Application of maremaxostat in preparation of medicine for promoting skin stretching and regeneration

Abstract

The invention provides application of maremastat in preparation of a medicine for promoting skin stretching and regeneration. The step of promoting skin stretching and regeneration comprises the substeps of treating or delaying skin stretching and regeneration capacity depletion; the step of promoting skin stretching regeneration comprises the substeps of promoting epidermal cell proliferation, increasing epidermal thickness, delaying damage of an epidermal adhesion structure and preventing epidermal stem cell identity loss; the invention provides the new application of the maremaxostat for the first time, namely the application of the maremaxostat in preparation of the medicine for promoting skin stretching and regeneration.

Description

Technical Field

[0001] The invention relates to application of marimastat in preparing a medicine for promoting skin stretching and regeneration, and belongs to the technical field of biomedicine. Background Art

[0002] Skin soft tissue stretch regeneration technology utilizes the natural physiological characteristics of adult skin to continuously regenerate under the influence of mechanical force, applies controllable tension to induce skin regeneration, and produces additional skin tissue for transplantation and repair of large-area soft tissue defects. It is a treatment method. It is one of the few clinically practical in situ regeneration technologies of human physiological organs and a good model for studying the mechanism of changes in the process of skin regeneration ability. However, this excellent treatment method is limited to 2-3 times growth due to the limited regeneration capacity of the skin under tension. When the regeneration exceeds 4 times, it is very easy to cause thin skin, damage, ischemia due to insufficient regeneration capacity, and further cause serious complications such as expander exposure and infection. Studies have shown that Wang et al. (Wang, J., Zhang, Y., Gao, Y., Shan, S. & Li, Q. EZH2 Regulates the Correlation between Skin Regeneration and the Duration of Mechanical Stretch. J. Invest. Dermatol. 141, 894-902. e9 (2021).) found that cell proliferation and differentiation were active one month after human skin stretching, and cell proliferation activity reached a plateau at 2 months, while cell proliferation and differentiation activity decreased across the board after 5 months of long-term stretching. Xue et al. (Xue, Y., Lyu, C., Taylor, A. & Van Ee, A. Mechanical tension mobilizes Lgr6+ epidermal stem cells to drive skin growth. Sci. Adv. 8, (2022).) found that after long-term stretching of the rat back, the thickness of the epidermis in the stretch regeneration process thickened in the early stage, and became significantly thinner after one month, and the cell proliferation decreased significantly in the late stage; Huang et al. (Huang, X. et al. CDH1 is Identified as A Therapeutic Target for Skin Regeneration after Mechanical Loading. Int. J. Biol. Sci. 17, 353–367 (2021).) reported that during the stretching process of the rat back, excessive expansion can cause skin thinning and necrosis, leading to the failure of stretch regeneration. The above clinical experience and scientific research jointly suggest that although skin stretch regeneration technology promotes skin regeneration in situ through artificial means, its regeneration capacity is not unlimited. The lack of skin regeneration capacity during the stretch regeneration process is the main bottleneck limiting the long-term application of this technology.

[0003] Since the invention of skin soft tissue stretch regeneration technology, clinical scientists have been actively exploring effective intervention measures to enhance the efficiency of tension-induced skin regeneration. Previous means of auxiliary enhancement of stretch regeneration efficiency include: cytokines represented by epidermal growth factor and fibroblast growth factor; stem cell supplementation represented by bone marrow mesenchymal stem cells and adipose-derived stem cells, etc., which jointly achieve the purpose of promoting cell division, proliferation, migration, and improving tissue repair ability and vascularization level. However, simply stimulating excessive proliferation and differentiation of skin tissue to thicken the epidermis cannot be a sign of a good prognosis for stretch regeneration. In principle, we need to maintain the balance between epidermal stem cell self-renewal and differentiation homeostasis and continuously maintain the regenerative ability of stem cells. However, previous studies have mostly focused on the early stage of the regenerative response of skin epithelial cells triggered by tension stimulation, and rarely explained the specific phenomenon and mechanism of insufficient regenerative ability of long-term stretch skin, and there is no effective therapeutic drug that can delay the exhaustion of long-term stretch regeneration ability. Summary of the invention

[0004] The present invention provides the use of marimastat in the preparation of a drug for promoting skin stretch regeneration. The present invention has experimentally confirmed that the drug marimastat can promote long-term skin stretch regeneration, specifically by promoting epidermal cell proliferation, increasing epidermal thickness, delaying the destruction of epidermal adhesion structures, and preventing the loss of epidermal stem cell identity.

[0005] To achieve this object, the present invention provides the following technical solutions:

[0006] The first aspect of the present invention provides the use of marimastat in preparing a medicament for promoting skin stretch regeneration.

[0007] In the present invention, Marimastat (CAS: 154039-60-8) is the first to be used for anti-cancer treatment to limit tumor metastasis. Oral administration of the drug also has good pharmacokinetic characteristics in humans, and short-term treatment is well tolerated by patients.

[0008] Preferably, the promoting skin stretch regeneration includes: treating or delaying the exhaustion of skin stretch regeneration capacity.

[0009] Preferably, the promoting skin stretch regeneration includes: promoting the proliferation of epidermal cells, increasing the thickness of the epidermis, delaying the destruction of the epidermal adhesion structure, and preventing the loss of the identity of epidermal stem cells.

[0010] In the present invention, loss of stem cell identity means that the number of stem cells does not change, but the properties change.

[0011] Preferably, the administration method of Marimastat is not limited to: subcutaneous injection, topical application, intradermal injection, oral administration and the like.

[0012] Preferably, the administration time of marimastat is: after the 20th day of skin stretch regeneration treatment, or after the stretch regeneration shows signs of regeneration exhaustion.

[0013] Preferably, the effective concentration of marimastat is not less than 100 μg / mL.

[0014] Preferably, the medicine is a tincture, an aqueous solution, an emulsion, a mixture, a syrup, an ointment, a suppository, a tablet, a water pill, a honey pill, a capsule, a soft capsule, a pill, an injection, a powder, a granule, a patch, or a targeted preparation.

[0015] Preferably, the medicine is an injection.

[0016] The second aspect of the present invention provides the use of a metalloproteinase 2 / 9 type I inhibitor, MMP2-IN-3, in the preparation of a drug for promoting skin stretch regeneration.

[0017] Preferably, the promoting skin stretch regeneration includes: treating or delaying the exhaustion of skin stretch regeneration capacity.

[0018] Preferably, the promoting skin stretch regeneration includes: promoting the proliferation of epidermal cells, increasing the thickness of the epidermis, delaying the destruction of the epidermal adhesion structure, and preventing the loss of the identity of epidermal stem cells.

[0019] Compared with the prior art, the beneficial effects and significant improvements of the technical solution of the present invention are:

[0020] 1. The present invention proposes for the first time a new application of Marimastat, namely, the application of Marimastat in the preparation of a drug for promoting skin stretch regeneration. The present invention verifies through experiments that Marimastat can promote long-term skin stretch regeneration, specifically by promoting epidermal cell proliferation, increasing epidermal thickness, delaying the destruction of epidermal adhesion structures, and preventing the loss of epidermal stem cell identity.

[0021] 2. The present invention screened the drug Marimastat from 10 small molecule protease inhibitors through in vitro experiments, which has a significant effect of preventing COL17A1 protein degradation, and further verified through in vivo drug experiments that Marimastat can be used to delay the treatment of skin regeneration exhaustion in stretch regeneration therapy and promote the maintenance of the skin's long-term stretch regeneration ability.

[0022] 3. The present invention proposes for the first time a new application of MMP-2 / MMP-9inibitorⅠ (metalloproteinase 2 / 9 type I inhibitor) and MMP2-IN-3, namely, the application of metalloproteinase 2 / 9 type I inhibitor and metalloproteinase 2 inhibitor in the preparation of drugs for promoting skin stretch regeneration. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solution of the present invention, the drawings used in the embodiments of the present invention are briefly introduced below.

[0024] Figure 1 1 is a schematic diagram of the operation of the mouse expansion model in Example 1 (top) and a representative lateral view after expansion (bottom);

[0025] Figure 2 It is a representative immunofluorescence section display (A) and statistics (B) of skin proliferation (KI67+) and differentiation (KRT10+) in the early, middle and late stages of expansion in Example 1, legend: 20 μm;

[0026] Figure 3 Figure 1 is a transmission electron microscopy image of Example 1, wherein Figure A is a representative schematic diagram of the 36 days after expansion (DPE36) and the control group (DPE0) taken by transmission electron microscopy, legend: 2μm (black), 200nm (blue), 500nm (red), arrows and H at D: hemidesmosomes; Figure B is the statistics of the width of hemidesmosomes, the number of hemidesmosomes per unit basement membrane length, and the number of microlayers per unit basement membrane length;

[0027] Figure 4 The results of the changes in COL17A1 protein and clone formation ability in Example 2; A and B are immunofluorescence slice display diagrams and fluorescence quantitative statistics of COL17A1 protein, legend: 20 μm; C and D are clone formation ability display diagrams, as well as clone growth area and adhesion rate statistics;

[0028] Figure 5 is the result of the drug screening experiment in Example 2; A is a schematic diagram of the drug screening experiment process, HFKs: human primary foreskin cells; CHX: cycloheximide; B is the change in COL17A1 protein expression after different drug screening;

[0029] Figure 6 This is a flow chart of the experiment of screening test of the drug effect of Marimastat in mice in Example 3;

[0030] Figure 7 The changes (A) and statistics (B) of epidermal proliferation (KI67), differentiation (KRT10), and COL17A1 protein after injection of the drug and control preparations for 36 days of expansion in Example 3, legend: 20 μm;

[0031] Figure 8The transmission electron microscopy results in Example 3; wherein A is a transmission electron microscopy image showing that the epidermal basement membrane hemidesmosome structure is intact after the injection of the drug at 36 days of expansion, legend: 2μm and 200nm; B is a statistical analysis of the recovery of the basement membrane structure after the injection of the drug in the transmission electron microscopy image, and the indicators include: the width of hemidesmosomes (HDs) (nm), the number of hemidesmosomes per unit basement membrane length, and the number of microlayers per unit basement membrane length;

[0032] Fig. 9 This is the epidermal clone formation experiment after the injection of the drug and control preparations for 36 days in Example 3, and the statistics of the clone area (A) and the recovery of the adhesion rate (B). DETAILED DESCRIPTION

[0033] To make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified.

[0034] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by ordinary technicians in the technical field to which the application belongs. It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments of the present application.

[0035] In order to more fully understand the present invention, the professional terms in the present invention are explained below.

[0036] Marimastat is a broad-spectrum metalloproteinase inhibitor. In the prior art, in vitro studies have shown that Marimastat (100nM) can significantly inhibit the expression of MMP2, MMP9, and MMP14 in U251, U87, GBM39, and GBM43 tumor cells. Marimastat can specifically inhibit the growth of glioma cells and has no effect on normal human astrocytes (NHA). Marimastat can downregulate the expression of Notch target genes, such as Hes1 and HES5, in the early stage. In vivo studies of the in situ squamous cell carcinoma transplantation model, marimastat (150mg / kg / day, oral administration) administered by osmotic pump can significantly inhibit cervical lymph node metastasis and MMP-2 activation, and the survival period is significantly prolonged compared with the control group. Marimastat can reduce polycystic MMP hyperactivity in human and rat bile ducts and block PCK bile duct cystic dilatation. In eight-week-old PCK rats, chronic treatment with marimastat can inhibit liver cyst formation and fibrosis.

[0037] Hemidesmosomes, in desmosome connections, if the extracellular domain of the transmembrane glycoprotein is connected to the extracellular matrix, the morphology is similar to half of the desmosome, and this connection is called a hemidesmosome. Compared with desmosome connections, there are two differences: first, the transmembrane protein involved in the connection is not cadherin but integrin; second, the extracellular domain of integrin is not connected to the integrin of the adjacent cell but to the extracellular matrix. Hemidesmosomes are mainly located on the bottom surface of epithelial cells, and their function is to connect epithelial cells to the basement membrane below them. The binding device between epithelial cells and connective tissue is called a hemidesmosome. The same structure as desmosomes can be seen in epithelial cells, but there are no cells on the opposite side and the basement membrane is used instead. It is believed to have the function of strengthening the connection between epithelial cells and connective tissue. Located on the basal surface of epithelial cells, it is half of the desmosome structure. There is also an attachment plate in the plasma membrane, to which the tension filaments are attached, folded into a trip shape and returned to the cytoplasm. The main function is to fix the epithelial cells on the basement membrane.

[0038] Ki67+, a nuclear protein encoded by the MKI-67 gene, is also called MKI-67. It is often used in pathological immunohistochemistry and indicates the degree of cell proliferation activity.

[0039] Krt10+thickness is the thickness of the KRT10 (keratin 10) positive cell layer. In skin tissue, KRT10 is a specific keratin that is expressed during the differentiation of the epidermis, especially during the formation of the stratum corneum of the epidermis. The thickness of KRT10 positive can reflect the development of the stratum corneum of the skin, which is an important parameter in skin pathology and skin biology research. KRT10 is expressed in different layers of the skin, especially in the mature epidermis. In a study, spatial proteomic analysis revealed that KRT10 plays a key role in the transition from the basal layer (expressing KRT14 and COL17A1) to the mature epidermis (KRT10 positive) during epidermal development. This suggests that the thickness of the KRT10 positive layer can be used as an indicator to assess skin differentiation and maturity. In addition, the expression of KRT10 is also associated with epithelialization during skin wound healing. In a study, keratin dressings were found to accelerate epithelialization in deep partial thickness wounds, which may be related to the activity of KRT10 positive cells. In general, “Krt10+thickness” may refer to the thickness of the KRT10-positive cell layer, a parameter that is of great significance in skin biology and pathology research and can be used to evaluate the differentiation state of the skin and the wound healing process.

[0040] Nafamostat mesylate is a synthetic serine protease inhibitor with the following characteristics and uses: Anticoagulant effect: Nafamostat mesylate is used as an anticoagulant in hemodialysis to prevent coagulation during extracorporeal circulation of blood. It works by inhibiting the activity of enzymes including Factor Xa, Factor XIIa and Factor VIIa in the coagulation system, as well as in the complement system; Anticancer and antiviral effects: Nafamostat mesylate has anticancer and antiviral effects and can induce cell apoptosis by upregulating the expression of tumor necrosis factor receptor-1 (TNFR1); Anti-inflammatory effect: In in vitro studies, Nafamostat mesylate showed anti-inflammatory effects and was able to inhibit the reduction in the total amount of kininogen caused by the activation of kallikrein.

[0041] Leupeptin Hemisulfate is a widely used protease inhibitor. Leupeptin Hemisulfate is a broad-spectrum, cell membrane-penetrating protease inhibitor that effectively inhibits serine, cysteine, and threonine proteases. It can also inhibit the main protease Mpro of SARS-CoV-2 and has anti-inflammatory activity.

[0042] Apigenin-7-glucuronide is a compound with multiple pharmacological activities. It can inhibit the activity of matrix metalloproteinases (MMPs), and its IC50 values ​​for MMP-3, MMP-8, MMP-9, and MMP-13 are 12.87, 22.39, 17.52, and 0.27 μM, respectively. It has antioxidant, anti-complement, anti-inflammatory, and aldose reductase inhibitory activities.

[0043] JNJ0966, a highly selective matrix metalloproteinase-9 (MMP-9) zymogen inhibitor. Molecular formula: C 16 H 16 N4O2S2, molecular weight: 360.45, CAS number: 315705-75-0.

[0044] Upamostat, a serine protease inhibitor. Molecular weight: 629.81, molecular formula: C 32 H 47 N5O6S, CAS number: 590368-25-5.

[0045] BAY-85-8501, a potent and selective inhibitor of human neutrophil elastase (HNE). Molecular weight: 474.46, molecular formula: C 22 H 17 F3N4O3S, CAS number: 1161921-82-9.

[0046] MEGA-9 is N-Nonanoyl-N-methylglucamine, a biochemical reagent that can be used as a biomaterial or organic compound for life science related research. The CAS number of MEGA-9 is 85261-19-4, and the molecular formula is C 16 H 33 NO6, molecular weight is 335.44.

[0047] MMP-2 / MMP-9inibitorⅠ, a metalloproteinase 2 / 9 type I inhibitor, is a potent, highly selective and orally available type IV collagenase (MMP-9 and MMP-2) inhibitor. Molecular formula: C 21 H 19 NO4S, molecular weight: 381.44, CAS number: 193807-58-8.

[0048] MMP-2-IN-3 is an effective inhibitor of matrix metalloproteinase (MMP-2). Molecular weight: 355.43, molecular formula: C 23 H 21 N 3O, CAS number: 897799-81-4.

[0049] Example 1 Mouse expansion experiment

[0050] All animals used in this example were 7-8 weeks old and weighed 22-25 grams.

[0051] Experimental methods

[0052] 1.1. Before the surgical procedure, mice were anesthetized using isoflurane. The dorsal skin was thoroughly disinfected with 75% alcohol to minimize the risk of postoperative infection. A 1 cm transverse incision was made in the skin of the dorsal neck, and then a subcutaneous pocket was created with forceps, extending to both ends of the head and tail, and a silicone expander was implanted under the mouse scalp.

[0053] 1.2. In the experimental group, tissue expansion was initiated by injecting 0.6 ml of PBS into the expander. The incision was then sutured. The optimal expander inflation regimen was determined to be an incremental injection of 0.3 ml of saline every four days, ensuring controlled and gradual expansion over 36 days, with the day of surgery designated as day 0. The control group of mice underwent the same procedural steps, excluding the placement of the expander and the injection of saline, as a baseline for comparison.

[0054] 1.3. Skin samples were collected at specific days post-expansion (DPE) to assess tissue response. All analyses were focused on the skin covering the top of the expander-induced dome, which experienced the most consistent mechanical stress. The collected skin samples were tested as follows:

[0055] 1.31. Representative lateral views of mouse skin were taken at 0, 8, 16, 28, 32, and 36 days after expansion.

[0056] 1.32. The Ki67+% and Krt10+ layer thickness of mouse skin were tested at 0, 8, 20, and 36 days after expansion. Specifically, frozen sections of skin samples with different expansion times were used for immunofluorescence staining, and the required antibodies included Krt14 (chicken, Biolegend, 906004), Krt10 (rabbit; Biolegend, 905404), and Ki67 (rat, Invitrogen). The Ki67+% test was performed using the ratio of the number of Ki67+ cells to the number of epidermal cells, and the thickness of the Krt10+ layer was calculated using the ratio of the area of ​​the Krt10+ layer to the length of the basal layer.

[0057] 1.33. Transmission electron microscopy was performed on the skin of mice treated with drug and control drugs at 0 and 36 days after expansion and at 36 days after expansion.

[0058] Experimental Results

[0059] like Figure 1 As shown, the operation schematic diagram of the mouse expansion model (above) and the representative lateral display diagram after expansion (below) are shown. This embodiment establishes a mouse stretch regeneration model that simulates human stretch regeneration therapy, which can stimulate skin growth and expand skin surface area.

[0060] like Figure 2 As shown in Figure 2, during the gradual decrease of days post expansion (DPE), the skin proliferation (Ki67+) and differentiation (Krt10+thickness) abilities experienced a process of first increasing and then declining ( Figure 2 A, B).

[0061] like Figure 3 As shown in Figure 2, transmission electron microscopy images revealed that at 36 days of DPE, the basement membrane structure was destroyed, the width and density of hemidesmosomes (HDs) decreased, and the basement membrane micro-delaminations increased ( Figure 3 A, B).

[0062] Example 2 In vitro drug screening experiment

[0063] Experimental methods

[0064] Human foreskin keratinocytes (HFKs, P5) were seeded into cell culture plates. Ten small molecule protease inhibitors (Nafamostat mesylate, Leupeptin Hemisulfate, Marimastat, Apigenin-7-glucuronide, JNJ0966, Upamostat, BAY-85-8501, MEGA-9, MMP-2 / MMP-9inibitorⅠ, MMP-2-IN-3) obtained from TargetMol were added to the culture at a concentration of 6 μM for 24 hours. To inhibit nascent protein synthesis, 10 μM cyclohexamide (CHX) was introduced into the culture medium for human keratinocytes 17 hours before. After treatment, WB (western blot) analysis of keratinocyte protein changes was performed to evaluate the effect of protease inhibitors on Col17a1 protein expression.

[0065] Experimental Results

[0066] The epidermal stemness marker COL17A1 protein increased significantly in the early stage of expansion and decreased significantly after 36 days of expansion ( Figure 4 A, B), the clone formation ability also decreased significantly after 36 days of expansion ( Figure 4 C, D).

[0067] Based on the above phenomenon of loss of epidermal stemness, degradation of COL17A1 protein, and exhaustion of epidermal regeneration capacity in the late expansion period, we added the same dose of the drug to be screened and the protein synthesis inhibitor cycloheximide (CHX) to the primary human foreskin cell line cultured in vitro and cultured for 24 hours before collecting samples ( Figure 5 A). It was found that among the 10 small molecule protease inhibitors, the drugs Marimastat, MMP-2 / MMP-9inibitorⅠ (metalloproteinase 2 / 9 type I inhibitor) and MMP-2-IN-3 have significant properties to prevent COL17A1 protein degradation ( Figure 5 B). The numbers are the results of protein quantification. The expression ratio of the target protein COL17A1 and the internal reference protein GAPDH was statistically analyzed using ImageJ software, and then compared with the change value of the target protein after the control reagent DMSO treatment group. It was screened out that Marimastat, MMP-2 / MMP-9inibitorⅠ and MMP2-IN-3 all have protective effects on the target protein.

[0068] Example 3 In vivo drug delivery experiment

[0069] Experimental methods

[0070] like Figure 6 As shown, this example performed a screening test on the drug effect of Marimastat in mice.

[0071] This example was performed on mice 20-36 days after dilation. The mice were anesthetized and the skin surface was disinfected with 75% alcohol. Multiple intradermal (ID) injections were performed at multiple points at a 15-degree angle in the skin plane using a microinjection needle (Hamilton, 21-2065), once every two days, and we should avoid puncturing the underlying dilator. Experimental drug Marimastat (Sigma). Initially dissolved in DMSO (dimethyl sulfoxide) at a concentration of 10 mg / mL, and then diluted with PBS to a final concentration of 100 μg / mL. Control injections included equal amounts of DMSO and PBS solutions.

[0072] The experimental group was labeled as MM, and the control group was labeled as DMSO.

[0073] Experimental Results

[0074] Intradermal injection of 100ug / ml of Marimastat every 2 days from 20 days to 36 days of expansion can antagonize the phenomenon of expansion-induced regeneration capacity exhaustion caused by epidermal proliferation attenuation, epidermal thinning, basement membrane structure destruction, and stem loss. Specifically, the comparison between drug injection (experimental group MM) and blank solvent group (control group DMSO) showed that proliferation was restored (Ki67+), epidermal differentiation ability (Krt10+thickness) was increased, COL17A1 protein degradation was reduced, and expression was increased ( Figure 7 A, B), the basement membrane microstructure is more complete, the width and density of hemidesmosomes are increased, and the micro-stratification is reduced ( Figure 8 A, B), and the clone formation ability was also significantly restored ( Fig. 9 A, B).

[0075] In summary, this example demonstrates that the drug Marimastat is used to delay the treatment of skin regeneration exhaustion in stretch regeneration therapy and promote the maintenance of the long-term stretch regeneration ability of the skin.

[0076] The applicant declares that, in the description of the above specification:

[0077] The descriptions of the terms "this embodiment", "an embodiment of the present invention", "as shown in...", "further", "a further improved technical sub-scheme", etc., mean that the specific features, structures, materials or characteristics described in the embodiment or example are included in at least one embodiment or example of the present invention; in this specification, the schematic expressions of the above terms are not necessarily for the same embodiment or example, and the specific features, structures, materials or characteristics described may be combined or combined in a suitable manner in any one or more embodiments or examples; in addition, a person of ordinary skill in the art may combine or combine the different embodiments or examples and the features of the different embodiments or examples described in this specification without causing any contradiction.

[0078] Finally, it should be noted that:

[0079] The above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit them.

[0080] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some or all of the technical features therein, and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention. The non-essential improvements, adjustments or replacements made by those skilled in the art based on the contents of this specification are all within the scope of protection required by the present invention.

Claims

1. Application of Marimastat in the preparation of drugs for promoting skin stretch regeneration.

2. The use according to claim 1, characterized in that The promoting of skin stretch regeneration includes: treating or delaying the exhaustion of skin stretch regeneration capacity.

3. The use according to claim 1, characterized in that The promotion of skin stretch regeneration includes: promoting the proliferation of epidermal cells, increasing the thickness of the epidermis, delaying the destruction of the epidermal adhesion structure, and preventing the loss of the identity of epidermal stem cells.

4. The use according to claim 1, characterized in that The administration of Marimastat is not limited to: subcutaneous injection, topical application, intradermal injection, and oral administration.

5. The use according to claim 1, characterized in that The administration time of Marimastat is after the 20th day of skin stretch regeneration treatment, or after the stretch regeneration shows signs of regeneration exhaustion.

6. The use according to claim 1, characterized in that The effective concentration of marimastat is not less than 100 μg / mL.

7. The use according to claim 6, characterized in that The medicine is tincture, aqueous solution, emulsion, mixture, syrup, ointment, suppository, tablet, water pill, honey pill, capsule, soft capsule, drop pill, injection, powder, granule, patch, and targeted preparation.

8. Application of metalloproteinase 2 / 9 type I inhibitor, MMP2-IN-3 in the preparation of drugs for promoting skin stretch regeneration.

9. The use according to claim 8, characterized in that The promoting of skin stretch regeneration includes: treating or delaying the exhaustion of skin stretch regeneration capacity.

10. The use according to claim 8, characterized in that The promotion of skin stretch regeneration includes: promoting the proliferation of epidermal cells, increasing the thickness of the epidermis, delaying the destruction of the epidermal adhesion structure, and preventing the loss of the identity of epidermal stem cells.

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