CN113274354A - Air-dried sheep membrane powder and application thereof - Google Patents
Air-dried sheep membrane powder and application thereof Download PDFInfo
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- CN113274354A CN113274354A CN202110458798.4A CN202110458798A CN113274354A CN 113274354 A CN113274354 A CN 113274354A CN 202110458798 A CN202110458798 A CN 202110458798A CN 113274354 A CN113274354 A CN 113274354A
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- amniotic membrane
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
An air-dried amniotic membrane powder and application thereof, relating to an amniotic membrane product, in particular to a preparation method and application of the amniotic membrane powder. The air-dried amniotic membrane powder is prepared by air-drying fresh sterile virus-free amniotic membrane at a constant temperature of 36-37 ℃ and grinding into amniotic membrane powder. The air-dried amnion powder is simple and convenient to prepare, stable in property at room temperature and easy to store, and is a convenient and effective amnion product. The AM-FS daub prepared from the amniotic membrane powder is prepared by taking fibrin glue as a transfer substrate to load the amniotic membrane powder, contains rich growth factors from amniotic tissues, combines the excellent biological properties of the fibrin glue, has similar effect on repairing the damage of the ocular surface tissues to fresh amniotic membranes, overcomes the defects of suture of the fresh amniotic membranes, high difficulty of operation, easy falling off, operation failure and the like, and is suitable for repairing various ocular surface tissues and skin tissue damages.
Description
Technical Field
The invention relates to an amnion product, in particular to a preparation method and application of amnion powder.
Background
The amnion is located in the innermost layer of the fetal membrane, has the characteristics of anti-inflammation, anti-angiogenesis, immunoregulation, antibiosis, anti-fibrosis, good histocompatibility and the like, is often used as an epithelial basement membrane substitute, and is widely used for repairing epithelial tissues of eyes, particularly treating chemical burns on the ocular surface. The application of the amnion in the treatment of eye diseases is limited by the factors of difficult acquisition and long-term storage of fresh amnion, thin texture, complex operation of surgical suture and the like. The search for a new amnion product which can retain the excellent biological characteristics of amnion and is convenient for storage and use has been the hot point of research.
There are many studies on amnion products, but these amnion products still show many limitations in clinical application and popularization. The method comprises the following steps:
glycerol-preserved amniotic membrane adequately retains the histological structure and cytokine content of the amniotic membrane, but is difficult to sterilize, and may lead to disease transmission.
The freeze-dried amnion can well retain the activity of growth factors, but the activity of the freeze-dried amnion is lower than that of fresh amnion, the mechanical strength of the freeze-dried amnion is weak, the cross-linking result of the freeze-dried amnion with a cross-linking agent is not ideal, and the freeze-dried amnion can cause the remarkable loss of bioactive components.
The amnion extract is another hot spot of the current novel amnion product development, has various high-level growth factors, is easy to flow out of nasolacrimal ducts when being applied to eyes, has low bioavailability, is inconvenient to use at night, and has short shelf life.
The novel composite amnion combines the amnion with absorbable biological material with excellent characteristics, can improve the mechanical strength and plasticity of the amnion while retaining the excellent characteristics of the amnion, but increases the risk of inflammatory reaction by a complex chemical process, and is still in the experimental stage at present.
Disclosure of Invention
The invention aims to provide a preparation method of air-dried amniotic membrane powder, which can retain the excellent biological characteristics of amniotic membrane and is convenient to store.
Air-dried amniotic membrane powder is characterized in that fresh sterile virus-free amniotic membrane is air-dried and ground into amniotic membrane powder at the constant temperature of 36-37 ℃.
The application of the air-dried amniotic membrane powder comprises the steps of preparing the air-dried amniotic membrane powder into amnion-fibrin glue (AM-FS glue), and specifically, fully mixing the amniotic membrane powder with a catalyst solution in porcine fibrin glue to obtain an amniotic membrane powder-catalyst solution mixed solution; then mixing the amniotic membrane powder-catalyst mixed solution with the equal volume of the main body gelatin solution to obtain amniotic membrane-fibrin cement;
the catalyst component is porcine thrombin;
the main glue component is porcine fibrinogen.
The concentration of the amnion-fibrin glue mud (AM-FS glue mud) is 0.25 mg/ml.
The invention firstly proposes that fresh amnion is air-dried at a constant temperature of 36-37 ℃ to obtain dry amnion tissue, and the temperature of 36-37 ℃ is the growth environment temperature of cells under simulated physiological conditions. And pre-cooling the dried amniotic tissues in liquid nitrogen, and grinding into novel amniotic powder with the diameter of less than 260 um. The mode has small damage to active ingredients in the amniotic tissue, has stable property at room temperature, is easy to store, is a convenient and effective amniotic product, can be compounded with various materials to prepare amniotic gel, spray and ointment for minimally invasive intervention or wound repair with special requirements, can also be crosslinked with biomacromolecule polymers and synthetic polymers to be applied to the field of tissue engineering, and provides a new idea for the research and development of novel amniotic products.
The AM-FS daub prepared from the amniotic membrane powder is prepared by loading the amniotic membrane powder by taking fibrin glue as a transfer matrix, contains rich growth factors from amniotic tissues, combines the excellent biological properties of the fibrin glue, can form a uniform and soft gel-like substance on the ocular surface, has good adhesiveness and plasticity, and can be used for repairing ocular surface and skin injury.
Drawings
FIG. 1 is a graph showing the comparison of the growth factor content in amniotic membrane powder and fresh amniotic membrane at various time points and under different storage conditions in example 1 of the present invention;
comparison of growth factor content in the novel amniotic powder with that in the fresh amniotic membrane at various time points under different storage conditions ([ lambda ] denotes FC > (1.2 or <0.83, logFC > 0.263)).
FIG. 2 is a graph showing the effect of AM-FS cement containing different concentrations of amniotic powder on the proliferation of Corneal Epithelial Cells (CEC);
the A value is increased along with the decrease of the concentration of the amnion powder, the absorbance is highest at 0.25mg/ml, and then the A value is steeply decreased and gradually becomes gentle after 4 mg/ml.
FIG. 3 is a graph comparing the haze scores of various groups of corneas at different time points;
comparison of the corneal haze scores for each group at different time points (, indicates P < 0.05).
FIG. 4 is a graph comparing groups of corneal neovascularization at different time points;
comparison of each group of corneal neovascularisation at different time points (, P < 0.05).
FIG. 5, HE staining and immunohistochemistry in 28d groups.
FIG. 6 is a pictorial representation; wherein:
FIGS. 6A and 6B show the washed fresh amnion to form a translucent membrane;
FIG. 6C is a novel amniotic membrane powder which is air-dried at a constant temperature of 36-37 ℃ and ground into a diameter of <260 um;
FIG. 6D AM-FS cement made by fusion with fibrin glue.
Detailed Description
Example 1: the preparation method of the air-dried amniotic membrane powder comprises the following steps:
s1, obtaining amnion, selecting pregnant woman with negative infectious disease detection such as HIV, HBV, HCV, syphilis, etc., obtaining waste placenta within 24h after delivery, and separating amnion.
S2, washing blood clots and mucus on amnion with sterile physiological saline, then repeatedly rinsing in physiological saline containing 50ug/ml penicillin-streptomycin, 100ug/ml neomycin and 215ug/ml amphotericin B for 45min, and finally rinsing with sterile physiological saline for 3 times.
S3, drying the amnion by air, flattening the washed amnion, fixing the amnion on a support frame, then placing the amnion in a constant-temperature circulating air drying box at 37 ℃, standing for 2h, and fully removing water to obtain the air-dried amnion.
S4, grinding into powder, placing the amnion tissue dried at the constant temperature of 37 ℃ into a stainless steel centrifugal tube specially matched with a grinder, precooling in liquid nitrogen for 2min, grinding, and grinding for 75HZ for 180S to obtain the amnion powder with the diameter less than 260 um.
And S5, sterilizing, and performing irradiation sterilization by adopting gamma rays of 15-30KGy to obtain the novel sterile air-dried amniotic membrane powder.
The amniotic powder obtained in this example 1 was examined and compared with the expression of TGF- β, NGF R, HGF, EGF, bFGF in fresh amniotic membrane. Except that the expression quantity of NGF R in the five cytokines is lower than that of a fresh amniotic membrane group, the expression quantities of other cytokines in the initial amniotic membrane powder are all higher than that of the fresh amniotic membrane group, the differences have statistical significance (adj. P.Val is less than 0.05 and logFC is greater than 0.263), and the expression quantity of TGF beta in the initial amniotic membrane powder has no statistical significance (logFC is less than 0.263) compared with that of the fresh amniotic membrane group, so that the novel amniotic membrane powder well retains active ingredients in amniotic tissues. The results are shown in Table 1.
Table 1: the expression difference of the growth factors in the novel air-dried amniotic membrane powder and the fresh amniotic membrane tissue;
note: the adjusted P-value (adj.p.val) <0.05, logFC > 0.263 difference is statistically significant
The data is subjected to normalization processing by Raybiotech software from original data, and Result data is selected for analysis, wherein the analysis method is modulated t-statistics, and the data packet is limma and comes from R/Bioconductor; the analysis was performed using fold difference screening for statistically significant results.
Although the freeze-dried amnion can retain active cytokines to a certain degree, the content of various cytokines is lower than that of fresh amnion tissues, therefore, the experiment directly compares the novel air-dried amnion powder with the fresh amnion tissues, and the obtained conclusion is that the expression quantity of the rest cytokines in the amnion powder is higher than that of the fresh amnion groups except that the expression quantity of NGF R in the five cytokines is lower than that of the fresh amnion groups, so that the novel air-dried amnion powder can be proved to have the content of the active cytokines similar to that of the fresh amnion tissues.
The prepared amniotic membrane powder is stored at room temperature, 4 ℃ and-20 ℃ for 10d, 20d and 30d respectively, and the change of the expression level of each growth factor at three time points is detected respectively, and the result is shown in figure 1. The expression levels of EGF and NGF are both reduced at 30 days and are lower than those of a fresh amniotic membrane group, and the expression level of the growth factor of the amniotic membrane powder stored at normal temperature is higher than that of the amniotic membrane powder stored at-20 ℃; the expression quantity of bFGF and HGF in the amniotic membrane powder under various storage conditions and storage time groups is higher than that of bFGF and HGF in a fresh amniotic membrane group, and the difference of the expression of growth factors of the amniotic membrane powder in a room-temperature storage group and a-20 ℃ storage group is not obvious, so that the amniotic membrane powder is stable in property and can be stored at room temperature.
Example 2: the preparation method of the amnion-Fibrin glue mud comprises the following steps:
s1, the amnion powder prepared in the example 1 and the catalyst solution in the porcine fibrin glue are fully mixed, and amnion powder-catalyst mixed solution with the amnion powder concentration of 130mg/ml, 65mg/ml, 32mg/ml, 16mg/ml, 8mg/ml, 4mg/ml, 2mg/ml, 1mg/ml, 0.5mg/ml, 0.25mg/ml and 0mg/ml is respectively prepared according to the mass ratio.
S2, sequentially and respectively taking 50ul of the amnion powder-catalyst with the concentration, respectively adding the amnion powder-catalyst into a 24-hole cell culture plate, uniformly paving the amnion powder-catalyst at the bottom of the cell culture plate, sequentially adding equal-volume main colloid solution into each culture hole, slightly shaking, and uniformly mixing to form the amnion powder with the concentration of: 65mg/ml, 32mg/ml, 16mg/ml, 8mg/ml, 4mg/ml, 2mg/ml, 1mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml, 0mg/ml of AM-FS cement.
Selecting cell activity and growth of the daub of the amniotic membrane powder with different concentrationsCorneal epithelial cells (CEC: Corneal epithelial cells) cultured in a long state up to the 2 nd generation were subjected to in vitro cell experiments to examine the effect on CEC proliferation. By 1 × 103CEC density per well was seeded on AM-FS cement-plated 24-well cell culture plates, and the 24-well cell culture plates were placed in 5% volume fraction CO at 37 ℃%2Culturing for 72h in an incubator. Digesting and resuspending the cells in each well by using 0.25% trypsin, collecting the cell suspension in each well respectively, centrifuging for 5min at 1000r/min, resuspending again, adding the cell suspension in a 96-well cell culture plate respectively, and continuously culturing for 24 h. 10ul of CCK-8 solution was added to each well, and the incubation was continued for 2 hours to measure the absorbance (A) at 450 nm. Each set of 4 secondary wells, all experiments were repeated 3 times.
According to the CCK-8 result, the AM-FS daub with the maximum absorbance (A), namely the amnion powder concentration of 0.25mg/ml, is screened to be the optimal proportioning concentration, and the result is shown in figure 2.
And (3) performing curative effect experiment on severe rabbit ocular surface alkali burn by using AM-FS daub with the concentration of amniotic powder of 0.25 mg/ml. Constructing a rabbit severe ocular surface alkali burn model with 32 eyes in total; model animals were randomized into 4 groups according to different treatment regimens: 8 eyes of AM-FS daub group, 8 eyes of fresh amnion transplantation group, 8 eyes of Fibrin glue FS (FS is fiber serum abbreviation) group, 8 eyes of antibiotic control group and 8 eyes of antibiotic control group. Four groups of rabbits were subjected to slit-lamp microscopy and sodium corneal fluorescein staining at postoperative 7d, 14d, 21d, and 28d, respectively, and compared with corneal haze and corneal neovascular area as shown in fig. 3 and 4:
corneal opacity was statistically insignificant in the AM-FS cement group compared to the fresh amniotic membrane graft group 28 days after treatment (P < 0.05), and both corneal opacity scores were lower than the antibiotic control group (P < 0.05). The lower the corneal opacity score, the more transparent the cornea, and the same effect of AM-FS daub on reducing the corneal opacity after alkali burn and restoring the corneal transparency as that of fresh amnion transplantation, both of which are superior to those of the antibiotic control group.
After alkali burn, the area of the cornea neovascular of each group of rabbits is increased along with time, but the area of the AM-FS daub group, the area of the cornea neovascular of the fresh amniotic membrane transplantation group and the area of the cornea neovascular of the FS group are all smaller than that of the antibiotic control group (P is less than 0.05), although the area of the cornea neovascular of the fresh amniotic membrane transplantation group is smaller than that of the AM-FS daub group (P is less than 0.05) at 7d, 21d and 28d, the difference values are smaller (0.34, 0.38 and 0.88 respectively), and the AM-FS daub and the fresh amniotic membrane transplantation can inhibit the cornea neovascular generation after alkali burn, and the effects of the two methods are similar.
Four groups of rabbits were sacrificed at 28d, the tissue fixative fixated the eye, and the degree of neovascularization and inflammatory responses of corneal tissue were compared, and the results are shown in fig. 5. AM-FS daub reduced corneal inflammatory responses and neovascularization compared to FS and antibiotic controls.
The attached figure shows that the AM-FS daub can effectively promote the restoration of the eye surface of the rabbit after severe alkali burn. The effects of healing corneal epithelium, recovering transparency and inhibiting the formation of corneal neovascularization after AM-FS daub treatment are superior to those of antibiotics and simple fibrin glue treatment groups, and the same treatment effect as that of fresh amnion transplantation can be achieved.
The air-dried amnion powder is simple and convenient to prepare, stable in property at room temperature and easy to store, and is a convenient and effective amnion product. The amnion powder prepared by the method has small damage to active ingredients in the amnion tissue, can be compounded with various materials to prepare amnion glue, spray and ointment for minimally invasive intervention or wound repair with special requirements, can also be crosslinked with biomacromolecule polymers and synthetic polymers to be applied to the field of tissue engineering, and provides a new idea for the research and development of novel amnion products.
The AM-FS daub prepared from the amniotic membrane powder is prepared by loading the amniotic membrane powder by taking fibrin glue as a transfer matrix, contains rich growth factors from amniotic tissues, combines the excellent biological properties of the fibrin glue, has similar effect on repairing the damage of the ocular surface tissues to fresh amniotic membranes, overcomes the defects that the fresh amniotic membranes need to be sutured, has high operation difficulty and is easy to fall off to cause operation failure and the like, can be repeatedly dropped on the ocular surface to form a uniform and soft gel-like substance on the ocular surface, has certain adhesiveness and plasticity, does not need to be sutured, is convenient to use, has strong comfort of the ocular surface, and is suitable for repairing various ocular surface tissues and skin tissue damages for various types.
Claims (3)
1. Air-dried amniotic membrane powder is characterized in that fresh sterile virus-free amniotic membrane is air-dried and ground into amniotic membrane powder at the constant temperature of 36-37 ℃.
2. The application of the air-dried amniotic membrane powder is characterized in that the air-dried amniotic membrane powder is prepared into amnion-fibrin glue mud, and the specific method is that the amniotic membrane powder is fully mixed with a catalyst solution in porcine fibrin glue to obtain an amniotic membrane powder-catalyst solution mixed solution; then mixing the amniotic membrane powder-catalyst mixed solution with the equal volume of the main body gelatin solution to obtain amniotic membrane-fibrin cement;
the catalyst component is porcine thrombin;
the main glue component is porcine fibrinogen.
3. The air-dried amniotic membrane powder of claim 1, wherein the concentration of the amniotic membrane powder is 0.25 mg/ml.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140342015A1 (en) * | 2012-09-10 | 2014-11-20 | Wake Forest University Health Sciences | Amniotic Membrane Powder and Methods of Making |
| CN107137768A (en) * | 2017-04-12 | 2017-09-08 | 苏州诺普再生医学有限公司 | A kind of preparation method of de- cell amnion powder |
| CN110404119A (en) * | 2019-08-29 | 2019-11-05 | 陈万娟 | Amnion tissue engineering goes the preparation method of immunogene dermal scaffold |
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- 2021-04-27 CN CN202110458798.4A patent/CN113274354A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140342015A1 (en) * | 2012-09-10 | 2014-11-20 | Wake Forest University Health Sciences | Amniotic Membrane Powder and Methods of Making |
| CN107137768A (en) * | 2017-04-12 | 2017-09-08 | 苏州诺普再生医学有限公司 | A kind of preparation method of de- cell amnion powder |
| CN110404119A (en) * | 2019-08-29 | 2019-11-05 | 陈万娟 | Amnion tissue engineering goes the preparation method of immunogene dermal scaffold |
Non-Patent Citations (1)
| Title |
|---|
| 李楠钰: "羊膜-纤维蛋白胶泥的制备及其治疗兔重度眼表碱烧伤的实验研究", 《中国优秀博硕士学位论文全文数据库(硕士)医药卫生科技辑》 * |
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Application publication date: 20210820 |