Dispelling the Myths of Isotretinoin and Implications for Rhinoplasty.

SUMMARY: Despite concerns from 1980s case reports, oral isotretinoin, a derivative of Vitamin A, has largely proven to be safe in surgical procedures with the exception of deep skin resurfacing. Isotretinoin modulates thinning skin and internal scarring in select rhinoplasty patients who may otherwise have poor definition and excessive scarring. A review of patients undergoing surgical interventions including rhinoplasty in the setting of concomitant isotretinoin was performed to examine safety and therapeutic potential. Forty-nine studies were reviewed. Isotretinoin use appears to be safe in a wide variety of surgical procedures relying on internal scar formation. In rhinoplasty, studies utilized oral isotretinoin to thin skin and improve appearance, patient and surgeon satisfaction. As such, the clinical potential for using oral isotretinoin in select rhinoplasty candidates such as those with thick glaborous sebaceous skin, ethnic, male, and/or revision patients, could mitigate internal scarring processes. Further studies examining the optimal dosing regimen and long-term benefits are warranted.

Minimally invasive surgical approach to model hypertrophic scarring in the rabbit ear.

BACKGROUND: Current strategies for hypertrophic scar prevention and treatment are limited. OBJECTIVE: To facilitate these efforts, a minimally invasive hypertrophic scar model was created in a rabbit ear for the first time based on previous methods used to induce ischemia. METHODS: Six New Zealand white rabbits (12 ears total) were studied. First, ischemia was achieved by ligating the cranial artery, cranial vein and central artery, while preserving the caudal artery, caudal vein and central vein, respectively. The relative level of ischemia induced at time of surgery, both baseline and maximum perfusion, was assessed with a fluorescent light-assisted angiography and demonstrated lower rates of perfusion in the ischemic ears. Following vascular injury, a 2-cm full thickness linear wound was created on the ventral ear and closed with 4 - 0 Nylon sutures under high tension. For each rabbit, one ear received a combination of ischemia and wounding with suture tension (n = 6), while the other ear was non-ischemic with wounding and suture tension alone (n = 6). RESULTS: Four weeks post-operatively, ischemic ears developed scar hypertrophy (histological scar thickness: 1.1 ± 0.2 mm versus 0.5 ± 0.1 mm, p < 0.05). CONCLUSION: Herein, we describe a novel, prototypical minimally invasive rabbit ear model of hypertrophic scar formation that can allow investigation of new drugs for scar prevention.

Clinicopathological and cellular senescence biomarkers in chronic stalled wounds.

BACKGROUND: Chronic wounds have been associated with an elevated burden of cellular senescence, a state of essentially irreversible cell cycle arrest, resistance to apoptosis, and a secretory phenotype. However, whether senescent cells contribute to wound chronicity in humans remains unclear. The objective of this article is to assess the role of clinicopathological characteristics and cellular senescence in the time-to-healing of chronic wounds. METHODS: A cohort of 79 patients with chronic wounds was evaluated in a single-center academic practice from February 1, 2005, to February 28, 2015, and followed for up to 36 months. Clinical characteristics and wound biopsies were obtained at baseline, and time-to-healing was assessed. Wound biopsies were analyzed histologically for pathological characteristics and molecularly for markers of cellular senescence. In addition, biopsy slides were stained for p16INK4a expression. RESULTS: No clinical or pathological characteristics were found to have significant associations with time-to-healing. A Cox proportional hazard ratio model revealed increased CDKN1A (p21CIP1/WAF1 ) expression to predict longer time-to-healing, and a model adjusted for gender and epidermal hyperplasia revealed increased CDKN1A expression and decreased PAPPA expression to predict longer time-to-healing. Increased p16INK4a staining was observed in diabetic wounds compared to non-diabetic wounds, and the same association was observed in the context of high dermal fibrosis. CONCLUSIONS: The findings of this pilot study suggest that senescent cells contribute to wound chronicity in humans, especially in diabetic wounds.

Practical management of hypertrophic scarring: the mayo clinic experience.

Hypertrophic scarring is a potential consequence of wound healing that causes functional and aesthetic disability. Common treatments include intralesional pharmacotherapy (e.g., triamcinolone), surgical excision, and energy-based laser devices. While numerous treatment methods have been described for hypertrophic scarring, an optimal treatment strategy has yet to be established given variability in clinical presentation. This study aims to identify patient- and provider-preferred treatment patterns. This is a single-center, retrospective study of adult patients that developed post-surgical hypertrophic scarring between 2007 and 2017. Specifically, trends in procedural management for hypertrophic scarring among this cohort were examined. A total of 442 procedures (intralesional steroid injection, surgical excision, laser-based treatment) were identified in 218 patients with a clinical diagnosis of hypertrophic scarring. Approximately 73% were female; 87% were Caucasian. The median age at first procedure was 45.6 years (SD = 17.4). The most frequent anatomical locations for procedures were the trunk (n = 242; 54.8%), followed by head/neck (n = 86; 19.5%), upper extremities (n = 67; 15.2%), and lower extremities (n = 45; 10.2%). Procedural therapies included intralesional steroid injection (n = 221; 50%), surgical excision (n = 112; 25.3%) and laser (fractional non-ablative laser vs. pulsed dye laser; n = 109; 24.5%). Treatment modality varied by stage of treatment, scar anatomical location, and scar size. This single-center series of patients with hypertrophic scarring highlights a patient-centered management approach and offers clinical guidelines for provider-patient shared decision making.

Mapping cellular senescence networks in human diabetic foot ulcers.

Cellular senescence, a cell fate defined by irreversible cell cycle arrest, has been observed to contribute to chronic age-related conditions including non-healing wounds, such as diabetic foot ulcers. However, the role of cellular senescence in the pathogenesis of diabetic foot ulcers remains unclear. To examine the contribution of senescent phenotypes to these chronic wounds, differential gene and network analyses were performed on publicly available bulk RNA sequencing of whole skin biopsies of wound edge diabetic foot ulcers and uninvolved diabetic foot skin. Wald tests with Benjamini-Hochberg correction were used to evaluate differential gene expression. Results showed that cellular senescence markers, CDKN1A, CXCL8, IGFBP2, IL1A, MMP10, SERPINE1, and TGFA, were upregulated, while TP53 was downregulated in diabetic foot ulcers compared to uninvolved diabetic foot skin. NetDecoder was then used to identify and compare context-specific protein-protein interaction networks using known cellular senescence markers as pathway sources. The diabetic foot ulcer protein-protein interaction network demonstrated significant perturbations with decreased inhibitory interactions and increased senescence markers compared to uninvolved diabetic foot skin. Indeed, TP53 (p53) and CDKN1A (p21) appeared to be key regulators in diabetic foot ulcer formation. These findings suggest that cellular senescence is an important mediator of diabetic foot ulcer pathogenesis.

Cellular Senescence in Human Skin Aging: Leveraging Senotherapeutics.

BACKGROUND: As the largest organ in the human body, the skin is continuously exposed to intrinsic and extrinsic stimuli that impact its functionality and morphology with aging. Skin aging entails dysregulation of skin cells and loss, fragmentation, or fragility of extracellular matrix fibers that are manifested macroscopically by wrinkling, laxity, and pigmentary abnormalities. Age-related skin changes are the focus of many surgical and nonsurgical treatments aimed at improving overall skin appearance and health. SUMMARY: As a hallmark of aging, cellular senescence, an essentially irreversible cell cycle arrest with apoptosis resistance and a secretory phenotype, manifests across skin layers by affecting epidermal and dermal cells. Knowledge of skin-specific senescent cells, such as melanocytes (epidermal aging) and fibroblasts (dermal aging), will promote our understanding of age-related skin changes and how to optimize patient outcomes in esthetic procedures. KEY MESSAGES: This review provides an overview of skin aging in the context of cellular senescence and discusses senolytic intervention strategies to selectively target skin senescent cells that contribute to premature skin aging.

3D bioprinting-a model for skin aging.

Human lifespan continues to extend as an unprecedented number of people reach their seventh and eighth decades of life, unveiling chronic conditions that affect the older adult. Age-related skin conditions include senile purpura, seborrheic keratoses, pemphigus vulgaris, bullous pemphigoid, diabetic foot wounds and skin cancer. Current methods of drug testing prior to clinical trials require the use of pre-clinical animal models, which are often unable to adequately replicate human skin response. Therefore, a reliable model for aged human skin is needed. The current challenges in developing an aged human skin model include the intrinsic variability in skin architecture from person to person. An ideal skin model would incorporate innate functionality such as sensation, vascularization and regeneration. The advent of 3D bioprinting allows us to create human skin equivalent for use as clinical-grade surgical graft, for drug testing and other needs. In this review, we describe the process of human skin aging and outline the steps to create an aged skin model with 3D bioprinting using skin cells (i.e. keratinocytes, fibroblasts and melanocytes). We also provide an overview of current bioprinted skin models, associated limitations and direction for future research.

Skin Cancer Associated With Chronic Leg Ulcers in the Population of Olmsted County, Minnesota.

Malignant skin tumors in the setting of chronic leg ulcers (CLUs) are often underdiagnosed which may contribute to treatment delay and poor outcomes. The aims of our study were to determine the incidence and clinical characteristics of skin cancers in leg ulcers in the Olmsted County population from 1995 to 2020. We used the Rochester Epidemiology Project (a collaboration between health care providers) infrastructure to describe this epidemiology, allowing "population-based" research. Electronic medical records of adult patients with International Classification of Diseases diagnosis codes for leg ulcers and skin cancers on the legs were queried. Thirty-seven individuals with skin cancers in nonhealing ulcers were identified. The cumulative incidence of skin cancer over the 25-year period was 37:7864 (0.47%). The overall incidence rate was 470 per 100,000 patients. Eleven (29.7%) men and 26 (70.3%) women were identified with mean age of 77 years. History of venous insufficiency was present in 30 (81.1%) patients and diabetes in 13 (35.1%) patients. Clinical characteristics of CLU with skin cancer included abnormal granulation tissue in 36 (94.7%) and irregular borders in 35 (94.6%) cases. Skin cancers among CLUs included 17 (41.5%) basal cell carcinomas, 17 (41.5%) squamous cell carcinomas, 2 (4.9%) melanomas, 2 (4.9%) porocarcinomas, 1 (2.4%) basosquamous cell carcinoma, and 1 (2.4%) eccrine adenocarcinoma. The apparent association between chronic wounds and subsequent biopsy-proven skin cancer of the same site was primarily observed in elderly patients; malignant transformation of wounds favored basal cell carcinoma and squamous cell carcinoma. This retrospective cohort study further characterizes the association between skin cancers and chronic leg wounds.

Cellular senescence in skin-related research: Targeted signaling pathways and naturally occurring therapeutic agents.

Despite the growing interest by researchers into cellular senescence, a hallmark of cellular aging, its role in human skin remains equivocal. The skin is the largest and most accessible human organ, reacting to the external and internal environment. Hence, it is an organ of choice to investigate cellular senescence and to target root-cause aging processes using senolytic and senomorphic agents, including naturally occurring plant-based derivatives. This review presents different aspects of skin cellular senescence, from physiology to pathology and signaling pathways. Cellular senescence can have both beneficial and detrimental effects on the skin, indicating that both prosenescent and antisenescent therapies may be desirable, based on the context. Knowledge of molecular mechanisms involved in skin cellular senescence may provide meaningful insights for developing effective therapeutics for senescence-related skin disorders, such as wound healing and cosmetic skin aging changes.

A chronic wound model to investigate skin cellular senescence.

Wound healing is an essential physiological process for restoring normal skin structure and function post-injury. The role of cellular senescence, an essentially irreversible cell cycle state in response to damaging stimuli, has emerged as a critical mechanism in wound remodeling. Transiently-induced senescence during tissue remodeling has been shown to be beneficial in the acute wound healing phase. In contrast, persistent senescence, as observed in chronic wounds, contributes to delayed closure. Herein we describe a chronic wound murine model and its cellular senescence profile, including the senescence-associated secretory phenotype.

Diabetic kidney disease induces transcriptome alterations associated with angiogenesis activity in human mesenchymal stromal cells.

BACKGROUND: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach. METHODS: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log2fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state. RESULTS: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm). CONCLUSIONS: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia.

Exosomes: the latest in regenerative aesthetics.

Regenerative aesthetics is a burgeoning field for skin rejuvenation and skin health restoration. Exosomes, or extracellular vesicles, represent a new and minimally invasive addition to the regenerative aesthetic toolbox. These nano-sized vesicles contain bioactive cargo with crucial roles in intercellular communication. Exosome technology, while still in its infancy, is now leveraged in regenerative aesthetic medicine due to its multifaceted role in targeting root causes of skin aging and improving overall tissue homeostasis. The main considerations for practice utilization include variation in exosome purification, isolation, storage, scalability and reproducibility. This review aims at highlighting the current and emerging landscape of exosomes in aesthetic medicine including skin rejuvenation and hair restoration.

What is this article about? The purpose of this paper is to review available studies that look at the effects of exosomes in aesthetic medicine and cosmetic surgery. A thorough literature search of all available studies was performed. What were the results? Topical exosomes, although variable in source and method of isolation, are generally considered safe in humans on intact skin. The current published research literature does not yet provide a clear consensus on long-term use for skin rejuvenation or hair restoration, nor does it delineate which patients would benefit most from this technology. There are no currently US FDA-approved exosome products on the market for medical indications. What do the results of this literature review mean? More clinical studies with proper regulatory oversight are needed.

A Novel Hair Restoration Technology Counteracts Androgenic Hair Loss and Promotes Hair Growth in A Blinded Clinical Trial.

Androgenic alopecia (AGA) is a genetically predetermined condition that occurs as a result of stepwise miniaturization of the dermal papilla. During this process, the hair follicle suffers from increasing malnutrition and eventually dies, causing progressive hair loss. We recently highlighted that HIF-1α modulation may counteract hair loss. Here, we aim to demonstrate the positive influence of Tomorrowlabs HIF strengthening factor [HSF] hair restoration technology on hair biology in a monocentric blinded clinical trial over a total period of 9 months. A trial with 20 subjects (4 female and 16 male) and once-daily application of [HSF] hair restoration technology to the scalp was conducted. To assess the tolerability and efficacy of [HSF], testing included dermatological assessment, determination of hair loss by counting after combing, macro images of the head and TrichoScan evaluation of hair density as well as the proportion of anagen hair versus telogen hair. The clinical data show Tomorrowlabs [HSF] hair restoration to be safe and effective to counteract AGA. The use of Tomorrowlabs [HSF] hair restoration resulted in improvements in the clinical parameters of hair quality such as thickness (+7.2%), hair density (+14.3%) and shine and elasticity (+20.3%) during the test period. The effectiveness of the test product was further determined by a significant reduction in hair loss of an average of 66.8% in treatment-responsive subjects after 6 months and an increase in hair growth reaching up to 32.5%, with an average percentage change of 8.4% in all participants and 10.8% in the responsive patients (85% of the study cohort) after 9 months on TrichoScan evaluation. The hair growth cycle was harmonized with the result of an average anagen hair percentage increase of +8.0% and telogen hair percentage reduction of -14.0% shown in the test area. Applicable for both sexes in an alcohol-free formulation, beneficial to scalp health and free of complications or side effects, this novel product provides objectively measurable results counteracting hair loss paired with an improved look and feel of the hair.

Targeting Cellular Senescence for Age-Related Diseases: Path to Clinical Translation.

SUMMARY: Beyond the palliative reach of today's medicines, medical therapies of tomorrow aim to treat the root cause of age-related diseases by targeting fundamental aging mechanisms. Pillars of aging include, among others, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The unitary theory of fundamental aging processes posits that by targeting one fundamental aging process, it may be feasible to impact several or all others given its interdependence. Indeed, pathologic accumulation of senescent cells is implicated in chronic diseases and age-associated morbidities, suggesting that senescent cells are a good target for whole-body aging intervention. Preclinical studies using senolytics, agents that selectively eliminate senescent cells, and senomorphics, agents that inhibit production or release of senescence-associated secretory phenotype factors, show promise in several aging and disease preclinical models. Early clinical trials using a senolytic combination (dasatinib and quercetin), and other senolytics including flavonoid, fisetin, and BCL-xL inhibitors, illustrate the potential of senolytics to alleviate age-related dysfunction and diseases including wound healing. Translation into clinical applications requires parallel clinical trials across institutions to validate senotherapeutics as a vanguard for delaying, preventing, or treating age-related disorders and aesthetic aging.

Efficacy and Tolerability of Topical Platelet Exosomes for Skin Rejuvenation: Six-Week Results.

BACKGROUND: Exosomes are regenerative mediators for skin rejuvenation. Human platelet extract (HPE) is an allogeneic exosome product derived from US-sourced, leukocyte-reduced apheresed platelets with consistent purity and potency. OBJECTIVES: The authors sought to better characterize the safety and tolerability of novel HPE (plated) Intensive Repair Serum (Rion Aesthetics, Rochester, MN) and its maximal effects on skin rejuvenation at 6 weeks. METHODS: This prospective, single-arm, non-randomized, longitudinal study investigated the safety and efficacy of HPE. Structured sub-analysis evaluated multifactorial improvement in skin health following standardized skin care regimen to determine the maximal effect. Evaluation at baseline and 6 weeks included participant questionnaires and photo documentation with VISIA-CR Generation 5 3D PRIMOS (Canfield Scientific Inc, Fairfield, NJ). RESULTS: VISIA-CR imaging yielded quantifiable and statistically significant improvements in overall skin health (skin health score). A greater score correlated to greater overall skin health, and there was a statistically significant mean delta improvement of 224.2 ± 112.8 (mean ± standard deviation, P ≤ 0.0001) in skin health score at 6 weeks compared with baseline. This correlated to reduction in redness, wrinkles, and melanin production across all cosmetic units (P = 0.005, P = 0.0023, P ≤ 0.0001, respectively) and significant improvements in luminosity and color evenness (P ≤ 0.001). CONCLUSIONS: A topically applied platelet-derived exosome product, HPE, induced normalization to skin health at 4 to 6 weeks with improved various clinical measures of facial photodamage and cutaneous aging. It is safe, well-tolerated, and well-liked by participants.

Platelet-rich plasma for the treatment of lichen sclerosus.

AIM: Evaluate the clinical effectiveness of platelet-rich plasma as a treatment for lichen sclerosus. METHODS: A systematic review was performed. The electronic databases PubMed, Ovid MEDLINE®, Web of Science, Cochrane, clinicaltrials.gov were used to identify case studies, case series, prospective uncontrolled, and randomized controlled studies published between 1946 and April 21, 2021. Six prospective uncontrolled studies, one randomized double-blind prospective study, and one case report were included. RESULTS: Platelet-rich plasma treatment was subjectively reported to improve quality of life, but objective measures demonstrating treatment efficacy were not observed. In addition, platelet-rich plasma preparation and administration between studies lacked standardization. CONCLUSION: Platelet-rich plasma may be used for symptomatic adjuvant treatment of lichen sclerosus, though additional double-blind controlled studies with standardized platelet-rich plasma protocols are needed to better characterize the efficacy of platelet-rich plasma.

Emerging workforce readiness in regenerative healthcare.

The biology of regenerative medicine has steadily matured, providing the foundation for randomized clinical trials and translation into validated applications. Today, the growing regenerative armamentarium is poised to impact disease management, yet a gap in training next-generation healthcare providers, equipped to adopt and deliver regenerative options, has been exposed. This special report highlights a multiyear experience in developing and deploying a comprehensive regenerative curriculum for medical trainees. For academicians and institutions invested in establishing a formalized regenerative medicine syllabus, the Regenerative Medicine and Surgery course provides a patient-focused prototype for next-generation learners, offering a dedicated educational experience that encompasses discovery, development and delivery of regenerative solutions. Built with the vision of an evolving regenerative care model, this transdisciplinary endeavor could serve as an adoptable education portal to advance the readiness of the emergent regenerative healthcare workforce globally.