CN117065102A - Natural injection type gel-particle composite material with controllable degradation time - Google Patents
Natural injection type gel-particle composite material with controllable degradation time Download PDFInfo
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- CN117065102A CN117065102A CN202311059886.2A CN202311059886A CN117065102A CN 117065102 A CN117065102 A CN 117065102A CN 202311059886 A CN202311059886 A CN 202311059886A CN 117065102 A CN117065102 A CN 117065102A
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- 230000015556 catabolic process Effects 0.000 title claims abstract description 34
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 34
- 239000002131 composite material Substances 0.000 title claims abstract description 31
- 239000007863 gel particle Substances 0.000 title claims abstract description 26
- 238000002347 injection Methods 0.000 title claims abstract description 19
- 239000007924 injection Substances 0.000 title claims abstract description 19
- 239000011159 matrix material Substances 0.000 claims abstract description 39
- 239000002245 particle Substances 0.000 claims abstract description 29
- 102000008186 Collagen Human genes 0.000 claims abstract description 19
- 108010035532 Collagen Proteins 0.000 claims abstract description 19
- 229920001436 collagen Polymers 0.000 claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 12
- 238000001727 in vivo Methods 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims abstract description 10
- 241001465754 Metazoa Species 0.000 claims abstract description 6
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 210000001519 tissue Anatomy 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000002002 slurry Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 210000001691 amnion Anatomy 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 238000000502 dialysis Methods 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 102000057297 Pepsin A Human genes 0.000 claims description 6
- 108090000284 Pepsin A Proteins 0.000 claims description 6
- 238000000354 decomposition reaction Methods 0.000 claims description 6
- 229940111202 pepsin Drugs 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- 239000000512 collagen gel Substances 0.000 claims description 5
- 239000012620 biological material Substances 0.000 claims description 4
- 239000011859 microparticle Substances 0.000 claims description 4
- 102000004142 Trypsin Human genes 0.000 claims description 3
- 108090000631 Trypsin Proteins 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000002791 soaking Methods 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000012588 trypsin Substances 0.000 claims description 3
- 241000283690 Bos taurus Species 0.000 claims description 2
- 241001494479 Pecora Species 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 210000003516 pericardium Anatomy 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 claims description 2
- 210000002435 tendon Anatomy 0.000 claims description 2
- 241000282898 Sus scrofa Species 0.000 claims 1
- 210000000845 cartilage Anatomy 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000010382 chemical cross-linking Methods 0.000 abstract description 2
- 239000003431 cross linking reagent Substances 0.000 abstract description 2
- 238000010298 pulverizing process Methods 0.000 abstract description 2
- 230000001079 digestive effect Effects 0.000 abstract 1
- 230000014759 maintenance of location Effects 0.000 abstract 1
- 239000002861 polymer material Substances 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000003519 biomedical and dental material Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000005297 material degradation process Methods 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000024288 Rotator Cuff injury Diseases 0.000 description 1
- 206010039227 Rotator cuff syndrome Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000009525 mild injury Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 208000037974 severe injury Diseases 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
-
- 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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
-
- 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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
-
- 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
Abstract
The invention relates to the technical field of biomedicine, and provides a natural injection type gel-particle composite material with controllable degradation time, which is prepared by decellularizing, crushing, digesting sol, purifying and uniformly dispersing particles of tissues obtained from animals or people to obtain gel-particle composites containing collagen with different concentrations and matrix particles with different degrees after sol; the gel-particle compound is prepared by partially digesting sol by particles after tissue pulverization, and then dispersing the rest part of tissue matrix which does not generate sol in situ in a gel solution; the gel-particle compound is digestive sol which controls tissue particles to generate different degrees, the higher the concentration of the obtained collagen is, the more the residual tissue matrix is decomposed, and the in vivo degradation time is in a proportional relation with the matrix retention; the gel-particle composite material has single component, is formed by mixing a tissue matrix material and collagen of sol derivatives thereof, has no addition of other high polymer materials and chemical cross-linking agents, is safer to use, can regulate the degradation time of the material in vivo by controlling different sol degrees, and brings more proper selection for different clinical indications.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to a natural injection type gel-particle composite material with controllable degradation time.
Background
The natural biomedical material is mostly derived from human or animal organ tissues, can remove immunogenic substances through special processing, has a triple-helix collagen framework structure, simultaneously retains various active factor components, has good biocompatibility, and has wide application in the medical fields of neurology, ophthalmology, burns and scalds, orthopaedics, medical shaping and the like. Based on some products on the market, most of the products are used by taking biological tissues out of cells and then preparing the biological tissues into a membrane-shaped patch form. In order to increase the range of applications, for example, in the field of injectable fillers, researchers have enzymatically prepared collagen hydrogels, and have also produced powders having a certain particle size by freeze-grinding them. However, the pure hydrogel state or powder has a single application because of the excessive rapid or slow degradation time in vivo for the injection material, and the injection of the single powder state is easy to block the needle and has larger granular feel, and needs to be carried out by other mediums, so that the immune risk is further increased. In general, no material can realize the regulation and control of in vivo degradation time, and materials with corresponding degradation time are used according to the repair period of different organism tissues, so that the synchronization of material degradation and tissue regeneration is realized, and the immune rejection is reduced.
In view of this, the present invention has been proposed.
Disclosure of Invention
The invention provides a natural injection type gel-particle composite material with controllable degradation time, which is used for realizing the synchronization of material degradation and repair of different parts of organism tissues. The material of the invention is not added with any chemical crosslinking reagent and other high molecular polymers, and is treated by a single purely natural tissue material to obtain gel-particle composites with different property states. The collagen gel is extracted in situ by using a pure natural tissue matrix, and the residual matrix is compounded in the gel in a particle shape, so that the problem of short degradation time of the single collagen gel is solved, the degradation time can be prolonged by preserving the residual matrix particles, and in addition, the degradation time of the material in the body can be regulated by controlling different sol degrees, thereby bringing more proper choices for different clinical indications. The individual powder is not easy to inject, and the tissue particles can be injected by taking the collagen gel extracted in situ as a medium, so that the safety and the stability are greatly improved.
Specifically, the preparation method of the natural injection type gel-particle composite material with controllable degradation time is obtained by mixing collagen with different concentrations and sol-gel matrix particles with different degrees.
The collagen with different concentrations is obtained by decellularizing biological tissues, crushing, digesting sol and purifying; the matrix particles are the undigested and decomposed part of the matrix remaining after the tissue sol (see fig. 1).
The natural injection type gel-particle composite material with controllable degradation time has the composition of two different compounds derived from the same biological material, and the degradation time of the composite material in vivo is controlled by controlling the contents of collagen with different concentrations and in-situ matrix residues.
The biological material tissue used in the natural injection type gel-particle composite material with controllable degradation time can be human or animal skin, amniotic membrane, tendon, pericardium and the like, and the animal source can be pigs, cattle and sheep.
The specific preparation steps of the natural injection type gel-particle composite material with controllable degradation time and collagen with different concentrations are as follows:
(1) The tissue is treated by hydrogen peroxide with the volume concentration of 1 to 10 percent to remove the miscellaneous proteins and partial cells, and is soaked for 12 to 20 hours by trypsin with the concentration of 0.25 percent at the temperature of 4 ℃ after being washed for 4 to 8 times to continuously remove the residual cells;
(2) Adding purified water into the tissue after cell removal for crushing; when crushing, the feed liquid ratio of the decellularized tissue to the purified water is 1:2-1:10; the crushing time is 1-30 min;
(3) Adding 0.5% pepsin into the crushed slurry, adjusting the pH to 2-3 with acetic acid, and reacting for 12-72h at room temperature;
(4) The pH of the slurry is regulated to be neutral by 0.5% sodium hydroxide solution, then the slurry substrate is put into a dialysis bag (40 KD), the dialysis bag is put into a container filled with pure water, and the container is kept stand at 4 ℃ for soaking and dialysis, and water is changed once for 24 hours, and the total time is changed for 3 to 8 times.
The preparation method of the natural injection type gel-particle composite material with controllable degradation time comprises the following steps of:
(1) By adjusting the process parameters in steps 2-3 of claim 3, matrix particles after different degrees of sol can be prepared;
(2) Digesting the sol for 12-72 hours by using tissue particles after crushing for 10min, wherein the decomposition degree of the matrix is 15-55%; digesting the sol for 12-72 hours by using tissue particles after crushing for 20min, wherein the decomposition degree of the matrix is 20-75%; the sol is digested for 12-72 hours by using tissue particles which are crushed for 30min, and the decomposition degree of the matrix is 22-80%.
(3) The undegraded matrix portion is suspended throughout the collagen gel solution and the collagen as a whole is a controllably degradable gel-microparticle composite.
The tissue sol time is generally more than 12 hours, which is based on ensuring certain gel concentration, keeping the minimum viscosity of the system after sol to ensure the uniformity and stability of the dispersion of the particle matrix, wherein the concentration of the sol is too low, the whole solution is too thin, and the particle matrix can be partially precipitated to cause uneven dispersion and influence the injectability.
FIG. 1 is a schematic system diagram of the tissue matrix sol before and after;
FIG. 2 is a graph of the degree of sol corresponding to tissue matrices of different particle sizes at different sol times.
Detailed Description
The human source materials can be obtained from a regular hospital or tissue warehouse, the animal sources can be obtained from a regular slaughterhouse, and the reagents or instruments used are not specific to manufacturers and are conventional products purchased by regular channel providers.
Example 1
The preparation method of the natural injection type gel-particle composite material with controllable degradation time comprises the following specific steps:
the amniotic membrane is treated by hydrogen peroxide with the volume concentration of 10% to remove the impurity proteins and part of cells, and is washed for 4 times and then soaked by trypsin with the concentration of 0.25% for 18 hours at the temperature of 4 ℃ to continuously remove the residual cells;
washing the amniotic membrane after cell removal, and adding purified water for crushing; when the materials are crushed, the feed liquid ratio of the acellular biological amniotic membrane to the purified water is 1:5 (g/ml); the crushing time is respectively 10min, 20min and 30min;
respectively adding 0.5% pepsin into the crushed slurry, adjusting the pH to 2-3 with acetic acid, and reacting for 12h at room temperature;
adjusting pH of the slurry to neutrality with 0.5% sodium hydroxide solution, placing the slurry substrate into dialysis bag (40 KD), placing the dialysis bag into container filled with pure water, standing at 4deg.C, soaking, dialyzing, changing water once for 24 hr, and changing water for 4 times;
the ungosol amniotic membrane matrix particles and the collagen solution together form the gel-particle composite material.
Example 2
The preparation method of the natural injection type gel-particle composite material with controllable degradation time comprises the following steps of: respectively adding 0.5% pepsin into the crushed slurry, adjusting the pH to 2-3 with acetic acid, and reacting for 24 hours at room temperature.
Example 3
The preparation method of the natural injection type gel-particle composite material with controllable degradation time comprises the following steps of: respectively adding 0.5% pepsin into the crushed slurry, adjusting the pH to 2-3 with acetic acid, and reacting for 48h at room temperature.
Example 4
The preparation method of the natural injection type gel-particle composite material with controllable degradation time comprises the following steps of: respectively adding 0.5% pepsin into the crushed slurry, adjusting the pH to 2-3 with acetic acid, and reacting for 72h at room temperature.
Comparative example 1
The amniotic membrane matrix samples before and after the sol in examples 1, 2, 3 and 4 were weighed and respectively denoted as m 1 And m 2 The sol degree w= (m) was calculated from the amount of dissolution 1 -m 2 )/m 1 。
The result shows that in a certain range, the sol degree is increased along with the increase of the sol time, when the tissue sol time is 48 hours, the maximum sol degree is basically reached, the sol is not obviously increased after the continuous extension time, and the change of the particle matrix is not obvious any more. The size of the matrix particle also has a certain influence on the sol, and the size of the particle is determined by the crushing time of the matrix, the longer the crushing time is, the smaller the particle size is, the more complete the reaction is, the greater the sol degree is, but the increase of the excessive crushing sol degree is not obvious any more. (see FIG. 2).
Comparative example 2
The samples prepared in examples 1, 2, 3 and 4 after 20min of pulverization were subjected to irradiation sterilization, and then were injected into subcutaneous rabbit tissue, respectively, and the in vivo degradation rate (%) was calculated at 4 weeks, 8 weeks, 12 weeks and 24 weeks according to the change in the size of the swollen skin dome.
The result shows that the smaller the amniotic membrane matrix sol degree is, the longer the in vivo degradation time is; the greater the degree of sol, the shorter the in vivo degradation time. The amniotic membrane matrix after sol is decomposed into collagen, the pure collagen solution is easier to degrade in vivo, and the greater the collagen concentration is, the greater the degree of matrix sol is, and the greater the degree of matrix destruction is. Therefore, the degradation speed is mainly based on the size of the whole sol.
In general, the need for degradation time is long or short for different clinical indications. If medical shaping requires longer degradation time and longer maintenance time is generally more desirable, a gel-particle composite material with a smaller sol level is more suitable for such clinical situations. While some other injuries, such as rotator cuff injury, recover from mild injury generally for 1-3 months, and severe injury for 3-6 months, depending on the degree of injury, the gel-particle composites of different sol degrees may be reasonably utilized. The clinical application conditions described above are not limited to this, and the application of the material can be extended to various related indications, and the natural properties and excellent controllability of the material have great advantages in the biomedical material field.
The above embodiments are merely exemplary to illustrate the technical aspects of the present invention, and are not limited in use; it is still possible to modify the technical solutions of the foregoing embodiments according to the need, without affecting the scope of protection claimed by the present invention.
Claims (5)
1. The natural injection type gel-particle composite material with controllable degradation time is characterized in that the natural injection type gel-particle composite material is obtained by mixing collagen with different concentrations and sol-gel matrix particles with different degrees;
the collagen with different concentrations is obtained by decellularizing tissues, crushing, digesting sol and purifying; the matrix particles are the undigested and decomposed part of the matrix remaining after the tissue sol.
2. The natural injectable gel-microparticle composite material with controllable degradation time according to claim 1, wherein the composition of the two composites in different states is derived from the same biological material tissue, and the degradation time of the composite material in vivo is controlled by controlling the contents of collagen and in-situ matrix residues with different concentrations.
3. The gel-particle composite material of claim 2, wherein the biological material tissue used is human or animal skin, amniotic membrane, tendon, pericardium, cartilage, etc., and the animal source is pig, cattle or sheep.
4. The natural injection type gel-particle composite material with controllable degradation time according to claim 1, wherein the specific preparation steps of collagen with different concentrations are as follows:
(1) The tissue material is treated by hydrogen peroxide with the volume concentration of 1 to 10 percent to remove the miscellaneous proteins and partial cells, and is soaked for 12 to 20 hours by trypsin with the concentration of 0.25 percent at the temperature of 4 ℃ after being washed for 4 to 8 times to continuously remove the residual cells;
(2) Adding purified water into the tissue after cell removal for crushing; when crushing, the feed liquid ratio of the decellularized tissue to the purified water is 1:2-1:10; the crushing time is 1-30 min;
(3) Adding 0.5% pepsin into the crushed slurry, adjusting the pH to 2-3 with acetic acid, and reacting for 12-72h at room temperature;
(4) The pH of the slurry is regulated to be neutral by 0.5% sodium hydroxide solution, then the slurry substrate is put into a dialysis bag (40 KD), the dialysis bag is put into a container filled with pure water, and the container is kept stand at 4 ℃ for soaking and dialysis, and water is changed once for 24 hours, and the total time is changed for 3 to 8 times.
5. The natural injectable gel-microparticle composite material with controllable degradation time according to claim 1, wherein the preparation steps of the matrix particles after sol of different degrees are as follows:
(1) By adjusting the process parameters in steps 2-3 of claim 3, matrix particles after different degrees of sol can be prepared;
(2) Digesting the sol for 12-72 hours by using tissue particles after crushing for 10min, wherein the decomposition degree of the matrix is 15-55%; digesting the sol for 12-72 hours by using tissue particles after crushing for 20min, wherein the decomposition degree of the matrix is 20-75%; the sol is digested for 12-72 hours by using tissue particles which are crushed for 30min, and the decomposition degree of the matrix is 22-80%.
(3) The undegraded matrix portion is suspended throughout the collagen gel solution and the collagen as a whole is a controllably degradable gel-microparticle composite.
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