Use of marimastat in the preparation of a medicament for promoting skin stretch regeneration

Abstract

The application provides application of marimastat in preparation of a medicine for promoting skin stretch regeneration, the skin stretch regeneration promotion comprises: treating or delaying exhaustion of skin stretch regeneration capacity; the skin stretch regeneration promotion comprises: promoting epidermal cell proliferation, increasing epidermal thickness, delaying destruction of epidermal adhesion structure and preventing loss of epidermal stem cell identity; the application first proposes a new application of marimastat, that is, the application of marimastat in preparation of the medicine for promoting the skin stretch regeneration.

Description

Technical Field

[0001] This invention relates to the application of marimusta in the preparation of drugs that promote skin stretch regeneration, and belongs to the field of biomedical technology. Background Technology

[0002] Skin soft tissue stretch regeneration technology utilizes the natural physiological characteristic of adult skin to continuously regenerate under the influence of mechanical force. It applies controllable tension to induce skin regeneration, generating additional skin tissue for transplantation and repair of large-area soft tissue defects. It is one of the few clinically practical in-situ regeneration technologies for human physiological organs and a good model for studying the process and mechanism of skin regeneration. However, this excellent treatment method has limited regenerative capacity of the skin under tension-induced growth, mostly limited to 2-3 times growth. When regeneration exceeds 4 times, insufficient regenerative capacity can easily lead to thinning, damage, and ischemia of the skin, further causing serious complications such as exposure of the expander 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 human skin traction surgery showed active cell proliferation and differentiation 1 month after surgery, cell proliferation reached a plateau at 2 months, and cell proliferation and differentiation decreased across the board after 5 months of long-term traction. Xue et al. (Xue, Y., Lyu, C., Taylor, A. & Van Ee, A. Mechanical tension mobilizes Lgr6+ epidermal stem cells to drive skin In a study published in *Growth. Sci. Adv. 8* (2022), it was found that after prolonged stretching of the rat back, the thickness of the regenerated epidermis increased in the early stage, then thinned significantly after one month, and 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 excessive stretching during rat back stretching led to skin thinning and necrosis, resulting in stretching regeneration failure. These clinical experiences and scientific studies collectively suggest that although skin stretching regeneration technology promotes in-situ skin regeneration through artificial means, its regenerative capacity is not unlimited. Insufficient skin regeneration capacity during the stretching regeneration process is the main bottleneck limiting the long-term application of this technology.

[0003] Since the invention of stretch-induced skin regeneration technology, clinical scientists have been actively exploring effective interventions to enhance the efficiency of tension-induced skin regeneration. Previous methods to enhance stretch-induced regeneration efficiency include cytokines such as epidermal growth factor and fibroblast growth factor, and stem cell supplementation methods such as bone marrow mesenchymal stem cells and adipose-derived stem cells, all aimed at promoting cell division, proliferation, migration, and improving tissue repair and vascularization. However, simply stimulating excessive proliferation and differentiation of skin tissue to thicken the epidermis is not a good indicator of a positive prognosis in stretch-induced regeneration. In principle, it is more important to maintain the balance between epidermal stem cell self-renewal and differentiation homeostasis, continuously sustaining the regenerative capacity of stem cells. However, previous studies have mostly focused on the early stages of the skin epithelial cell regeneration response triggered by tension stimulation, rarely explaining the specific phenomena and mechanisms of insufficient long-term stretch-induced skin regeneration capacity, and there are still no effective therapeutic drugs to delay the depletion of long-term stretch-induced regeneration capacity. Summary of the Invention

[0004] This invention provides the application of marimastat in the preparation of drugs that promote skin stretch regeneration. This invention experimentally demonstrates 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 objective, the present invention provides the following technical solution:

[0006] A first aspect of the invention provides the use of marimasta in the preparation of a medicament that promotes skin stretch regeneration.

[0007] In this invention, marimastat (CAS: 154039-60-8) was first used in anticancer treatment to limit tumor metastasis. This drug also exhibits good pharmacokinetic characteristics when taken orally in humans, and short-term treatment is well-tolerated by patients.

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

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

[0010] In this invention, stem cell identity loss means that the number of stem cells has not changed, but their properties have changed.

[0011] Preferably, the administration methods of marimastat are not limited to: subcutaneous injection, topical application, intradermal injection, oral administration, etc.

[0012] Preferably, marimastastat is administered 20 days after the start of skin stretch regeneration therapy, or after stretch regeneration shows signs of depletion.

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

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

[0015] Preferably, the drug is an injection.

[0016] In a second aspect, the invention provides the use of metalloproteinase 2 / 9I type inhibitors, MMP2-IN-3, in the preparation of medicaments that promote skin stretch regeneration.

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

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

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

[0020] 1. This invention proposes a novel application for marimastat, specifically its use in the preparation of drugs that promote skin stretch regeneration. Experiments have verified 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. This invention screened the drug marimastat from 10 small molecule protease inhibitors through in vitro experiments, and found that it significantly prevents the degradation of COL17A1 protein. Furthermore, in vivo drug experiments verified that marimastat can delay the treatment of skin regeneration exhaustion in stretch regeneration therapy and promote the maintenance of long-term stretch regeneration capacity of the skin.

[0022] 3. This invention proposes for the first time a new application of MMP-2 / MMP-9inibitorⅠ (metalloproteinase 2 / 9I type inhibitor) and MMP2-IN-3, namely the application of metalloproteinase 2 / 9I type inhibitor and metalloproteinase 2 inhibitor in the preparation of drugs that promote skin stretch regeneration. Attached Figure Description

[0023] To more clearly illustrate the technical solution of the present invention, the accompanying drawings used in the embodiments of the present invention will be briefly described below.

[0024] Figure 1 The diagram above shows the operation of the mouse expansion model in Example 1, and the representative lateral view after expansion is shown below.

[0025] Figure 2 The images show representative immunofluorescent sections (A) and statistics (B) of early, middle and late stages of skin proliferation (KI67+) and differentiation (KRT10+) in Example 1. Legend: 20μm.

[0026] Figure 3 These are transmission electron microscope (TEM) images from Example 1. Image A is a representative schematic diagram taken by TEM showing the expansion 36 days later (DPE36) and the control group (DPE0). Legend: 2μm (black), 200nm (blue), 500nm (red), arrow and H at D: hemidesmosome; Image B shows the hemidesmosome width, number of hemidesmosomes per unit basement membrane length, and the number of microstratifications per unit basement membrane length.

[0027] Figure 4 The results show the changes in COL17A1 protein and colony-forming energy in Example 2; A and B are immunofluorescence sections of COL17A1 protein and quantitative fluorescence statistics, legend: 20μm; C and D are colony-forming ability diagrams, as well as colony growth area and adhesion rate statistics;

[0028] Figure 5 These are the results 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: actinomycin; B shows the changes in COL17A1 protein expression after screening with different drugs;

[0029] Figure 6 This is the flowchart of the screening test of the drug efficacy of marimastat in mice in Example 3;

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

[0031] Figure 8These are the transmission electron microscopy (TEM) images from Example 3; where A shows the intact hemidesosome structure of the epidermal basement membrane after drug injection 36 days after the expansion, with the legend: 2 μm and 200 nm; B shows the statistics on the recovery of the basement membrane structure after drug injection based on the TEM images, including indicators such as: hemidesosome (HDs) width (nm), number of hemidesosomes per unit length of basement membrane, and number of microlayers per unit length of basement membrane.

[0032] Figure 9 This is the epidermal colony formation experiment after injection of the expanded 36-day drug and control preparation in Example 3, and the statistics of the recovery of the colony area (A) and adhesion rate (B). Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the experimental materials and reagents used in the following embodiments are commercially available.

[0034] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. It should be noted that the terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the exemplary embodiments of this application.

[0035] To better understand this invention, the technical terms used in this invention will be explained below.

[0036] Marimastat, a broad-spectrum inhibitor of metalloproteinases, has been shown in in vitro studies to significantly inhibit the expression of MMP2, MMP9, and MMP14 in U251, U87, GBM39, and GBM43 tumor cells. Marimastat specifically inhibits the growth of glioma cells without affecting normal human astrocytes (NHA). Early-stage studies show that Marimastat downregulates the expression of Notch target genes, such as Hes1 and HES5. In an in vivo orthotopic squamous cell carcinoma transplantation model, marimastat (150 mg / kg / day, orally administered) via an osmotic pump significantly inhibited cervical lymph node metastasis and MMP-2 activation, and significantly prolonged survival compared to the control group. Marimastat can reduce polycystic MMP hyperactivity in the bile ducts of humans and rats, and block cystic dilatation of the PCK bile ducts. In eight-week-old PCK rats, chronic treatment with marimastat inhibited liver cyst formation and fibrosis.

[0037] Hemidesmosomes are junctions in desmosomes where the extracellular domain of a transmembrane glycoprotein is attached to the extracellular matrix, resembling half a desmosome in morphology. They differ from desmosomes in two ways: first, the transmembrane protein involved is an integrin, not a cadherin; second, the extracellular domain of the integrin is attached to the extracellular matrix, not to the integrin of adjacent cells. Hemidesmosomes are primarily located on the basal surface of epithelial cells, connecting the epithelial cell to its underlying basement membrane. The hemidesmosome is a binding device between epithelial cells and connective tissue. While it shares the same structure as a desmosome within epithelial cells, it lacks a cell on the opposite side, replaced by the basement membrane. It is believed to strengthen the connection between epithelial cells and connective tissue. Located on the basal surface of epithelial cells, it is half the structure of a desmosome. It also has attachment plates within the plasma membrane, tonofilaments attach to it, and fold back into the cytoplasm, its main function being to anchor the epithelial cell to the basement membrane.

[0038] Ki67+ is a nuclear protein encoded by the MKI-67 gene, also known as MKI-67. It is frequently used in pathological immunohistochemistry to indicate the degree of cell proliferation activity.

[0039] Krt10 thickness is the thickness of the KRT10 (keratin 10) positive cell layer. KRT10 is a specific keratin protein expressed during epidermal differentiation, particularly during stratum corneum formation. KRT10-positive thickness reflects the development of the stratum corneum, an important parameter in dermatopathology and skin biology research. KRT10 is expressed in different layers of the skin, especially in the mature epidermis. In one study, spatial proteomics analysis revealed that KRT10 plays a crucial 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 serve as an indicator of skin differentiation and maturity. Furthermore, KRT10 expression is also associated with epithelialization during wound healing. In one study, keratin dressings were found to accelerate epithelialization in deeper wounds, which may be related to the activity of KRT10-positive cells. In summary, "Krt10+thickness" likely refers to the thickness of the KRT10-positive cell layer. This parameter is of great significance in skin biology and pathology research, as it can be used to assess the skin's differentiation status and 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 blood clotting during extracorporeal circulation. It works by inhibiting the activity of factors Xa, XIIa, and VIIa in the coagulation system, as well as enzymes in the complement system; Anticancer and antiviral effects: Nafamostat mesylate has anticancer and antiviral effects, inducing apoptosis by upregulating the expression of tumor necrosis factor receptor-1 (TNFR1); Anti-inflammatory effect: In in vitro studies, Nafamostat mesylate has shown anti-inflammatory effects, inhibiting the reduction in total kininogen caused by kinin-releasing enzyme activation.

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

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

[0043] JNJ0966, a highly selective inhibitor of matrix metalloproteinase-9 (MMP-9) proenzyme. 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 No.: 590368-25-5.

[0045] BAY-85-8501 is a potent and selective inhibitor of human neutrophil elastase (HNE). Molecular weight: 474.46, Molecular formula: C 22 H 17 F3N4O3S, CAS No.: 1161921-82-9.

[0046] MEGA-9, or N-Nonanoyl-N-methylglucamine, is a biochemical reagent that can be used as a biomaterial or organic compound in life science research. MEGA-9's CAS number is 85261-19-4, and its molecular formula is C2. 16 H 33 NO6 has a molecular weight of 335.44.

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

[0048] MMP-2-IN-3 is a potent inhibitor of matrix metalloproteinase (MMP-2). Molecular weight: 355.43, Molecular formula: C 23 H 21 N 3OCAS No.: 897799-81-4.

[0049] Example 1: Mouse Expansion Experiment

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

[0051] Experimental methods

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

[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 protocol was determined to be an increase 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. Control mice underwent the same procedure but without expander placement and saline injection, serving as the baseline for comparison.

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

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

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

[0057] 1.33. The skin of mice treated with the drug and its control drug at 0 and 36 days after expansion, and at 36 days after expansion, was observed by transmission electron microscopy.

[0058] Experimental results

[0059] like Figure 1 As shown, the diagram above illustrates the operation of the mouse expansion model, and the representative lateral view after expansion is shown below. This embodiment establishes a mouse stretch regeneration model that simulates human stretch regeneration therapy. This model can stimulate skin growth and increase the skin surface area.

[0060] like Figure 2 As shown, during the process of decreasing and increasing day post-expansion (DPE), the skin proliferation (Ki67+) and differentiation (Krt10+ thickness) capabilities undergo a process of first increasing and then decreasing. Figure 2 A, B).

[0061] like Figure 3 As shown, transmission electron microscopy images reveal that at 36 days of DPE, the basement membrane structure is disrupted, with a decrease in the width and density of hemidesmosomes (HDs) and an increase in basement membrane micro-delaminations. Figure 3 A, B).

[0062] Example 2 In vitro drug screening experiment

[0063] Experimental methods

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

[0065] Experimental results

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

[0067] Based on the above phenomena of late-stage epidermal dryness loss, COL17A1 protein degradation, and depletion of epidermal regeneration capacity, we added equal doses of the selected drug and the protein synthesis inhibitor cycloheximide (CHX) to the in vitro cultured human foreskin primary cell line, respectively, and cultured for 24 hours before collecting samples. Figure 5 A). It was found that among 10 small molecule protease inhibitors, the drugs marimasitol, MMP-2 / MMP-9 inibitor I (inhibitors of metalloproteinases 2 / 9I), and MMP-2-IN-3 have significant properties in preventing the degradation of COL17A1 protein. Figure 5 B). The numbers represent protein quantification results. The expression ratio of the target protein COL17A1 and the internal reference protein GAPDH was statistically analyzed using ImageJ software. The changes in the target protein were then compared with those after treatment with the control reagent DMSO. Three drugs, Marimastat, MMP-2 / MMP-9 inbitor I, and MMP2-IN-3, were found to 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 embodiment performed a screening test on the efficacy of marimastat in mice.

[0071] This procedure was performed on mice 20–36 days after dilation. Mice were anesthetized, and the skin surface was disinfected with 75% alcohol. Multiple intradermal (ID) injections were administered at a 15-degree angle to the skin plane using a microinjection needle (Hamilton, 21–2065), every two days, taking care to avoid puncturing the underlying dilator. The experimental drug, Marimastat (Sigma), was initially dissolved in DMSO (dimethyl sulfoxide) at a concentration of 10 mg / mL, then diluted with PBS to a final concentration of 100 μg / mL. Control injections consisted of equal volumes of DMSO and PBS solution.

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

[0073] Experimental results

[0074] Intradermal injection of 100 ug / ml marimastastat every two days during the 20-36 day expansion period antagonized the expansion-induced depletion of regenerative capacity, including epidermal proliferation decline, epidermal thinning, basement membrane structure damage, and loss of dryness. Specifically, compared with the control group (DMSO), the drug injection group (experimental group MM) showed increased proliferation (Ki67+), increased epidermal differentiation capacity (Krt10+ thickness), decreased COL17A1 protein degradation, and increased expression (Ki67+). Figure 7 A, B), the basement membrane microstructure is more complete, the hemidesmosome width increases, the density increases, and the microstratification decreases. Figure 8 A, B), and the ability to form clones was also significantly restored. Figure 9 A, B).

[0075] In summary, this embodiment demonstrates that the drug marimastat can be used to delay the depletion of skin regeneration in stretch regeneration therapy and promote the maintenance of the skin's long-term stretch regeneration capacity.

[0076] The applicant declares that, in the process of describing the above-mentioned specification:

[0077] The terms "this embodiment," "an embodiment of the present invention," "as shown," "further," and "further improved technical solutions," etc., indicate 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 illustrative expressions of the above terms are not necessarily directed at the same embodiment or example, and the specific features, structures, materials, or characteristics described can be combined or combined in any suitable manner in one or more embodiments or examples. Furthermore, without causing contradiction, those skilled in the art can combine or combine the different embodiments or examples described in this specification and the features of the different embodiments or examples.

[0078] Finally, it should be noted that:

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

[0080] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention. Non-essential improvements, adjustments or substitutions made by those skilled in the art based on the content of this specification are all within the scope of protection claimed by the present invention.

Claims

1. The use of marimusta in the preparation of drugs that promote skin stretch regeneration, characterized in that, Timing of administration of marimusta: 20 days after the start of stretch regeneration therapy, or when stretch regeneration shows signs of depletion, or as a preventative measure.

2. The application as described in claim 1, characterized in that, The promotion of skin stretch regeneration includes: treating or delaying the depletion of skin stretch regeneration capacity.

3. The application as described in claim 1, characterized in that, The promotion of skin stretch regeneration includes: promoting epidermal cell proliferation, increasing epidermal thickness, delaying the destruction of epidermal adhesion structures, and preventing the loss of epidermal stem cell identity.

4. The application as described in claim 1, characterized in that, The administration methods of marimusta are not limited to: subcutaneous injection, topical application, intradermal injection, and oral administration.

5. The application as described in claim 1, characterized in that, The effective concentration of melistat is not less than 100 μg / mL.

6. The application as described in claim 5, characterized in that, The drugs are tinctures, aqueous solutions, emulsions, mixtures, syrups, ointments, suppositories, tablets, water pills, honey pills, capsules, drop pills, injections, granules, and patches.

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