Injectable collagen polymer microsphere as well as preparation method and application thereof

Abstract

The invention discloses an injectable collagen polymer microsphere, a preparation method thereof and application of the injectable collagen polymer microsphere in preparation of an injection filler. The injectable collagen polymer microspheres comprise a polymer cross-linked network and collagen intercepted and entangled in the polymer cross-linked network; the polymer cross-linked network is formed by polymerizing raw materials including a monomer and a cross-linking agent. The preparation method adopts an inverse emulsion method and comprises the following steps: preparing a water phase: dissolving collagen, a monomer and a cross-linking agent in an acid solution to form a uniform water phase; and microsphere preparation: pouring the water phase into the oil phase containing the surfactant while stirring, continuously stirring, carrying out a polymerization reaction in the presence of an initiator at 25-35 DEG C, and after the reaction is completed, washing, screening, drying and sterilizing to obtain the injectable collagen polymer microspheres.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and particularly relates to an injectable collagen polymer microsphere, a preparation method thereof, and an application thereof. Background Art

[0002] Collagen is the main structural protein in the extracellular matrix and plays an important role in the biological activity, strength, and structural integrity of tissues. Collagen has low immunogenicity, hydrophilicity, and unique biological properties. It can bind to various cell transmembrane receptors, regulate cell adhesion, migration, and proliferation, and enhance tissue regeneration ability. It is an excellent regenerative biomedical material and has been widely used in the field of aesthetic facial filling. However, collagen materials will degrade rapidly in the human body, affecting their duration in the body. At the same time, the mechanical properties of collagen are low and the water absorption is poor, resulting in that collagen facial fillers cannot meet the demand for tissue morphology support and have no shaping effect. This limits the application of collagen materials in facial injection filling.

[0003] To solve the problem of rapid degradation in the body, many products and studies have turned to chemically cross-linking collagen to extend the retention time in the body by masking the enzyme cleavage sites of collagen. At the same time, cross-linking will also prevent the relative sliding of collagen molecules under pressure, thereby improving part of the mechanical properties. The cross-linking agent currently used is generally glutaraldehyde, but it has extremely strong biological toxicity. Experiments have shown that 3 ppm of glutaraldehyde causes 99% apoptosis of fibroblasts (Speer DP et al. Biological effects of residual glutaraldehyde in glutaraldehyde-tanned collagen biomaterials. J Biomed Mater Res. 1980 Nov;14(6):753-64).

[0004] Regarding the need to improve the water absorption of collagen, there is currently a study on grafting collagen onto polyacrylic acid to improve its solubility and water absorption (Yang J et al. Novel Modification of Collagen: Realizing Desired Water Solubility and Thermostability in a Conflict-Free Way. ACS Omega. 2020 Mar 11;5(11):5772-5780). The material obtained in this case dissolves in neutral aqueous solutions and has no mechanical properties, and this grafting method will cause collagen to lose its biological activity.

[0005] Therefore, the development of an injectable collagen facial filling material with good mechanical properties, a slow degradation time in vivo, strong water absorption, and plastic shaping ability still remains a technical gap that urgently needs to be filled in the current market. Summary of the Invention

[0006] In view of the above technical problems and the deficiencies existing in the art, the present invention provides an injectable collagen polymer microsphere, its preparation method, and application.

[0007] The specific technical solutions are as follows: In a first aspect, the present invention provides an injectable collagen polymer microsphere, which includes a polymer crosslinked network and collagen entrapped and entangled therein by the polymer crosslinked network; the polymer crosslinked network is formed by polymerization of raw materials including the monomer and the crosslinking agent; The monomer includes one or more of acrylic acid, acrylamide, vinylsulfonic acid, itaconic acid, N-isopropylacrylamide (CAS No.: 2210-25-5), vinylpyrrolidone (CAS No.: 88-12-0), acryloyloxyethyl carboxybetaine (CAS No.: 79704-35-1), sodium 2-acrylamido-2-methyl-1-propanesulfonate (CAS No.: 5165-97-9), 3-[N,N-dimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]ammonium] propane-1-sulfonate inner salt (CAS No.: 3637-26-1), 2-methacryloyloxyethyl phosphorylcholine (CAS No.: 67881-98-5); The crosslinking agent includes one or several of N,N'-methylenebisacrylamide (CAS No.: 110-26-9), polyethylene glycol diacrylamide (CAS No.: 160556-48-9), polyethylene glycol diacrylate (CAS No.: 26570-48-9), polyethylene glycol dimethacrylate (CAS No.: 25852-47-5), gelatin grafted with methacrylic acid; The weight ratio of the crosslinking agent to the monomer is 0.001~0.5:1, such as 0.005:1, 0.01:1, 0.04:1, 0.05:1, 0.08:1, 0.1:1, etc., preferably 0.005~0.08:1, which is suitable for mechanical matching of facial tissues.

[0008] The above monomers and crosslinking agents can be polymerized to form a water-absorbing polymer, which has the ability to swell and can retain a large amount of water inside the human face, etc. The present invention introduces this water-absorbing polymer to improve the water absorption performance and shaping ability of the microspheres, and adjusts the content of the crosslinking agent to improve the mechanical properties of the microspheres, so that the microspheres have injectability. The formed collagen polymer microspheres include a polymer crosslinking network and collagen entangled and trapped therein by the polymer crosslinking network. In this structure, the collagen is wrapped by the polymer crosslinking network, covering some of the enzyme cleavage sites, thereby prolonging its degradation time in the body.

[0009] In the present invention, the crosslinking agent only crosslinks the monomers, and the collagen does not participate in the crosslinking, so it can maintain its biological activity.

[0010] For the injectable collagen polymer microspheres, the mass ratio of the collagen to the monomer can be 0.5 - 10:10 - 60. Let X be the mass of the collagen and Y be the mass of the monomer. The units of X and Y are the same. The value of X can be 0.5 - 10, such as 1, 2, 5, 8, etc., and the value of Y can be 10 - 60, such as 20, 30, 40, etc.

[0011] The dry diameter of the injectable collagen polymer microspheres is 0.5 - 100 microns, and further preferably 20 - 75 microns.

[0012] In a second aspect, the present invention provides a method for preparing the injectable collagen polymer microspheres described in the first aspect. The preparation method uses the inverse emulsion method, as Figure 1 shown, and includes: Preparation of the aqueous phase: Dissolve collagen, monomers and a crosslinking agent in an acidic solution to form a homogeneous aqueous phase; Preparation of the microspheres: Pour the aqueous phase into an oil phase containing a surfactant under stirring, continuously stir, and carry out a polymerization reaction at 25 - 35 °C (such as 32 °C, etc.) in the presence of an initiator. After the reaction is completed, the injectable collagen polymer microspheres are obtained through washing, screening, drying, and sterilization.

[0013] The mass concentration of collagen in the aqueous phase can be 0.5% - 10%, such as 1%, 2%, 5%, 8%, etc.

[0014] The mass concentration of monomers in the aqueous phase can be 10% - 60%, such as 20%, 30%, 40%, etc.

[0015] The pH of the aqueous phase can be 1 - 6.

[0016] The acidic substance in the acidic solution can include one or more of acetic acid, hydrochloric acid, citric acid, and lactic acid.

[0017] The initiator can be an oxidation-reduction system, specifically, it can include a combination of persulfate and sulfite, or a combination of persulfate and bisulfite, or a combination of persulfate and tetramethylethylenediamine (CAS No.: 110-18-9). The persulfate can include at least one of ammonium persulfate and potassium persulfate. The sulfite can include sodium sulfite. The bisulfite can include sodium bisulfite.

[0018] The molar ratio of the initiator to the monomer can be 2-16:100, such as 4:100, 6:100, 8:100, 12:100, etc.

[0019] The surfactant can include one or more of sorbitan monooleate (CAS No.: 1338-43-8), polyoxyethylene sorbitan oleate (CAS No.: 9005-65-6), sodium dodecyl sulfate, cetyltrimethylammonium bromide, cocamidopropyl betaine, and polyvinyl alcohol.

[0020] The mass concentration of the surfactant in the oil phase can be 0.1%-10%, such as 2%, 4%, 5%, 6%, etc.

[0021] The oil phase can include one or more of liquid corn oil, liquid paraffin, and n-hexane.

[0022] During the preparation of the microspheres, the volume ratio of the water phase to the oil phase can be 1:7-20, such as 1:8, 1:10, etc.

[0023] During the preparation of the microspheres, the continuous stirring speed can be 400-5000 rpm, such as 550 rpm, 1200 rpm, 3000 rpm, etc.

[0024] During the preparation of the microspheres, the time of the polymerization reaction can be 1-8 h, such as 2 h, 3 h, etc.

[0025] The dry diameter of the injectable collagen polymer microspheres prepared by the preparation method described in the second aspect is 0.5-100 microns, further 20-75 microns, and can be obtained by sieving.

[0026] In the third aspect, the present invention provides the use of the injectable collagen polymer microspheres described in the first aspect or the injectable collagen polymer microspheres prepared by the preparation method described in the second aspect in the preparation of an injection filler.

[0027] The injectable collagen polymer microspheres of the present invention are a collagen filler with adjustable mechanical properties, extended degradation time, plastic shaping ability, reduced production cost, and easy storage and transportation.

[0028] Fourthly, the present invention provides an injectable filler, which is obtained by redissolving the injectable collagen polymer microspheres described in the first aspect and / or the injectable collagen polymer microspheres prepared by the preparation method described in the second aspect. The solvent used for redissolving can be physiological saline, phosphate aqueous solution, etc.

[0029] The application described in the third aspect and the injectable filler described in the fourth aspect. The injectable filler can be an injectable liquid gel material, specifically a medical material, a medical aesthetic facial filling material, etc. The concentration at which the injectable collagen polymer microspheres are uniformly dispersed in the injectable filler can be 20-100 mg / mL.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention improves the deficiencies of collagen fillers in facial fillers: introducing a polymer that can retain a large amount of water inside and has swelling ability to improve the water absorption performance of the material. Compared with existing collagen fillers, the ability to maintain the shape after injection can be significantly improved. At the same time, the prepared microspheres can regulate the mechanical properties under the condition of retaining the biological activity of collagen. By adjusting the content of the cross-linking agent, the elastic modulus of the material can be improved to meet the mechanical matching requirements of different facial tissues. Using the emulsion method to prepare good microsphere morphology makes it injectable. At the same time, the method of the present invention is synthesized in one step, and the preparation method is simple. The collagen polymer microspheres formed in the emulsion microdroplets include a polymer cross-linking network and collagen entangled and trapped in the polymer cross-linking network. The collagen is wrapped by the polymer network to cover some enzyme cleavage sites and prolong the in vivo degradation time of the material. The collagen polymer microspheres obtained by the present invention not only maintain the excellent biological activity of collagen, but also significantly improve the mechanical properties, water absorption performance and shaping ability (the ability to maintain volume after injection) of the material and prolong the in vivo degradation time, and have extremely high clinical application potential.

[0031] Since collagen is relatively expensive, the present invention introduces a polymer to reduce the production cost. At the same time, the obtained collagen polymer microspheres are in a dry powder state, which is easy to store and transport. When used, they can be redissolved in physiological saline or phosphate buffer solution, and their applicability is greater than that of most collagen fillers on the market that need to be stored and transported frozen. Description of the Drawings

[0032] Figure 1 It is a schematic structural diagram of a preparation method of an injectable collagen polymer microsphere of the present invention and the prepared microsphere.

[0033] Figure 2 It is a scanning electron microscope (SEM) photograph of the microspheres obtained in Example 1 of the present invention.

[0034] Figure 3This is the particle size distribution diagram of the microspheres obtained in Example 1 of the present invention after redissolution in an aqueous phosphate solution.

[0035] Figure 4 This is the diagram showing the change of the pushing force during the injection process of the microspheres obtained in Example 1 of the present invention after redissolution in an aqueous phosphate solution as the injection process progresses.

[0036] Figure 5 This is the SEM photograph of the microspheres obtained in Example 2 of the present invention. Detailed implementation manners

[0037] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0038] Example 1:

[0039] Acrylic acid was selected as the polymer monomer, polyethylene glycol dimethacrylate as the crosslinking agent, ammonium persulfate and sodium sulfite as the initiators, pharmaceutical corn oil as the oil phase, sorbitan monooleate and polyoxyethylene sorbitan oleate as the surfactants.

[0040] (1) Preparation of the aqueous phase: Collagen was dissolved in a 10 wt% aqueous acetic acid solution with a collagen concentration of 8 wt%. 20 wt% acrylic acid was added. The crosslinking agent polyethylene glycol dimethacrylate (mass ratio to the monomer of 0.04:1) was weighed and added to the collagen solution, and stirred until the collagen was completely dissolved.

[0041] (2) Preparation of the oil phase: Sorbitan monooleate and polyoxyethylene sorbitan oleate (mass fraction 2%) were added to pharmaceutical corn oil and mixed evenly to form the reaction oil phase.

[0042] (3) Ammonium persulfate and sodium bisulfite were weighed (molar ratio to the monomer of 2% respectively) and added to the aqueous phase and mixed evenly. Under stirring conditions, the aqueous phase was poured into the oil phase at a volume ratio of the aqueous phase to the oil phase of 1:20, and the stirring speed was controlled at 550 rpm. The oil-water mixed emulsion system was stirred and reacted at 32 °C for 2 h. After the reaction, the reaction mixture was washed successively with acetone and ethanol, screened with 200-mesh and 900-mesh cell sieves, and then obtained injectable collagen polymer microspheres through vacuum drying and ultraviolet sterilization. Their morphology is as Figure 2 shown. The results show that the microspheres prepared in Example 1 have regular morphology and relatively uniform particle size. The particle size distribution of the microspheres obtained in this example after redissolution in an aqueous phosphate solution is as Figure 3 shown. The water absorption rate of the microspheres can be increased to 414%. In the in vitro degradation experiment, the degradation time is longer than that of collagen, and the extrusion process through a 29G 1 / 2 fine needle is stable and injectable after redissolution in an aqueous phosphate solution, as Figure 4 shown.

[0043] Example 2:

[0044] 2-Methacryloyloxyethyl phosphorylcholine was selected as the polymer monomer, polyethylene glycol diacrylate as the crosslinking agent, potassium persulfate and sodium bisulfite as the initiators, and pharmaceutical corn oil was selected as the oil phase, and sorbitan monooleate and polyoxyethylene sorbitan monooleate as the surfactants.

[0045] (1) Preparation of the aqueous phase: Collagen was dissolved in a 20 wt% acetic acid aqueous solution with a collagen concentration of 5 wt%. 20 wt% of 2-methacryloyloxyethyl phosphorylcholine was added. The crosslinking agent polyethylene glycol diacrylate (mass ratio to the monomer of 0.05:1) was weighed and added to the collagen solution, and stirred until the collagen was completely dissolved.

[0046] (2) Preparation of the oil phase: Sorbitan monooleate and polyoxyethylene sorbitan monooleate (concentration 4 wt%) were added to the pharmaceutical corn oil and mixed evenly to form the reaction oil phase.

[0047] (3) Potassium persulfate and sodium bisulfite were weighed (molar ratio to the monomer of 8% respectively) and added to the aqueous phase and mixed evenly. Under stirring conditions, the aqueous phase was poured into the oil phase at a volume ratio of the aqueous phase to the oil phase of 1:20, and the stirring speed was controlled at 1200 rpm. The oil-water mixed emulsion system was stirred and reacted at 32 °C for 3 h. After the reaction, the reaction mixture was washed successively with acetone and ethanol, screened with 100-mesh and 900-mesh cell sieves, and then obtained injectable collagen polymer microspheres through vacuum drying and ultraviolet sterilization, as Figure 5 shown. The results showed that the microspheres prepared in Example 2 had regular morphology, the water absorption rate could be increased to 1223%, and the degradation time was longer than that of collagen in the in vitro degradation experiment.

[0048] Example 3:

[0049] Acryloylethyl carboxybetaine and 3-[N,N-dimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]ammonium]propane-1-sulfonate inner salt were selected as the polymer monomers, N,N'-methylenebisacrylamide as the crosslinking agent, ammonium persulfate and tetramethylethylenediamine as the initiator system, n-hexane was selected as the oil phase, and sorbitan monooleate and polyoxyethylene sorbitan monooleate as the surfactants.

[0050] (1) Preparation of the aqueous phase: Collagen was dissolved in a 20 wt% acetic acid aqueous solution with a collagen concentration of 2 wt%. Acryloylethyl carboxybetaine and 3-[N,N-dimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]ammonium]propane-1-sulfonate inner salt (concentration 30 wt%) were added. The crosslinking agent N,N'-methylenebisacrylamide (mass ratio to the monomer of 0.005:1) was weighed and added to the collagen solution, and stirred until the collagen was completely dissolved.

[0051] (2) Preparation of the oil phase: Take sorbitan monooleate and polyoxyethylene sorbitan oleate (concentration 5 wt%) and add them to n-hexane, mix evenly to form the reaction oil phase.

[0052] (3) Weigh ammonium persulfate (molar ratio to the monomer is 2%) and add it to the aqueous phase. Under stirring conditions, pour the aqueous phase into the oil phase according to the volume ratio of the aqueous phase to the oil phase of 1:10, and control the stirring speed at 3000 rpm. Weigh N,N,N',N'-tetramethylethylenediamine (volume ratio to the emulsion is 1%) and add it to the emulsion, mix evenly. The oil-water mixed emulsion system is stirred and reacted at 32 °C for 3 h. After the reaction is completed, wash the reaction mixture successively with acetone and ethanol, sieve it with 100-mesh and 900-mesh cell sieves, and obtain injectable collagen polymer microspheres after vacuum drying and ultraviolet sterilization.

[0053] Example 4:

[0054] Select sodium 2-acrylamido-2-methyl-1-propanesulfonate as the polymer monomer, polyethylene glycol diacrylamide as the crosslinking agent, ammonium persulfate and N,N,N',N'-tetramethylethylenediamine as the initiator system, select liquid paraffin as the oil phase, and sorbitan monooleate as the surfactant.

[0055] (1) Preparation of the aqueous phase: Dissolve collagen in a 10 wt% acetic acid aqueous solution with a collagen concentration of 1 wt%, add sodium 2-acrylamido-2-methyl-1-propanesulfonate (concentration 30 wt%), weigh the crosslinking agent polyethylene glycol diacrylamide (mass ratio to the monomer is 0.01:1) and add it to the collagen solution, stir until the collagen is completely dissolved.

[0056] (2) Preparation of the oil phase: Take sorbitan monooleate (concentration 6 wt%) and add it to liquid paraffin, mix evenly to form the reaction oil phase.

[0057] (3) Weigh ammonium persulfate (molar ratio to the monomer is 2%) and add it to the aqueous phase. Under stirring conditions, pour the aqueous phase into the oil phase according to the volume ratio of the aqueous phase to the oil phase of 1:8, and control the stirring speed at 3000 rpm. Weigh N,N,N',N'-tetramethylethylenediamine (volume ratio to the emulsion is 0.5%) and add it to the emulsion. The oil-water mixed emulsion system is stirred and reacted at 32 °C for 3 h. After the reaction is completed, wash the reaction mixture successively with acetone and ethanol, sieve it with 100-mesh and 900-mesh cell sieves, and obtain injectable collagen polymer microspheres after vacuum drying and ultraviolet sterilization.

[0058] Example 5:

[0059] N-isopropylacrylamide was selected as the polymer monomer, polyethylene glycol dimethacrylate as the crosslinking agent, potassium persulfate and sodium sulfite as the initiators, and pharmaceutical corn oil as the oil phase, and sorbitan monooleate and polyoxyethylene sorbitan monooleate as the surfactants.

[0060] (1) Preparation of the aqueous phase: Collagen was dissolved in a 10 wt% acetic acid aqueous solution with a collagen concentration of 1 wt%, 20 wt% N-isopropylacrylamide was added, and the crosslinking agent polyethylene glycol dimethacrylate (mass ratio to the monomer was 0.08:1) was weighed and added to the collagen solution, and stirred until the collagen was completely dissolved.

[0061] (2) Preparation of the oil phase: Sorbitan monooleate and polyoxyethylene sorbitan monooleate (concentration 6 wt%) were added to pharmaceutical corn oil and mixed evenly to form the reaction oil phase.

[0062] (3) Potassium persulfate and sodium sulfite were weighed (molar ratios to the monomer were 6% respectively) and added to the aqueous phase and mixed evenly. Under stirring conditions, the aqueous phase was poured into the oil phase at a volume ratio of the aqueous phase to the oil phase of 1:20, and the stirring speed was controlled at 3000 rpm. The oil-water mixed emulsion system was stirred and reacted at 32 °C for 3 h. After the reaction was completed, the reaction mixture was washed successively with acetone and ethanol, sieved with 100-mesh and 900-mesh cell sieves, and then obtained injectable collagen polymer microspheres after vacuum drying and ultraviolet sterilization.

[0063] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. An injectable collagen polymer microsphere, characterized in that, It includes a polymer cross-linked network and collagen that is entrapped and entangled therein by the polymer cross-linked network; the polymer cross-linked network is formed by polymerizing raw materials including the monomer and the cross-linking agent; The monomer includes one or more of acrylic acid, acrylamide, vinylsulfonic acid, itaconic acid, N-isopropylacrylamide, vinylpyrrolidone, acryloyloxyethyl carboxybetaine, sodium 2-acrylamido-2-methyl-1-propanesulfonate, 3-[N,N-dimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]ammonium] propane-1-sulfonate inner salt, 2-methacryloyloxyethyl phosphorylcholine; The cross-linking agent includes one or several of N,N'-methylenebisacrylamide, polyethylene glycol diacrylamide, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, gelatin grafted with methacrylic acid; The weight ratio of the cross-linking agent to the monomer is 0.001~0.5:

1.

2. The injectable collagen polymer microspheres according to claim 1, wherein The mass ratio of the collagen to the monomer is 0.5~10:10~60.

3. The method for preparing injectable collagen polymer microspheres according to claim 1 or 2, characterized in that, The preparation method adopts the inverse emulsion method, including: Aqueous phase preparation: Dissolve collagen, monomer and cross-linking agent in an acidic solution to form a homogeneous aqueous phase; Microsphere preparation: Pour the aqueous phase into an oil phase containing a surfactant under stirring, continuously stir, and carry out a polymerization reaction at 25~35 °C in the presence of an initiator. After the reaction is completed, the injectable collagen polymer microspheres are obtained through washing, screening, drying, and sterilization.

4. The preparation method according to claim 3, characterized in that, The mass concentration of collagen in the aqueous phase is 0.5%~10%; The mass concentration of the monomer in the aqueous phase is 10%~60%.

5. The preparation method according to claim 3, characterized in that, The pH of the aqueous phase is 1~6; The acidic substances in the acidic solution include one or more of acetic acid, hydrochloric acid, citric acid, lactic acid; 6. The preparation method according to claim 3, characterized in that, The initiator is an oxidation-reduction system, including a combination of persulfate and sulfite, or a combination of persulfate and bisulfite, or a combination of persulfate and tetramethylethylenediamine; the persulfate includes at least one of ammonium persulfate and potassium persulfate; the sulfite includes sodium sulfite; the bisulfite includes sodium bisulfite; The molar ratio of the initiator to the monomer is 2~16:

100.

7. The preparation method according to claim 3, characterized in that, The surfactant includes one or more of sorbitan monooleate, polyoxyethylene sorbitan oleate, sodium dodecyl sulfate, cetyltrimethylammonium bromide, cocamidopropyl betaine, polyvinyl alcohol; The mass concentration of the surfactant in the oil phase is 0.1%~10%; The oil phase includes one or more of liquid corn oil, liquid paraffin, n-hexane; During the microsphere preparation process, the volume ratio of the aqueous phase to the oil phase is 1:7~20.

8. The preparation method according to claim 3, characterized in that, During the microsphere preparation process: The continuous stirring speed is 400~5000 rpm; The time of the polymerization reaction is 1~8 h.

9. Use of the injectable collagen polymer microspheres according to claim 1 or 2 or the injectable collagen polymer microspheres prepared by the preparation method according to any one of claims 3~8 in the preparation of an injection filler.

10. An injection filler, characterized in that, It is obtained by redissolving the injectable collagen polymer microspheres described in claim 1 or 2 and / or the injectable collagen polymer microspheres prepared by the preparation method described in any one of claims 3 to 8.

Images