerol as matrix, degradable polylactic acid segments are arranged at two ends, the lactic acid unit is 6, and the tail end is a double bond. Preparing a tetrahydrofuran solution with the weight percentage of 20 percent. Adding 3ml of cross-linking agent solution and 1ml of NVP into a clean 5ml small beaker, adding 0.005g of AIBN, adding 6g of 40-60-mesh NaCl particles, volatilizing the solvent for 5 minutes in a fume hood, uniformly stirring, pouring into a circular white porcelain dish, irradiating for 10 minutes by using an infrared lamp (40W, 220V), reacting for 3 hours at 80 ℃, vacuumizing, removing the solvent, adding distilled water, stirring, leaching NaCl, extracting by using absolute ethyl alcohol in a Soxhlet extractor, removing the small-molecule homopolymer and other small-molecule substances of the NVP, obtaining the scaffold material with the porosity of 91%, and degrading for 60 days in vitro. The material can be used as cartilage bone tissue engineering scaffold material, and can induce osteocyte to adhere well and grow to form new cartilage tissue.
Example 4
The selected cross-linking agent is ethylene glycol 2000 as matrix, and degradable polylactic acid and polyglycolic acid copolymer (polymerization degree of 6 at 1: 1) segment is arranged at two ends, and double bond is arranged at the tail end. Preparing a tetrahydrofuran solution with the weight percentage of 20 percent. 2ml of the crosslinker solution and 0.5ml of NVP and 0.5ml of HEMA were added to a clean 5ml beaker, followed by 0.005g of AIBN and stirred well. The solvent was evaporated in a fume hood for 5 minutes, the film was cast on a flat PET film, irradiated with an infrared lamp (40W, 220V) for 15 minutes, reacted at 80 ℃ for 3 hours, vacuumed again, and the solvent was removed to give a colorless and transparent film having a thickness of 0.8mm, a contact angle of 54 degrees, a water absorption of 50%, and an in vitro degradation time of 90 days. The membrane material can be compounded with the b FGF to prepare a novel skin dressing and stimulate the generation of new skin tissues.
Example 5
The cross-linking agent is selected from glycerol as matrix, degradable polylactic acid and polyglycolic acid copolymer (polymerization degree of 6 at 1: 1) segment at two ends, and double bond at end. Preparing a tetrahydrofuran solution with the weight percentage of 20 percent. Adding 3ml of cross-linking agent solution, 0.5ml of NVP and 0.5ml of HEMA into a clean 5ml small beaker, adding 0.005g of BPO, adding 6g of NaCl particles with 40-60 meshes, volatilizing the solvent in a fume hood for 5 minutes, uniformly stirring, pouring into a round white porcelain plate, putting on a hot table in a vacuum drying oven, heating at 120 ℃, reacting for 3 hours, vacuumizing again, removing the solvent, putting into distilled water, stirring, leaching NaCl, extracting with absolute ethyl alcohol in a Soxhlet extractor, removing the small-molecule homopolymer and other small-molecule substances of the NVP to obtain the stent material with the porosity of 91%, and degrading for 120 days in vitro. The material is large and can be used as a bone tissue engineering scaffold material.
Claims (6)
1. The preparation method of the tissue engineering scaffold material is characterized by comprising the following steps:
(1) connecting degradable segments to the polyhydroxy micromolecules through chemical reaction by using the polyhydroxy micromolecules as a matrix to form degradable star-shaped molecules with hydroxyl at the tail ends, and finally activating the hydroxyl at the tail ends to introduce double bonds to finally obtain degradable cross-linking agent molecules with various controllable molecular weights; wherein the small polyhydroxy molecules are ethylene glycol, glycerol, pentaerythritol or polycondensates thereof; the degradable segment is polylactic acid, polyglycolic acid, polyhydroxy butyric acid or polycaprolactone and binary and ternary copolymers thereof;
(2) dissolving the degradable cross-linking agent molecule in (1) in organic solvent to prepare solution with mass concentration of 0.02-5g/ml, wherein the molar concentration of active group vinyl is 1 x 10-4×10-1mol/ml; the organic solvent is acetone or absolute ethyl alcohol;
(3) mixing the cross-linking agent solution of (2) with N-vinyl pyrrolidone monomer with the molar ratio of 0-100 and hydroxyethyl methacrylate monomer with the molar ratio of 0-100 according to the mass ratio of 100-1: 1-100, adding initiator accounting for 0-1% of the mass of the reactants, adding photosensitizer accounting for 0-1% of the mass of the reactants, heating at 60-150 ℃ for 1 minute to 6 hours for cross-linking reaction, adding pore-forming agent, and pouring into various forming molds to obtain the support material; the initiator used is Azobisisobutyronitrile (AIBN) or dibenzoyl peroxide (BPO); the photosensitizer is 2, 2-dimethyl-2-phenylacetophenone;
(4) the resulting scaffold material was extracted with an organic solvent for 3-6 hours.
2. The method for preparing a scaffold material for tissue engineering according to claim 1, wherein the pore-forming method in step (3) comprises pore-forming by adding pore-forming agent, and comprises pore-forming by water-soluble pore-forming method, using sodium salt, calcium salt or magnesium salt as pore-forming agent, wherein the particle size is 40-80 mesh, and the weight is 1.5-2.5 times of the mass of the reactant, leaching the pore-forming agent with sterile distilled water after reaction, and vacuum drying to obtain the porous scaffold material. The porosity of the porous support material is 80-100%, and the pore size is 100-300 microns. For hydrogel-based scaffold materials, the water absorption may range from 50-500% and the expansion may range from 1-5 times.
3. The method for preparing a scaffold material for tissue engineering according to claim 1 or 2, wherein the step (3) of crosslinking reaction is carried out by irradiation with an infrared lamp, irradiation with an ultraviolet lamp, or the like,60Co radiation, microwave radiation, ultrasonic radiation, or supercritical fluid reactions.
4. The method for preparing tissue engineering scaffold material according to claim 3, wherein the cross-linking reaction is performed under the irradiation of an infrared lamp with power of 40-200W and voltage range of 150-250V for 1 minute to 6 hours.
5. The method for preparing tissue engineering scaffold material according to claim 3, wherein said cross-linking reaction is performed under 20-120W UV lamp for 10 min to 6 hr.
6. A tissue engineering scaffold material prepared by the method of claim 1.
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| CN 02152164 CN1424115A (en) | 2002-12-06 | 2002-12-06 | Tissue engineering stent material and preparation thereof |
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| CN 02152164 CN1424115A (en) | 2002-12-06 | 2002-12-06 | Tissue engineering stent material and preparation thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100355405C (en) * | 2004-06-24 | 2007-12-19 | 同济大学 | Production of porous stand for tissue engineering |
| CN100465209C (en) * | 2006-08-17 | 2009-03-04 | 同济大学 | Preparation method of degradable polymer material for stent in shape memory pipe cavity |
| CN100540069C (en) * | 2006-12-22 | 2009-09-16 | 暨南大学 | Biodegradable active medical tissue adhesive and preparation method thereof |
| CN105934258A (en) * | 2014-01-20 | 2016-09-07 | 佰欧泰克股份公司 | Method of making a hydrogel, hydrogel and formulation for carriers and/or substitute of connective tissues obtained using such method |
| CN107793579A (en) * | 2017-10-30 | 2018-03-13 | 广州新诚生物科技有限公司 | A kind of hydrogel and its application |
| CN107789093A (en) * | 2017-10-30 | 2018-03-13 | 广州新诚生物科技有限公司 | The artificial nasolacrimal canal that self-expanding is fixed |
| CN113105593A (en) * | 2021-03-26 | 2021-07-13 | 四川大学 | Photocurable 3D printing-molded flexible degradable polymer composite resin and preparation method thereof |
| CN116606517A (en) * | 2023-05-22 | 2023-08-18 | 南京工业大学 | Biocompatible degradable interpenetrating network hydrogel and preparation method thereof |
-
2002
- 2002-12-06 CN CN 02152164 patent/CN1424115A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100355405C (en) * | 2004-06-24 | 2007-12-19 | 同济大学 | Production of porous stand for tissue engineering |
| CN100465209C (en) * | 2006-08-17 | 2009-03-04 | 同济大学 | Preparation method of degradable polymer material for stent in shape memory pipe cavity |
| CN100540069C (en) * | 2006-12-22 | 2009-09-16 | 暨南大学 | Biodegradable active medical tissue adhesive and preparation method thereof |
| CN105934258A (en) * | 2014-01-20 | 2016-09-07 | 佰欧泰克股份公司 | Method of making a hydrogel, hydrogel and formulation for carriers and/or substitute of connective tissues obtained using such method |
| CN107793579A (en) * | 2017-10-30 | 2018-03-13 | 广州新诚生物科技有限公司 | A kind of hydrogel and its application |
| CN107789093A (en) * | 2017-10-30 | 2018-03-13 | 广州新诚生物科技有限公司 | The artificial nasolacrimal canal that self-expanding is fixed |
| CN113105593A (en) * | 2021-03-26 | 2021-07-13 | 四川大学 | Photocurable 3D printing-molded flexible degradable polymer composite resin and preparation method thereof |
| CN116606517A (en) * | 2023-05-22 | 2023-08-18 | 南京工业大学 | Biocompatible degradable interpenetrating network hydrogel and preparation method thereof |
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