Preclinical and Clinical Studies on the Use of Extracellular Vesicles Derived from Mesenchymal Stem Cells in the Treatment of Chronic Wounds.

To date, the widespread implementation of therapeutic strategies for the treatment of chronic wounds, including debridement, infection control, and the use of grafts and various dressings, has been time-consuming and accompanied by many challenges, with definite success not yet achieved. Extensive studies on mesenchymal stem cells (MSCs) have led to suggestions for their use in treating various diseases. Given the existing barriers to utilizing such cells and numerous pieces of evidence indicating the crucial role of the paracrine signaling system in treatments involving MSCs, extracellular vesicles (EVs) derived from these cells have garnered significant attention in treating chronic wounds in recent years. This review begins with a general overview of current methods for chronic wound treatment, followed by an exploration of EV structure, biogenesis, extraction methods, and characterization. Subsequently, utilizing databases such as Google Scholar, PubMed, and ScienceDirect, we have explored the latest findings regarding the role of EVs in the healing of chronic wounds, particularly diabetic and burn wounds. In this context, the role and mode of action of these nanoparticles in healing chronic wounds through mechanisms such as oxygen level elevation, oxidative stress damage reduction, angiogenesis promotion, macrophage polarization assistance, etc., as well as the use of EVs as carriers for engineered nucleic acids, have been investigated. The upcoming challenges in translating EV-based treatments for healing chronic wounds, along with possible approaches to address these challenges, are discussed. Additionally, clinical trial studies in this field are also covered.

The FEDBD plasma's quantitative investigation of skin parameters: Skin elasticity, thickness, density, tissue oxygenation, perfusion, and edema.

This study used the FEDBD plasma device for skin rejuvenation in animal samples. There were two groups of six male Wistar rats. Before starting the treatment, immediately after the treatment, the fourth week, and the tenth week of follow-up, biometric tests were performed, including moisture level, evaporation from the skin surface, erythema and melanin, skin elasticity and firmness with an MPA9 device and cutometer. The thickness and density of the epidermis and dermis, an essential indicator in rejuvenation, were evaluated with a skin ultrasound device. Also, the level of oxygen, perfusion, and interstitial water (edema) was checked using a Tivita tissue hyperspectral camera at a depth of 6 mm of the skin.

The Therapeutic Efficacy of Freeze-Dried Human Amniotic Membrane Allograft Gel for Diabetic Foot Ulcers: A Phase-1 Clinical Trial.

Diabetic foot ulcers (DFUs) are classified as hard-to-heal wounds, which occur in approximately 15% of diabetic patients. Several interventions have shown efficacy in reducing the risk of amputation among patients with DFU, including timely diagnosis and management of infection and ischemia, debridement of necrotic tissues, reducing mechanical pressure on ulcers, and patient education. One major challenge in the management of DFUs is optimizing wound care to improve healing outcomes. Recently, interdisciplinary approaches proposed a new generation of wound dressing which increased efficacy and significantly decreased the healing time. The current study assessed the healing characteristics of chronic DFUs treated with lyophilized amniotic membrane gel (LAMG) in combination with standard care, versus a placebo hydrogel with standard care. In total, 18 patients (8 male, 10 female) were randomly assigned to the control group, which received standard care and a gelatin scaffold (placebo), or the intervention group, which received standard care along with LAMG. We evaluated the reduction in wound size and assessed the patient's health-related quality of life over 9 weeks. In the LAMG group (n = 9) and the Placebo group (n = 9), the wounds were reduced in size by a mean of 73.4% ± 15.3% and 13.1% ± 10.1%, respectively (P = .008). Patients treated with LAMG demonstrated significant improvements in the scores related to physical function, physical limitation, physical pain, general health, social function, emotional problems, and energy levels compared to the control group. The findings of this study indicate that using the LAMG with standard care significantly enhances wound healing.

Treatment of superficial and deep partial width second degree burn's wound with allogeneic cord blood platelet gel.

BACKGROUND: Burns are caused by a variety of mechanisms, including flames, hot liquids, metallurgy, chemicals, electric current, and ionizing and non-ionizing radiation. The most significant burn wound management involves complete repair and regeneration as soon as possible while minimizing infection, contraction, and scarring in the damaged tissue area. Some factors such as delivery of nutrients, growth factors, and oxygen are essential to promote and stimulate the wound healing progress in the burns area. When these factors are not provided, the burn wound undergoes a physiological crisis. The use of growth factors is a promising approach to overcoming this limitation. Umbilical cord blood platelet concentrates are a rich natural source of growth factors. METHODS: This clinical trial used growth factors released from the lysis of umbilical cord blood platelet concentrates that have a key role in promoting re-epithelization and regeneration of damaged tissues by forming a fibrin network. This study evaluated the effectiveness of allogeneic cord blood platelet gel topical dressing in a group of patients diagnosed with superficial and deep partial thickness (second-degree) burn wounds. Clinical outcomes were compared between the intervention group and a control group of patients with superficial second-degree burn wounds who received the standard routine treatment including paraffin gauze wound dressing and silver sulfadiazine ointment. RESULTS: The study's results showed that the increased rate of recovery and tissue granulation completely promoted to wound healing and burn wound closure, decreased the recovery time, and reduced inflammation and scars caused by burn injuries. However, the use of cord blood platelet gel topical dressing is not currently a routine treatment method in patients suffering from burn wounds. However, the study's results showed that allogenic cord blood platelet gel could be used to treat superficial and deep second-degree burns as a routine treatment. It was also shown that allogenic cord blood platelet gel topical dressing could be a candidate for autograft or after autograft skin transplantation surgery (in donor and recipient sites) instead of skin surgery in some patients. CONCLUSION: Allogeneic topical wound dressing provides an effective treatment that offers a faster rate of epithelialization and healing of wounds and also decreases patients' scar and inflammation level as well as the length of recovery time. This, finally, leads to better burn wound management and the improved quality of burn wound treatment.

The quantitative investigation of spark plasma on skin parameters with skin elasticity, thickness, density, and biometric characteristics.

Cold atmospheric plasma has been developed and utilized as a novel technique for skin rejuvenation because of its various effects on cells and living things. This study investigated the accuracy of this claim and any possible side effects of using spark plasma to rejuvenate skin. The present work is the first quantitative investigation using animal models. 12 Wistar rats were divided into two groups for this investigation. To compare the skin's natural process with the treated skin, the first group underwent a single session of plasma therapy, while the second group served as the control group. The back of the necks of the samples was shaved for 20 cm. Before beginning treatment, the MPA9 multifunctional skin tester was used to determine the melanin index, erythema index, and transepidermal water loss (TEWL). The skin's thickness and density were assessed using sonography, and its elasticity index was calculated using a Cutometer. The samples were exposed to plasma radiation in the designated area (in a triangular pattern). The abovementioned signs were examined immediately after the following therapy and at the weekly appointment 2-4 weeks later. Optical spectroscopy was also used to demonstrate the presence of active species. In this study, we found that a plasma spark therapy session significantly boosts skin elasticity, and the ultrasound results revealed a significantly increased skin thickness and density. The plasma increased the amount of skin surface evaporation, erythema, and melanin immediately following the treatment. However, 4 weeks later, it recovered to its former state and did not differ significantly from before the therapy.

Design and evaluation of a skin-on-a-chip pumpless microfluidic device.

The development of microfluidic culture technology facilitates the progress of study of cell and tissue biology. This technology expands the understanding of pathological and physiological changes. A skin chip, as in vitro model, consisting of normal skin tissue with epidermis and dermis layer (full thickness) was developed. Polydimethylsiloxane microchannels with a fed-batched controlled perfusion feeding system were used to create a full-thick ex-vivo human skin on-chip model. The design of a novel skin-on-a-chip model was reported, in which the microchannel structures mimic the architecture of the realistic vascular network as nutrients transporter to the skin layers. Viabilities of full-thick skin samples cultured on the microbioreactor and traditional tissue culture plate revealed that a precise controlled condition provided by the microfluidic enhanced tissue viability at least for seven days. Several advantages in skin sample features under micro-scale-controlled conditions were found such as skin mechanical strength, water adsorption, skin morphology, gene expression, and biopsy longevity. This model can provide an in vitro environment for localizing drug delivery and transdermal drug diffusion studies. The skin on the chip can be a valuable in vitro model for representing the interaction between drugs and skin tissue and a realistic platform for evaluating skin reaction to pharmaceutical materials and cosmetic products.

SWI/SNF complex, promising target in melanoma therapy: Snapshot view.

Therapeutic strategies based on epigenetic regulators are rapidly increasing in light of recent advances in discovering the role of epigenetic factors in response and sensitivity to therapy. Although loss-of-function mutations in genes encoding the SWItch/Sucrose NonFermentable (SWI/SNF) subunits play an important role in the occurrence of ~34% of melanomas, the potential of using inhibitors and synthetic lethality interactions between key subunits of the complex that play an important role in melanoma progression must be considered. Here, we discuss the importance of the clinical application of SWI/SNF subunits as a promising potential therapeutic in melanoma.

Promotion of cutaneous diabetic wound healing by subcutaneous administration of Wharton's jelly mesenchymal stem cells derived from umbilical cord.

Wound healing is a major problem in diabetic patients, and current treatments have been confronted with limited success. The present study examined the benefit of Wharton's jelly mesenchymal stem cells (WJ-MSCs) derived from the human umbilical cord (UC) in wound healing in diabetic rats. Thirty days after inducing diabetes, a circular excision was created in the skin of rats, and the treatments were performed for 21 days. Two groups were studied, which included the Control group and WJ-MSCs group. The studied groups were sampled on the 7th, 14th, and 21st days after wounding. Histological ultrasound imaging of dermis and epidermis in the wound area for thickness and density measurement and skin elasticity were evaluated. Our results on post-wounding days 7, 14, and 21 showed that the wound closure, thickness, and density of new epidermis and dermis, as well as skin elasticity in the healed wound, were significantly higher in the WJ-MSCs group compared to the Control group. Subcutaneous administration of WJ-MSCs in diabetic wounds can effectively accelerate healing. Based on this, these cells can be used along with other treatment methods in the healing of different types of chronic wounds.

Role of Cultured Skin Fibroblasts in Regenerative Dermatology.

The skin, as the largest organ, covers the entire outer part of the body, and since this organ is directly exposed to microbial, thermal, mechanical and chemical damage, it may be destroyed by factors such as acute trauma, chronic wounds or even surgical interventions. Cell therapy is one of the most important procedures to treat skin lesions. Fibroblasts are cells that are responsible for the synthesis of collagen, elastin, and the organization of extracellular matrix (ECM) components and have many vital functions in wound healing processes. Today, cultured autologous fibroblasts are used to treat wrinkles, scars, wounds and subcutaneous atrophy. The results of many studies have shown that fibroblasts can be effective and beneficial in the treatment of skin lesions. On the other hand, skin substitutes are used as a regenerative model to improve and regenerate the skin. The use of these alternatives, restorative medicine and therapeutic cells such as fibroblasts has tremendous potential in the treatment of skin diseases and can be a new window for the treatment of diseases with no definitive treatment. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description ofthese Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Osteogenic differentiation of human induced pluripotent stem cell in the presence of testosterone and 17 ß-estradiol in vitro.

Recently, numerous scientific approaches have been explored to treat various diseases using stem cells. In 2006, induced pluripotent stem cell (iPSC) were introduced by Takahashi and Yamanaka and showed the potential of self-renewing and differentiation into all types of targeted cells in vitro. In this investigation, we studied the effect of testosterone (T) individually or in the presence of 17 ß-estradiol (E2) on osteogenic differentiation of human iPSC (hiPSC) during 2 wk. The optimal concentrations of sex steroid hormones were examined by MTT assay and acridine orange (AO) staining. The impact of E2 and T either individually or together as a combination was examined by ALP activity; the content of total mineral calcium, by von Kossa and alizarin red staining. Additionally, the expression rate of osteogenic specific markers was studied via real-time RT-PCR and immunocytochemistry analyses at day 14 of differentiation. The obtained results illustrated that the differentiation medium supplemented with T-E2 increased not only the ALP enzyme activity and the content of calcium but also the osteogenic-related gene and protein expressions on the 14th day. Furthermore, the results were confirmed by mineralized matrix staining. In conclusion, these data suggest that T could be used as an effective factor for osteogenic induction of hiPSCs combined with the E2 in bone regeneration.

Tissue engineering in dermatology - from lab to market.

Tissue Engineering is a branch of regenerative medical technology which helps replace damaged tissue using appropriate scaffolding, living cells, and growth factors. Using tissue engineering products can be a promising method for treating skin lesions such as wounds and deep burns. The interaction and interconnection of cells within the bio-culture medium or within a three-dimensional scaffold provides the conditions for tissue regeneration and subsequent healing of skin wounds. Tissue engineering in the field of dermatology has evolved over time from a single application of skin cells or biopolymer scaffolds to the use of cell and scaffold combinations for the treatment, repair, and closure of acute and chronic skin wounds. It has evolved. This technology has reached a point where most products are accepted, and the body rejects a small number, which strengthens the tissue engineering market. In this article, we aimed to review and study the market of this field by reviewing various articles on tissue engineering in the field of dermatology. Tissue-engineered skin substitutes are future options for wound healing and tissue regeneration strategies.

Effect of Nanoalumina on Sex Hormones and Fetuses in Pregnant Rats.

OBJECTIVE: This study aimed at investigating the effect of nanoalumina on sex hormones, and fetuses in pregnant rats. METHODS: In this study, sixty-four pregnant rats were divided into eight groups. The control and the injection-control group received normal food and water, and 0.5 ml of distilled water, respectively. Treatment groups were treated with 25, 50, 100, 250, 500, and 1000µg/ml concentrations of Nanoalumina from the 7th day until the 18th day of pregnancy. On the 18th day, the rats were investigated in terms of their hormone levels. We evaluated the number of healthy and aborted offspring, as well as fetus size. RESULTS: Nanoalumina caused an increase in progesterone hormones at the concentrations of 250, and 500µg/ml, and a significant reduction in estrogen hormone and aborted fetuses at the concentrations of 250 and 500µg/ml (p<0.05). The largest and smallest size of fetuses were observed in 500µg/ml and 1000µg/ml, respectively. The highest number of aborted fetuses was observed in the group treated with the 500µg/ml concentration. There was no aborted fetuses with 25, 50,100, control, and injection-control groups. CONCLUSIONS: Due to nanoalumina toxicity, it must be used with caution.

Notable Enhancement of Facial Scarring Following Autologous Melanocyte-Keratinocyte Transplantation and NUVB Therapy: A Case Report.

Introduction: There are various types of treatment targeting healing traumatic or accidental skin scars. Transplantation of skin grafts and surgical alternatives, including autologous transplantation of melanocyte-keratinocyte suspension, have also been suggested previously. This study is representing a case of previous skin graft transplantation, complaining of scar formation and discoloration on the transplanted segment. Case Presentation: The patient was a 37-year-old lady. This patient underwent melanocyte-keratinocyte suspension transplantation and narrow-band ultraviolet B (NUVB) therapy and could reach 40% re-pigmentation enhancement. This method could be introduced as an efficient and safe method of approaching facial scarring. Conclusion: This method could be introduced as an efficient and safe method of approaching facial scarring.

Epigenetic targeting of cancer stem cells by polyphenols (cancer stem cells targeting).

Epigenetic alterations are one of the main factors that disrupt the expression of genes and consequently, they have an important role in the carcinogenicity and the progression of different cancers. Cancer stem cells (CSCs) are accountable for the recurrence, metastasis, and therapeutic failure of cancer. The noticeable and specific pathways in CSCs can be organized by epigenetic mechanisms such as DNA methylation, chromatin remodeling, regulatory RNAs, among others. Since epigenetics modifications can be changed and reversed, it is a possible tool for cancer control and treatment. Epigenetic therapies against CSCs are emerging as a very new strategy with a good future expectation to treat cancer patients. Phenolic compounds are a vast group of substances with anticarcinogenic functions, antiinflammatory, and antioxidative activities. It seems these characteristics are related to neutralizing CSCs development, their microenvironment, and metabolism through epigenetic mechanisms. In the current work, the types of epigenetic changes known in these cells are introduced. In addition, some studies about the use of polyphenols acting through a variety of epigenetic mechanisms to counteract these cells will be reviewed. The reported results seem to indicate that the use of these phenolic compounds may be useful for CSCs defeat.

Efficacy of allogeneic cord blood platelet gel on wounds of dystrophic epidermolysis bullosa patients after pseudosyndactyly surgery.

Epidermolysis bullosa (EB) is a rare genetic disorder characterized by the formation of blisters and wounds in skin and mucous membranes; it is classified into four types and has various methods of treatment. Management of previous wounds and prevention of formation of new lesions are the most important strategies in the course of therapy to improve patient's quality of life; lack of wound management can lead to further complications such as infection. The current study investigated the therapeutic effects of allogeneic platelet gel (prepared from umbilical cord blood) in a group of children diagnosed with dystrophic epidermolysis bullosa (DEB) eligible for surgical correction of pseudosyndactyly in the hand. The post-surgical clinical outcome in this group was compared with the clinical outcomes of DEB patients receiving the standard treatment (paraffin gauze wound dressing and topical antibiotics) after corrective surgery. The current study results showed an increase in the rate of recovery and promotion of tissue granulation, complete wound healing, and a decrease in pain level and treatment period. The application of cord blood platelet gel topical dressing was not a conventional method of treatment in patients with DEB wounds and blisters. However, the current study results demonstrated that this gel dressing could effectively accelerate epithelialization and healing of the wounds and decrease patients' pain and post-surgical recovery period, which altogether leads to improvements in patients' overall quality of life.

Update review on five top clinical applications of human amniotic membrane in regenerative medicine.

Due to the increasing number of studies performed in the field of regenerative medicine during the last two decades, more analytic studies are still needed to clarify the future prospect of this area of science. The main aim of this research was to review the clinical applications of human Amniotic membrane in the field of regenerative medicine critically. Furthermore, in the light of increasing numbers of available products derived from amniotic membrane, we aimed look in depth to see whether regenerative medicine research strategies have a place in the clinical setting. More specifically, in the present study, we attempted to provide insight on developing the new indication for more research and in the next step, for market leaders companies to expand cost-effectiveness of new derived AM products. 20 companies or distributers have offered some commercial products in this field. Survey on more than 90 clinical trials in last five years showed dermatology (and more specific wound healing), orthopedic, and ophthalmology are heavily biased toward multibillion dollar industry. Moreover, urology and dentistry with fewer numbers of clinical data in comparison with the above-mentioned areas, currently are in the path of translation (especially dentistry). In addition, otolaryngology and oncology with the lowest number showed more potential of research thorough understanding the properties that will help guiding the use of AM-derived products in these two areas in future. More than 50% of clinical studies were done or are developing in USA, which have the biggest share in market products. Subsequently, China, Egypt, India, Iran, and Germany with the ongoing clinical trials in different phases may have more approved products in near future.

Evaluating the Toxicity and Histological Effects of Al2O3 Nanoparticles on Bone Tissue in Animal Model: A Case-Control Study.

The applications of nanostructures have been limited by their different toxicities. So, the investigation of these toxicities is necessary before nanostructure application. This study aimed to evaluate the effect of aluminum oxide (Al2O3) nanoparticles on bone density in Wistar rat. Al2O3 nanoparticle was prepared by the sol-gel method. Characterization was done by X-ray diffraction (XRD) and transmission electron microscopy (TEM). Sixty-four male adult Wistar rats were divided into eight groups including six groups intravenously treated with Al2O3 nanoparticle at concentrations of 25, 50, 100, 250, 500, and 1000 µg/ml: one group received food and water as the control group, and one group received food and water as well as intravenously distilled water as an injection control group. After 41 days, bone density was analyzed by dual-energy X-ray absorptiometry (DEXA). According to X-ray diffraction, the average particle size for Al2O3 nanoparticles was 20.85 nm. The data of densitometry showed that the bone density of right and left foot was reduced in concentrations of 250, 500, and 1000 µg/ml that were statistically significant in comparison with the control group. The reduction of bone density was increased with the enhancement of nanostructures concentration. The effect of Al2O3 nanoparticles on bone density was similar in the left and right legs. Histopatholological assessment also showed that Al2O3 nanoparticles (250, 500, and 1000 µg/ml) lead to significant reduction of trabeculae. Empty lacunae are observed in these three groups. Considering that high concentrations of Al2O3 nanoparticles had toxicity on bone tissue, it must be used by more caution, especially its use as a coating in different devices such as implants, surgical instruments, and bone prostheses.

Engineered skin graft with stromal vascular fraction cells encapsulated in fibrin-collagen hydrogel: A clinical study for diabetic wound healing.

Despite the abundance of skin substitutes in the worldwide market, major hurdles in developing more complex tissues include the addition of skin appendages and vascular networks as the most important structure. The aim of this research was a clinical feasibility study of a novel prevascularized skin grafts containing the dermal and epidermal layer using the adipose stromal vascular fraction (SVF)-derived endothelial cell population for vascular network regeneration. Herein, we characterized hydrogel with emphasis on biological compatibility and cell proliferation, migration, and vitality. The therapeutic potential of the prevascularized hydrogel transplanted on five human subjects as an intervention group with diabetic wounds was compared with nonvascularized skin grafts as the control on five patients. Wound planimetric and biometric analysis was performed using a Mann-Whitney nonparametric t-test (p ≤ .05). The fibrin-collagen hydrogel was suitable for skin organotypic cell culture. There was a significant (p ≤ .05) increased in skin thickness and density in the vascular beds of the hypodermis measured with skin scanner compared with that in the control group. No significant macroscopic differences were observed between the intervention and control groups (p ≤ .05). In summary, we report for the first time the use of autologous dermal-epidermal skin grafts with intrinsic vascular plexus in a clinical feasibility study. The preliminary data showed that SVF-based full-thickness skin grafts are safe and accelerate the wound healing process. The next stage of the study is a full-scale randomized clinical trial for the treatment of patients with chronic wounds.

Skin regenerative medicine advancements in the Islamic Republic of Iran: a concise review.

In the last decade, the Islamic Republic of Iran has witnessed significant improvement and growth in the field of interdisciplinary medicine and in its translation to patients, including the field of cell and stem cell therapy. The main aim of this report is to highlight various advances in regenerative medicine for skin and dermatology using stem cell technology, and its translation to clinic in the past two decades, in Iranian academic centers, clinical institutes and hospitals. While there have been numerous positive advances in clinical outcomes reported in Iran, there is no comparative analytical information on these studies. Here we present a historical overview of the progress and key advancements seen in skin regeneration in this country, review the research frameworks, regulatory approach and pathways and offer perspectives for the future.

Engineering the niche for hair regeneration - A critical review.

Recent progress in hair follicle regeneration and alopecia treatment necessitates revisiting the concepts and approaches. In this sense, there is a need for shedding light on the clinical and surgical therapies benefitting from nanobiomedicine. From this perspective, this review attempts to recognize requirements upon which new hair therapies are grounded; to underline shortcomings and opportunities associated with recent advanced strategies for hair regeneration; and most critically to look over hair regeneration from nanomaterials and pluripotent stem cell standpoint. It is noteworthy that nanotechnology is able to illuminate a novel path for reprogramming cells and controlled differentiation to achieve the desired performance. Undoubtedly, this strategy needs further advancement and a lot of critical questions have yet to be answered. Herein, we introduce the salient features, the hurdles that must be overcome, the hopes, and practical constraints to engineer stem cell niches for hair follicle regeneration.