Multiscale spatial mapping of cell populations across anatomical sites in healthy human skin and basal cell carcinoma.

Our understanding of how human skin cells differ according to anatomical site and tumour formation is limited. To address this, we have created a multiscale spatial atlas of healthy skin and basal cell carcinoma (BCC), incorporating in vivo optical coherence tomography, single-cell RNA sequencing, spatial global transcriptional profiling, and in situ sequencing. Computational spatial deconvolution and projection revealed the localisation of distinct cell populations to specific tissue contexts. Although cell populations were conserved between healthy anatomical sites and in BCC, mesenchymal cell populations including fibroblasts and pericytes retained signatures of developmental origin. Spatial profiling and in silico lineage tracing support a hair follicle origin for BCC and demonstrate that cancer-associated fibroblasts are an expansion of a POSTN+ subpopulation associated with hair follicles in healthy skin. RGS5+ pericytes are also expanded in BCC suggesting a role in vascular remodelling. We propose that the identity of mesenchymal cell populations is regulated by signals emanating from adjacent structures and that these signals are repurposed to promote the expansion of skin cancer stroma. The resource we have created is publicly available in an interactive format for the research community.

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.

Paraneoplastic Pityriasis Rubra Pilaris Preceding Leukemia.

ABSTRACT: Pityriasis rubra pilaris (PRP) is a rare, chronic papulosquamous disorder that presents with scaling plaques, palmoplantar keratoderma, and keratotic follicular papules. Typically, there are distinctive unaffected areas referred to as "islands of sparing." Pityriasis rubra pilaris has been associated with various immunodeficient states and malignancies.The authors conducted a literature review using MEDLINE, PubMed, and Google Scholar, documenting all known cases of PRP associated with malignancy; 15 cases were found in the literature. They also present the case of a 49-year-old White man who, prior to referral to dermatology, was seen in urgent care for widespread pruritic rash. Physical examination in the dermatology clinic revealed confluent, scaly erythematous papules coalescing into plaques with island of sparing involving the trunk and upper and lower extremities. Bilateral palms and soles showed hyperkeratosis with fissuring. He was diagnosed with PRP after punch biopsy and began a new course of topical corticosteroid therapy. Hematology was consulted because of abnormal complete blood count results, and he was subsequently diagnosed with chronic lymphoid leukemia.Treatment of PRP is largely based on clinical experience and may involve corticosteroids, immunomodulators, or biologic therapy. The relationship between PRP and malignancy is unknown. Current theories postulate it may be driven by tumor production of functional peptides or antigen cross-reactivity between cancer cells and the skin. This is the second reported case of PRP as a manifestation of leukemia, and the first of chronic lymphoid leukemia. Although not yet understood, the documented relationship between PRP and malignancy prompts screening for cancer in all patients with new-onset PRP.

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.

Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in development and human disease, including cancer. It is currently thought that the four-point one, ezrin, radixin, moesin (FERM)-kinase domain linker, which contains autophosphorylation site tyrosine (Y) 397, is not required for in vivo FAK function until late midgestation. Here, we directly tested this hypothesis by generating mice with FAK Y397-to-phenylalanine (F) mutations in the germline. We found that Y397F embryos exhibited reduced mesodermal fibronectin (FN) and osteopontin expression and died during mesoderm development akin to FAK kinase-dead mice. We identified myosin-1E (MYO1E), an actin-dependent molecular motor, to interact directly with the FAK FERM-kinase linker and induce FAK kinase activity and Y397 phosphorylation. Active FAK in turn accumulated in the nucleus where it led to the expression of osteopontin and other FN-type matrix in both mouse embryonic fibroblasts and human melanoma. Our data support a model in which FAK Y397 autophosphorylation is required for FAK function in vivo and is positively regulated by MYO1E.

Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure. In families with autosomal-dominant DCM, heterozygous missense mutations were identified in RNA-binding motif protein 20 (RBM20), a spliceosome protein induced during early cardiogenesis. Dermal fibroblasts from two unrelated patients harboring an RBM20 R636S missense mutation were reprogrammed to human induced pluripotent stem cells (hiPSCs) and differentiated to beating cardiomyocytes (CMs). Stage-specific transcriptome profiling identified differentially expressed genes ranging from angiogenesis regulator to embryonic heart transcription factor as initial molecular aberrations. Furthermore, gene expression analysis for RBM20-dependent splice variants affected sarcomeric (TTN and LDB3) and calcium (Ca(2+)) handling (CAMK2D and CACNA1C) genes. Indeed, RBM20 hiPSC-CMs exhibited increased sarcomeric length (RBM20: 1.747 ± 0.238 µm versus control: 1.404 ± 0.194 µm; P < 0.0001) and decreased sarcomeric width (RBM20: 0.791 ± 0.609 µm versus control: 0.943 ± 0.166 µm; P < 0.0001). Additionally, CMs showed defective Ca(2+) handling machinery with prolonged Ca(2+) levels in the cytoplasm as measured by greater area under the curve (RBM20: 814.718 ± 94.343 AU versus control: 206.941 ± 22.417 AU; P < 0.05) and higher Ca(2+) spike amplitude (RBM20: 35.281 ± 4.060 AU versus control:18.484 ± 1.518 AU; P < 0.05). ß-adrenergic stress induced with 10 µm norepinephrine demonstrated increased susceptibility to sarcomeric disorganization (RBM20: 86 ± 10.5% versus control: 40 ± 7%; P < 0.001). This study features the first hiPSC model of RBM20 familial DCM. By monitoring human cardiac disease according to stage-specific cardiogenesis, this study demonstrates RBM20 familial DCM is a developmental disorder initiated by molecular defects that pattern maladaptive cellular mechanisms of pathological cardiac remodeling. Indeed, hiPSC-CMs recapitulate RBM20 familial DCM phenotype in a dish and establish a tool to dissect disease-relevant defects in RBM20 splicing as a global regulator of heart function.

Calreticulin secures calcium-dependent nuclear pore competency required for cardiogenesis.

Calreticulin deficiency causes myocardial developmental defects that culminate in an embryonic lethal phenotype. Recent studies have linked loss of this calcium binding chaperone to failure in myofibrillogenesis through an as yet undefined mechanism. The purpose of the present study was to identify cellular processes corrupted by calreticulin deficiency that precipitate dysregulation of cardiac myofibrillogenesis related to acquisition of cardiac phenotype. In an embryonic stem cell knockout model, calreticulin deficit (crt(-/-)) compromised nucleocytoplasmic transport of nuclear localization signal-dependent and independent pathways, disrupting nuclear import of the cardiac transcription factor MEF2C. The expression of nucleoporins and associated nuclear transport proteins in derived crt(-/-) cardiomyocytes revealed an abnormal nuclear pore complex (NPC) configuration. Altered protein content in crt(-/-) cells resulted in remodeled NPC architecture that caused decreased pore diameter and diminished probability of central channel occupancy versus wild type counterparts. Ionophore treatment of impaired calcium handling in crt(-/-) cells corrected nuclear pore microarchitecture and rescued nuclear import resulting in normalized myofibrillogenesis. Thus, calreticulin deficiency alters nuclear pore function and structure, impeding myofibrillogenesis in nascent cardiomyocytes through a calcium dependent mechanism. This essential role of calreticulin in nucleocytoplasmic communication competency ties its regulatory action with proficiency of cardiac myofibrillogenesis essential for proper cardiac development.

Is Local Infiltration Analgesia Superior to Peripheral Nerve Blockade for Pain Management After THA: A Network Meta-analysis.

BACKGROUND: Local infiltration analgesia and peripheral nerve blocks are common methods for pain management in patients after THA but direct head-to-head, randomized controlled trials (RCTs) have not been performed. A network meta-analysis allows indirect comparison of individual treatments relative to a common comparator; in this case placebo (or no intervention), epidural analgesia, and intrathecal morphine, yielding an estimate of comparative efficacy. QUESTIONS/PURPOSES: We asked, when compared with a placebo, (1) does use of local infiltration analgesia reduce patient pain scores and opioid consumption, (2) does use of peripheral nerve blocks reduce patient pain scores and opioid consumption, and (3) is local infiltration analgesia favored over peripheral nerve blocks for postoperative pain management after THA? METHODS: We searched six databases, from inception through June 30, 2014, to identify RCTs comparing local infiltration analgesia or peripheral nerve block use in patients after THA. A total of 35 RCTs at low risk of bias based on the recommended Cochrane Collaboration risk assessment tool were included in the network meta-analysis (2296 patients). Primary outcomes for this review were patient pain scores at rest and cumulative opioid consumption, both assessed at 24 hours after THA. Because of substantial heterogeneity (variation of outcomes between studies) across included trials, a random effect model for meta-analysis was used to estimate the weighted mean difference (WMD) and 95% CI. The gray literature was searched with the same inclusion criteria as published trials. Only one unpublished trial (published abstract) fulfilled our criteria and was included in this review. All other studies included in this systematic review were full published articles. Bayesian network meta-analysis included all RCTs that compared local infiltration analgesia or peripheral nerve blocks with placebo (or no intervention), epidural analgesia, and intrathecal morphine. RESULTS: Compared with placebo, local infiltration analgesia reduced patient pain scores (WMD, -0.61; 95% CI, -0.97 to -0.24; p = 0.001) and opioid consumption (WMD, -7.16 mg; 95% CI, -11.98 to -2.35; p = 0.004). Peripheral nerve blocks did not result in lower pain scores or reduced opioid consumption compared with placebo (WMD, -0.43; 95% CI, -0.99 to 0.12; p = 0.12 and WMD, -3.14 mg, 95% CI, -11.30 to 5.02; p = 0.45). However, network meta-analysis comparing local infiltration analgesia with peripheral nerve blocks through common comparators showed no differences between postoperative pain scores (WMD, -0.36; 95% CI, -1.06 to 0.31) and opioid consumption (WMD, -4.59 mg; 95% CI, -9.35 to 0.17), although rank-order analysis found local infiltration analgesia to be ranked first in more simulations than peripheral nerve blocks, suggesting that it may be more effective. CONCLUSIONS: Using the novel statistical network meta-analysis approach, we found no differences between local infiltration analgesia and peripheral nerve blocks in terms of analgesia or opioid consumption 24 hours after THA; there was a suggestion of a slight advantage to peripheral nerve blocks based on rank-order analysis, but the effect size in question is likely not large. Given the slight difference between interventions, clinicians may choose to focus on other factors such as cost and intervention-related complications when debating which analgesic treatment to use after THA. LEVEL OF EVIDENCE: Level I, therapeutic study.

Differential cytotoxicity of corticosteroids on human mesenchymal stem cells.

BACKGROUND: Corticosteroids are a common, short-term, local antiinflammatory and analgesic for treating patients with musculoskeletal disorders. Studies have shown the deleterious effects of corticosteroids on chondrocytes, suggesting a potentiation of degenerative joint disease. Mesenchymal stem cells (MSCs) are the direct progenitors of chondrocytes and other musculoskeletal tissue. Additionally, they serve an important antiinflammatory role, which can combat the chronic inflammatory state that mediates degenerative joint disease. Little is known about how corticosteroids interact with this regenerative and reparative cell population. QUESTIONS/PURPOSES: We asked: (1) Are corticosteroids cytotoxic to MSCs in a dose-response fashion? (2) Is there a differential effect in the level of cytotoxicity to MSCs between commercially available corticosteroid preparations? METHODS: Human MSCs were isolated and cultured from periarticular adipose tissue obtained from 20 patients undergoing primary THA. MSCs were exposed for 60 minutes to one of four commonly used corticosteroid preparations: betamethasone sodium phosphate-betamethasone acetate (6 mg/mL), dexamethasone sodium phosphate (4 mg/mL), methylprednisolone (40 mg/mL), or triamcinolone acetonide (40 mg/mL). Among the four preparations (treatment groups), cells were exposed to increasing concentrations of drugs according to the following titrations of the commercially available preparation: 0.0 (control solution of 1X phosphate buffered saline), 3.125, 6.25, 12.5, 25, 50, 75, and 100 % (undiluted commercial product). Cells were allowed to recover in standard culture media for 24 hours. After the recovery period, cell viability was measured using -(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) tetrazolium dye-based cellular viability assay and live-dead cell fluorescent staining. For the MTS assay, measurements were quantified in units of optical density (OD). ANOVA was performed at every experimental steroid concentration. When this global test was statistically significant, all pairwise comparisons were performed at that concentration with p values adjusted by the Tukey method to guard against Type I error. RESULTS: Exposure to corticosteroids decreased MSC viability in a curvilinear dose-response pattern. For betamethasone, the mean MTS OD at 0% steroid concentration was 1.03 (SD, 0.12) and decreased to 0.00 (SD, 0.00) at 25% steroid concentration. For dexamethasone, the mean MTS OD at 0% steroid concentration was 1.00 (SD, 0.07) and decreased to 0.00 (SD, 0.01) at 100% steroid concentration. For methylprednisolone, the mean MTS OD at 0% steroid concentration was 1.03 (SD, 0.09) and decreased to 0.00 (SD, 0.00) at 100% steroid concentration. For triamcinolone, the mean MTS OD at 0% steroid concentration was 1.02 (SD, 0.09) and decreased to 0.00 (SD, 0.00) at 75% steroid concentration. There were large differences among commercially available preparations, and these differences were present at every concentration. In general, dexamethasone was most gentle on MSCs (average OD by steroid concentration: 0% = 1.00; 3.125% = 0.86; 6.25% = 0.74; 12.5% = 0.53; 25% = 0.30; 50% = 0.20; 75% = 0.09; 100% = 0.00, triamcinolone and methylprednisolone were intermediate (triamcinolone average OD by steroid concentration: 0% = 1.02; 3.125% = 0.82; 6.25% = 0.64; 12.5% = 0.45; 25% = 0.18; 50% = 0.03; 75% = 0.00; 100% = 0.00; methylprednisolone average OD by steroid concentration: 0% = 1.03; 3.125% = 0.74; 6.25% = 0.54; 12.5% = 0.31; 25% = 0.12; 50% = 0.01; 75% = 0.00; 100% = 0.00), and betamethasone was most toxic (average OD by steroid concentration: 0% = 1.03; 3.125% = 0.74; 6.25% = 0.27; 12.5% = 0.02; 25% = 0.00; 50% = 0.00; 75% = 0.00; 100% = 0.00). ANOVA testing showed p values less than 0.0001 at every tested concentration (with the exception of the 0% control solution; p = 0.204) with subsequent pairwise comparisons supporting the relationships described above. The outcomes were maintained after stratifying by age, sex, or indication for THA (osteoarthritis versus avascular necrosis). CONCLUSIONS: Commonly used intraarticular corticosteroids had a dose-dependent, profound, and differential effect on MSCs in this in vitro model, with betamethasone being the most toxic. Further studies are needed to assess if the in vitro effects of these agents translate into similar in vivo outcomes. CLINICAL RELEVANCE: Corticosteroids frequently are used by physicians to reduce inflammation in patients with musculoskeletal disorders, but these agents may hinder MSCs' innate regenerative capacity in exchange for temporary analgesia. Our study suggests that choosing dexamethasone may result in less harmful effects when compared with other injectable steroids.

Stem cells: the pursuit of genomic stability.

Stem cells harbor significant potential for regenerative medicine as well as basic and clinical translational research. Prior to harnessing their reparative nature for degenerative diseases, concerns regarding their genetic integrity and mutation acquisition need to be addressed. Here we review pluripotent and multipotent stem cell response to DNA damage including differences in DNA repair kinetics, specific repair pathways (homologous recombination vs. non-homologous end joining), and apoptotic sensitivity. We also describe DNA damage and repair strategies during reprogramming and discuss potential genotoxic agents that can reduce the inherent risk for teratoma formation and mutation accumulation. Ensuring genomic stability in stem cell lines is required to achieve the quality control standards for safe clinical application.

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.

Ink-spiring innovations: 3D bioprinting skin models for disease discovery.

Tweetable abstract Inflammatory skin diseases account for most chronic skin conditions. 3D bioprinting is an exciting technology that can revolutionize the understanding and approach to treatment of atopic dermatitis and graft-versus-host disease.

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.

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.

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.

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.

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 Comparative Study of Two Topical Treatments for Photoaging of the Hands.

BACKGROUND: Multiple effective treatments exist for correction of skin photoaging. Topical L-ascorbic acid (Vitamin C) is a well-known anti-oxidant and topical human platelet extract (HPE), a novel off-the-shelf cosmetic ingredient has shown positive results in recent clinical studies. HPE is a leukocyte-depleted allogeneic product derived from U.S.-sourced, pooled, apheresed platelets produced with consistent batch quality, purity, and effect. AIMS: The authors sought to characterize the effect of topical HPE (plated ) Intense Serum (Rion Aesthetics, Rochester, MN) compared to vitamin C (C E Ferulic® with 15% L-Ascorbic Acid, SkinCeuticals, L'Oréal, Paris) in skin rejuvenation of dorsal hands after 12 to 26-weeks twice daily use. METHODS: This prospective, longitudinal study sought to compare the effectiveness of two known treatments for skin rejuvenation. Evaluations at baseline, 6, 12, and 26 weeks included photo documentation to assess common skin concerns related to aging. RESULTS: For age-related skin appearance on the dorsal hands, topical HPE was non-inferior to topical vitamin C for improvement in brown spot fractional area, wrinkle fractional area, and improvement in luminosity at 12 weeks after twice-daily topical use. CONCLUSIONS: HPE performed as well as vitamin C to rejuvenate the skin on the dorsal hands after 12 to 26 weeks of twice daily topical use. Both topical serums may yield similar or superior results than invasive procedures, such as intense pulsed light (IPL), in reducing brown spots on the dorsal hands. These topical products work equally well in both sexes. Skin improvements lasted through 6 months.

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.

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.