Skin Repair Research Articles

Effect of rolling texture on bearing capacity of aircraft repair patches and replaced panels

The article combines issues related to biaxial fatigue loading, corrections for equivalent stress calculations, and the practical application of new knowledge regarding biaxial fatigue in the aviation industry. It considers the possibility and expediency of taking into account the anisotropy of metals’ mechanical characteristics in aircraft repair procedures, such as patching and replacing damaged skin panels. The biaxial loading of the skin is shown to be a significant factor that should be considered in the aircraft skin repair process. It is shown that while well-known Huber-Mises formula works well for isotropic materials, the fuselage skin made of anisotropic alloys requires corrections to the Huber-Mises method. For aircraft parts subjected to biaxial loading, the assessment of equivalent uniaxial stresses can be done by introducing the crystallographic factor into the Huber-Mises formula. This is achieved by transforming the biaxial stress components of fuselage loading due to pressurization and bending into the resolved stresses in the activated crystallographic slip systems of the dominant texture.

Ulnar Bone Grafting for the Repair of Radial Fracture in a Dog with Degloving Injury

Background: A one-year-old female Poodle weighing 1.7 kg sustained an open wound and radial bone fracture due to a bicycle accident. The injury resulted in significant skin and bone loss. Skin reconstruction using an advancement flap and radial bone repair using an autologous ulnar bone graft were performed to restore limb function and appearance. Methods: The dog underwent surgery for skin and bone reconstruction. Necrotic tissue was debrided and an advancement flap was used to repair the skin. The radial bone defect was treated with an autologous ulnar graft and stabilized with a titanium plate. Postoperative care included pain management, antibiotics and restricted activity. Periodic radiographs were taken to monitor bone healing. Result: The dog experienced good recovery, with the skin healing fully within 15 days despite some initial necrosis. The ulnar bone graft successfully fused with the radial bone, allowing the dog to bear weight on the limb by day 65. By day 233, the bone had fully integrated and the dog showed no signs of lameness.

Skin Microbiota and Pathological Scars: A Bidirectional Two-Sample Mendelian Randomization Study.

Pathological scars (PSs), resulting from abnormal skin repair, chronic inflammation, and fibrosis, affect millions of people. Previous studies have demonstrated that skin microbiota (SM) plays a role in cutaneous inflammation and healing, but the interplay between PSs and SM remains unclear yet. To investigate the causal associations between SM and two specific PSs: hypertrophic scars (HSs) and keloids. A bidirectional two-sample mendelian randomization (MR) analysis using genetic data for SM, HS, and keloids was conducted. The random-effects inverse variance weighted (IVW) method was used as the primary approach, along with multiple MR methods. False discovery rate (FDR) correction was employed to address multiple testing. In forward analysis, the family Moraxellaceae and order Pseudomonadales exhibited the same significant protective effects on keloids (odds ratio [OR]: 0.849, 95% confidence interval [CI]: 0.770-0.935, q2 = 0.03626). The class Betaproteobacteria (OR: 0.938, 95% CI: 0.894-0.985, q1 = 0.01965) and genus Bacteroides (OR: 0.928, 95% CI: 0.884-0.973, q1 = 0.00889) each demonstrated a suggestive protective effect on HSs and keloids, respectively. Some limited evidence suggested that order Actinomycetales contributes to an increased risk of keloids. In reverse analysis, keloids were found to have negative effects on the class Gammaproteobacteria with limited evidence. There was no detectable evidence of horizontal pleiotropy or heterogeneity. This study provided evidence for the causalities between SM and PSs, which laid foundation for furthering clinical practice and research of microorganism-skin interaction.

USO DE POLIMETILMETACRILATO PARA FINS ESTÉTICOS EM PACIENTES NÃO IMUNODEPRIMIDO

In a world where the importance of care through aesthetic methods predominates, addressing the plastic component (polymethylmethacrylate - acronym PMMA) is fundamental, because it allows the understanding of its composition, its forms of use, its effects, as well as denounces its maximum risk and prohibition to the aesthetic purpose, in addition to directing the appropriate treatment, when, even then, procedures with the product are performed by professionals who are not trained and qualified. Considering the methods of application of polymethylmethacrylate, the gel form for cutaneous filling of small areas of the body is one of the most used and required by qualified medical professional, with restricted dose of use of the product, with proper certification from the National Health Surveillance Agency, only for repair of skin or integumentary defects.

Systematic characterization of the barrier function of diverse ex vivo models of damaged human skin

BackgroundThe skin barrier plays a crucial role in protecting our body against external agents. Disruption of this barrier’s function leads to increased susceptibility to infections and dermatological diseases. Damaged skin can be due to the use of detergents, sunburn or excessive scratching. In the context of the COVID-19 pandemic the recommended hygiene measures to prevent the spread of SARS-CoV-2, such as wearing masks, frequent handwashing, and the use of sanitizers, can also potentially alter the skin barrier.ObjectivesThe purpose of the study was to characterize the barrier function of ex vivo models of damaged human skin.MethodsSkin barrier damage was induced through different chemical and mechanical treatments, representative of the potential factors damaging human skin. The skin barrier function was evaluated in terms of permeability, dermal absorption capacity, stratum corneum thickness and gene expression of barrier markers. As inflammation is linked to skin barrier integrity, inflammatory markers were also analyzed.Results and discussionThe different treatments applied to ex vivo skin models allow the simulation of diverse degrees of skin damage, making these models valuable for assessing the efficacy of topical products targeted at skin repair and for studying the effects of compromised skin barrier on viral penetration.

Atorvastatin calcium alleviates UVB-induced HaCat cell senescence and skin photoaging

Excessive exposure to ultraviolet radiation B (UVB) has been shown to contribute to the aging of human skin cells. Previous research has demonstrated that atorvastatin calcium (Ato) can mitigate the aging effects caused by chemotherapy drugs. However, it remains unclear whether Ato can alleviate skin aging induced by ultraviolet radiation. In this study, through in vitro experiments with Hacat cells, we found that Ato can significantly reduce the UVB-induced increased expression of age-related protein p16 and age-related gene p21, and also reduce the up-regulation of inflammatory factors such as IL-1 and IL-6. Besides, it can reduce the expression of metallomatrix protein (MMP1 and MMP9), and inhibit cell senescence and inflammatory damage. Similarly, we found that Ato can enhance skin collagen fiber reduction and collagen volume decrease, repair skin photoaging and damage induced by UVB rays, and speed up the rate at which the wounded location heals in vivo using Balb/c mice. In the mechanism, Ato markedly decreased the expression of p-p38, p-p65, p-mTOR in vivo and in vitro, suggesting that it may act on Mitogen-activated protein kinase (MAPK), Nuclear factor κB (NF- κB) and Mammalian target of rapamycin (mTOR) signaling pathways to produce above marked effects. In conclusion, Ato obviously relieved UVB-induced photoaging and damage, thus providing evidence for its potential in mitigating skin aging caused by ultraviolet radiation.

Tissue Engineering with Hyaluronic-Acid : Advances Application of Skin Regeneration Bone and Cartilage Repair

One method that has shown promise for healing damaged tissues is tissue engineering. The naturally occurring glycosaminoglycan hyaluronic acid (HA) has drawn interest because of its potential applications in the regeneration of skin, cartilage, and bone. The purpose of this study was to find out how well HA-based scaffolds work to encourage tissue repair and regeneration. We created and examined HA-based hydrogels, assessing their bioactivity, biocompatibility, and mechanical characteristics. Comparing HA-based scaffolds to controls, our findings showed increased tissue development, differentiation, and cell proliferation. HA-based constructions demonstrated noteworthy improvements in bone and cartilage regeneration in vivo, accompanied by notable increases in tissue integration and collagen deposition. These results demonstrate the potential of HA-based tissue engineering for the repair of bone, cartilage, and skin, providing a viable therapeutic approach for a range of dermatological and musculoskeletal applications.

568 Jellybush honey extract modulates and accelerates wound healing gene expression, for better skin repair

568 Jellybush honey extract modulates and accelerates wound healing gene expression, for better skin repair

Centellicum® improves scarring of traumatic wounds with irregular edges (lacerations).

Centellicum®, a standardized Centella Asiatica extract, has been used orally for fibrosis and scar prevention. The main aim of this 2-month registry pilot study was the reduction of visible, significant scars and keloids after suturing traumatic wounds with irregular edges (lacerations), using Centellicum®. The effects of oral Centellicum® (450 mg/day; 2 capsules) and a standard management (SM) on wound healing were compared with the effects of a control group that used only the standard management. Forty-eight otherwise healthy male subjects with lacerations requiring suturing were included in the study. 25 took Centellicum® in addition to the standard management and 24 followed the standard management only. No side effects were observed with the supplement. Centellicum® supplementation showed very good tolerability and compliance with 98% of the capsules correctly used. The two groups of otherwise healthy male subjects with lacerations were considered comparable at inclusion and there were no dropouts. No infections were observed. At 60 days, the scar dimensions were significantly smaller in the supplemented group (P<0.05). The elevation of the scar above the surrounding, non-affected skin, was also significantly reduced in the Centellicum® group compared to controls (P<0.05). Local pain levels were significantly lower (P<0.05) in the supplement group at 60 days. Additionally, the scar redness score was significantly lower in the supplement group compared to controls (P<0.05) by the end of the study. The incidence of initial keloid formation was significantly lower in the supplemented subjects at 60 days, as determined by finger-point pressure palpation and high-resolution ultrasound (P<0.05). Skin flux, as measured by laser Doppler flowmetry (indicating hypervascularization due to local inflammation) was lower (P<0.05) with Centellicum® at the end of the study. Inflammation, assessed via thermography (hot spots on the healing skin) was less visible and reduced in most areas in the supplement group (P<0.05) in comparison with the control group. Plasma oxidative stress was significantly lower in the Centellicum® group at the end of the study (P<0.05). Oral Centellicum® intake over 2 months improved healing of lacerations and reduced scarring, fibrosis and keloids at the level of the lesions. A larger study setup with more patients and with a prolonged study duration is needed to confirm these initial results.

Evaluation of smart bi-functional dressing based on polysaccharide hydrogels and Brassica oleracea extract for wound healing and continuous monitoring

Skin wounds can drive global impacts, socially and economically, in parallel with their elevated incidence rate. Therefore, utilizing the dual-activity of Brassica Oleracea (Red Cabbage) extract, of being pH-sensitive and biologically active in designing novel, therapeutic, and pH-sensitive wound dressings with an easily stripped-off feature, is critical. Wound dressings were designed using two separate hydrogels based on chitosan (CS) and hydroxyethylcellulose (HEC), each loaded with RCE. The pH sensitivity of prepared bandages exhibited a noticeable visual change in color during wound treatment. Wound closure has reached 99.69 % for CS/RCE dressings. Results showed that RCE had raised the hydroxyproline and collagen content in the healed skin. Histopathological investigation proves that skin returned to its regular thickness within 10 days of treatment. RCE showed marked improvement in the healing quality by acting as an antioxidant, anti-inflammatory, and antimicrobial agent. Therefore, dual-function dressings are potential candidates to sense and cure skin wounds.

INVITED REVIEW: Udder cleft dermatitis in dairy cows.

Udder cleft dermatitis (UCD) is a common dermatological condition of the udder skin in dairy cows. It is generally considered to be a multifactorial disease, being described in a rather limited amount of literature. Its cow-and within-herd prevalence widely ranges between studies depending on the study characteristics, environment and breed. Known risk factors include husbandry practices and environmental factors such as freestall housing, the use of mattresses as cubicle bases, and footbathing. Cow-related elements such as udder conformation, parity and lactation parameters are well-known risk factors for developing UCD. Despite being associated with a high incidence of veterinary-treated clinical mastitis and culling due to udder disease, the somatic cell count of the milk is not influenced by UCD. Severe UCD lesions are characterized by chronic and persistent, dysregulated inflammation accompanied by hampered skin healing and an impaired skin barrier. There is a decrease in microbial diversity followed by dysbiosis and a concomitant overgrowth of opportunistic bacteria negatively impacting beneficial commensal bacteria. Concurrently, a shift in virulence factors most likely contributes to the creation of an environment favorable to pathogens. Anecdotally, mange mites have been associated with UCD but current literature refutes this. The role of treponemes remains inconclusive. Multi-omics analysis of both transcriptomic and metagenomic severe UCD data sets, revealed the negative interaction of the facultative pathogen Streptococcus pyogenes with microbiome-associated virulence factors and the patient's transcriptome. No efficient curative treatments nor prevention strategies have been identified so far, although alginogel products have been described to have a positive effect on the healing process of severe lesions. All in all, UCD is a painful skin disease for which an array of miscellaneous risk factors have been identified. For the first time we assimilate literature on prevalence and risk factors, and results from recent elementary studies that provide insights into the pathogenesis of this challenging disease.

Homology-based identification and structural analysis of Pangasius hypophthalmus Annexins and Serine proteases to search molecules for wound healing applications

Chronic wounds and burns are a worldwide healthcare problem that erodes patients’ well-being and healthcare systems. This silent and costly epidemic requires new, cost-efficient solutions to improve patients’ physical and economic welfare. Eschar-degrading vegetal and bacterial proteases have been utilized as a solution. However, these proteins are evolutionarily far from those present in human wound healing. Serine protease (SP) and annexin (ANX) proteins interact within the skin healing process. A homology-based identification pipeline can help in discovering selective human SP and ANX analogs in the epithelial tissue of the fast-healing species, Pangasius hypophthalmus. In the present work, we found 14 candidates for RT-PCR in P. hypophthalmus using homology inference. The genetically detected candidates were then structurally and sequentially analyzed to understand their possible relation to SPs and ANXs involved in human wound healing. A total of six TBLASTN/BLASTX candidates (four SPs and two ANXs) were detected in P. hypophthalmus skin. Structural analysis revealed that all SP candidates resembled human KLK4, KLK5, KLK6, and KLK8, whereas all ANX only resembled human ANXA4. Structure and sequence analysis revealed high conservation of ANX Ca2+ binding sites (GDXD) and SP catalytic triad (HDS) motifs. In addition, structural analysis revealed that SP substrate selectivity position 186 was the main difference between human KLK5 and P. hypophthalmus SPs. These findings may allow the proposal and testing of more selective formulations, broadening treatments beyond debridement.

A hyaluronic acid-based dual-functional hydrogel microneedle system for sequential melanoma ablation and skin regeneration

Melanoma treatment remains a challenge due to the inadequacy of existing clinical approaches and the difficulty of tissue regeneration. Recently, microneedles have been widely studied in tumor therapy and skin repair. Hence, a hyaluronic acid (HA)-based dual-functional hydrogel microneedle (MN) system was constructed to sequentially achieve tumor ablation and skin regeneration. Carbon nanotubes@calcium peroxide@tannic acid-Fe/chlorin e6 (CCa@TF/Ce6) nanomaterial was encapsulated in dissolvable polyvinyl alcohol/polyvinylpyrrolidone tips and accurately released to the tumor site to suppress melanoma via the photothermal and photodynamic therapies under the dual laser irradiation due to the generation of reactive oxygen species (ROS) and heat. Particularly, ROS and heat triggered immunogenic cell death, promoted dendritic cells maturation and reshaped the tumor-associated macrophage phenotype from the protumor M2 phenotype to the anti-tumor M1 phenotype, ultimately activating autoimmunity to eliminate the tumor. Following tumor ablation, the MN base accelerated skin regeneration owing to HB-PVA hydrogel through reducing oxidative stress, promoting cell proliferation and facilitating cell migration. Overall, the dual-functional hydrogel MN designed in this study, offers a new avenue for sequential melanoma combination treatment and skin regeneration.

G(1-5)-EM2, a multi-targeted agonist to opioid and growth hormone secretagogue receptors exhibited nontolerance forming antinociceptive effects in a mouse model of burn pain

Burn induced-pain (BIP) is one of the most common pain symptoms, which seriously affects the quality of sufferer life. Researches show that multi-targeted drug therapies offer superior efficacy and fewer side effects compared to single-target drug therapies. Consequently, in this study, we developed G(1-5)-EM2, a multi-targeted peptide designed to target μ-opioid receptor and the growth hormone secretagogue receptor 1α (GHS-R1α), and explored its antinociceptive effects on burn injury pain. Calcium mobilization experiments revealed that G(1-5)-EM2 demonstrated weak multi-agonist activities to μ-opioid receptor and κ-opioid receptor as well as GHS-R1α in vitro. Near-infrared fluorescence imaging experiments demonstrated that G(1-5)-EM2 could penetrate the blood-brain barrier (BBB) and access the brain following intravenous injection. The enzymatic stability of G(1-5)-EM2 was significantly enhanced compared to EM2. Our results indicated that intrathecal administration of G(1-5)-EM2 mitigated mechanical allodynia and thermal hyperalgesia in BIP. These antinociceptive effects of G(1-5)-EM2 were partially mediated through μ-opioid receptor and GHS-R1α. Moreover, intrathecal administration of G(1-5)-EM2 significantly decreased burn-induced up-regulation of phosphorylated p38 MAPK, phosphorylated NF-κBp65 and TRPV1 in the ipsilateral spinal cord, reduced the levels of IL-1β, IL-6 and TNF-α in serum, and enhanced wound healing in burned skin. Repeated intrathecal administration of G(1-5)-EM2 produced a non-tolerance-forming antinociception in BIP. These results suggest that the multi-targeted peptide G(1-5)-EM2 exhibits a novel role in alleviating BIP with fewer side effects and may represent a promising strategy for developing new analgesic drugs.

Thymoquinone loaded nanoemulgel in streptozotocin induced diabetic wound.

Aim: To treat diabetic wound healing with a novel Thymoquinone (TQ) loaded nanoformulation by using combination of essentials oils.Methods: TQ nanoemulsion (NE) was developed with seabuckthorn & lavender essential oils by phase inversion method and mixture design. Further, DIAGEL is obtained by incorporating NE into 1% carbopol®934. Furthermore, particle size, polydispersity index, thermodynamic stability studies, rheology, spreadability, drug content, in-vitro drug release, ex-vivo permeation, anti-oxidant assay, antimicrobial studies, angioirritance, HAT-CAM assay, in-vitro and in-vivo studies were determined.Results: NE has a particle size of 17.79±0.61nm, 0.206±0.012 PDI & found to be thermodynamically stable. DIAGEL exhibited pseudoplastic behavior, sustained drug release, better permeation of TQ and a drug content of 98.54±0.08%. DIAGEL stored for 6months at room temperature and 2-8°C showed no degradation. Further, an improved angiogenesis, absence of angio-irritancy, remarkable antioxidant and antimicrobial activities against Candida albicans & S. aureus were observed. Cytotoxicity analysis revealed nearly 2.28 -folds higherIC50 value than drug solution. Furthermore, inflammatory mediators were reduced in DIAGEL treated animal groups. The histopathological studies confirmed skin healing with regeneration and granulation of tissue.Conclusion: The novel formulation has strong anti-inflammatory, angiogenesis, antioxidant and appreciable diabetic wound healing properties.

Application of infrared and near-infrared photosensitive pi-conjugated materials in the diagnosis and rehabilitation of sports injuries in aerobics

According to a survey in 2021, around 12% of people were injured during the exercise, and they require the immediate healing process. Several tissue healing materials are incorporated into the sports rehabilitation process. However, the materials have a high rejection reaction rate, poor effect, and low healing speed, which affects aerobics rehabilitation training. The research difficulties are overcome by applying infrared and near-infrared photosensitive pi-conjugated materials to tissue healing procedures to maximize the result of sports rehabilitation. The research analysis discusses the conjugated materials composition and biocompatibility properties which helps to manage the skin healing drug release rate and durations. In addition, the pi-conjugated materials having a high Nearer-Infrared (NIR) observation rate between 600 nm to 1000nm then the materials are suitable for the photobiomodulation therapy wavelength. Then, NIR triggers the drug release from conjugated materials that are used to locate the injured area for treatment and rehabilitation process. Therefore, infrared and NIR-based conjugated materials effectively support injury rehabilitation and damaged tissue regeneration processes. The system efficiency is evaluated using various skin healing rates with different experiments and experimental groups.

Exploring the Efficacy of pH-Responsive Vancomycin/Ag/ZIF-8 Nanoparticles Modified with Hyaluronic Acid for Enhanced Antibacterial Therapy and Wound Healing.

This study introduces a novel type of metal-organic framework material, specifically zeolitic imidazolate framework-8 (ZIF-8), that is integrated with silver nanoparticles and further enhanced by incorporating vancomycin (Van) to create a composite named as Van/Ag/ZIF-8. This composite demonstrates a potent and smart antimicrobial effect due to its ability for releasing silver ions and Van in a controlled manner, especially in the microacidic conditions surrounding bacterial cells. Furthermore, we used hyaluronic acid to modify Van/Ag/ZIF-8, resulting in a composite denoted as Van/Ag/ZIF-8@HA. This composite exhibits a significant inhibition effect against the proliferation of both Gram-negative (Escherichia coli 100%) and Gram-positive (Staphylococcus aureus 99.9%) resistant bacterial strains while exerting no adverse effects on animal cellular growth. These findings underscore its favorable biocompatibility profile. The experimental results show a combined antibacterial action against prevalent bacterial infections, which is supported by in vivo experiments using a skin wound model. This work confirms the composite's significant role in fighting pathogenic infections and aiding in healing skin wounds. The innovative strategy not only tackles the pressing issue of antibiotic-resistant bacterial infections but also marks a significant advancement in the areas of wound healing and medical research, offering a promising path for future investigations and therapeutic uses.

Sulfated Galactan Derivative from Gracilaria fisheri Improves Histopathology and Alters Wound Healing-Related Proteins in the Skin of Excision Rats.

The biological activities of sulfated polysaccharides (SP) are well-documented, especially regarding wound healing. Sulfated galactan (SG), a type of SP extracted from the red seaweed Gracilaria fisheri, has been identified as having multiple therapeutic properties related to its wound healing capacity. Recent research indicates that degraded SG (DSG) from G. fisheri, when combined with octanoyl ester (DSGO), can improve wound healing in fibroblasts. However, the effectiveness of natural products in clinical settings often differs from in vitro results. This study aimed to develop and evaluate ointments containing DSG and DSGO for skin repair in an animal model. Twenty-four Wistar rats were divided into four groups: (1) normal control, (2) ointment control, (3) DSG ointment, and (4) DSGO ointment. After inducing full-thickness excision wounds, these ointments were applied to the wounds. Wound contraction rate, histopathology, and protein related wound healing expression were then elucidated. Our findings showed that both DSG and DSGO ointments significantly enhanced wound closure compared to the control groups. Histopathological and biochemical analyses indicated increased extracellular matrix production and fibroblasts, marked by improved fibroblast activity, neovascularization, and collagen deposition. Furthermore, immunohistochemistry and immunoblot analysis revealed that the ointments altered the expression of Ki67, α-smooth muscle actin (α-SMA), E-cadherin, vimentin, collagen, and components of the Smad signaling pathway, all of which are crucial for wound healing. The results also suggested that the DSGO ointment was marginally more effective in promoting wound healing in this model. These results indicate that ointment supplemented with DSG and DSGO have the potential to enhance skin repair by improving histopathology and altering wound healing-related proteins.

Novel integrated multiomics analysis reveals a key role for integrin beta-like 1 in wound scarring.

Exacerbation of scarring can originate from a minority fibroblast population that has undergone inflammatory-mediated genetic changes within the wound microenvironment. The fundamental relationship between molecular and spatial organization of the repair process at the single-cell level remains unclear. We have developed a novel, high-resolution spatial multiomics method that integrates spatial transcriptomics with scRNA-Seq; we identified new characteristic features of cell-cell communication and signaling during the repair process. Data from PU.1-/- mice, which lack an inflammatory response, combined with scRNA-Seq and Visium transcriptomics, led to the identification of nine genes potentially involved in inflammation-related scarring, including integrin beta-like 1 (Itgbl1). Transgenic mouse experiments confirmed that Itgbl1-expressing fibroblasts are required for granulation tissue formation and drive fibrogenesis during skin repair. Additionally, we detected a minority population of Acta2high-expressing myofibroblasts with apparent involvement in scarring, in conjunction with Itgbl1 expression. IL1β signaling inhibited Itgbl1 expression in TGFβ1-treated primary fibroblasts from humans and mice. Our novel methodology reveal molecular mechanisms underlying fibroblast-inflammatory cell interactions that initiate wound scarring.

Tissue-Engineered Skin Substitutes for Use in Clinical Dermatological Practice

Skin replacements are essential in dermatology as they serve to connect the gap between conventional wound care and surgical procedures. Due to pioneering innovations from the last century, tissue-engineered skin substitutes have significantly advanced in the field of dermatology, offering new hope for patients with complex wound healing needs. Whilst before, skin grafting was performed to act as an intermediary to promote skin healing, it has now evolved to also mimic skin structure and function. To our knowledge, there have not been any summaries on the use of tissue-engineered in dermatology. Therefore, we conducted a scoping review to summarize research papers which performed human clinical trials and follow-up work using synthetic lab-made skin with a clear clinical application from the last 30 years.