Integrated spatial multiomics reveals fibroblast fate during tissue repair.

In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive, in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to skin injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to reveal potential mechanisms controlling fibroblast fate during migration, proliferation, and differentiation following skin injury, and thereby reexamine the canonical phases of wound healing. These findings have broad implications for the study of tissue repair in complex organ systems.

Wounds Inhibit Tumor Growth In Vivo.

OBJECTIVE: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo. SUMMARY OF BACKGROUND DATA: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo. METHODS: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells. RESULTS: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds. CONCLUSION: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.

Tissue Engineering and Regenerative Medicine in Craniofacial Reconstruction and Facial Aesthetics.

The craniofacial region is anatomically complex and is of critical functional and cosmetic importance, making reconstruction challenging. The limitations of current surgical options highlight the importance of developing new strategies to restore the form, function, and esthetics of missing or damaged soft tissue and skeletal tissue in the face and cranium. Regenerative medicine (RM) is an expanding field which combines the principles of tissue engineering (TE) and self-healing in the regeneration of cells, tissues, and organs, to restore their impaired function. RM offers many advantages over current treatments as tissue can be engineered for specific defects, using an unlimited supply of bioengineered resources, and does not require immunosuppression. In the craniofacial region, TE and RM are being increasingly used in preclinical and clinical studies to reconstruct bone, cartilage, soft tissue, nerves, and blood vessels. This review outlines the current progress that has been made toward the engineering of these tissues for craniofacial reconstruction and facial esthetics.

Alloplastic Auricular Reconstruction: Review of Implant Types, Adverse Events, and Aesthetic Outcomes.

IMPORTANCE: Alloplastic implants have been applied successfully in reconstruction of the external ear, either for congenital microtia or traumatic injury. OBJECTIVE: The objective of this study was to conduct a comprehensive systematic review of alloplastic implant materials utilized in the reconstruction of the external ear stratified by indication, specific implant type, postoperative complications, and aesthetic outcomes. EVIDENCE REVIEW: A comprehensive systematic review of published literature on alloplastic external ear reconstruction data was conducted utilizing Medline/PubMed database without timeframe limitations in June 2019. Articles were stratified by (1) indication (microtia versus trauma reconstruction) and (2) implant material type. All postoperative complications were recorded and comparatively analyzed between implant types. Aesthetic outcomes were also identified and compared between implant types. FINDINGS: A total of 755 patients (14 case series; follow-up range = 3 months--10 years) met the criteria for this study. Overall complication rate was 12.05% across all indications and materials used. The most frequent complications reported were graft exposure (7.8%), graft explantation (1.72%), and wound dehiscence (0.8%). Of the patients requiring graft explantation (n = 13), 7 (53.85%) received Medpor implants, and the other 6 (46.15%) were identified in silicone implants. Infection was only reported in Medpor implants. The overall rate of an acceptable aesthetic outcome was 99.34%. CONCLUSIONS AND RELEVANCE: Alloplastic implants are a reliable means of achieving an acceptable complication profile in external ear reconstruction. While there was an overall high rate of acceptable aesthetic outcomes, the studies evaluated in this systematic review differed in their criteria for final evaluation of aesthetic outcomes.

Allogeneic and Alloplastic Augmentation Grafts in Nipple-Areola Complex Reconstruction: A Systematic Review and Pooled Outcomes Analysis of Complications and Aesthetic Outcomes.

BACKGROUND: With advancements in materials engineering, many plastic surgeons have looked to allogeneic tissue and alloplastic materials as a possible source of structure for long-lasting nipple-areola complex reconstruction. Furthermore, in light of the recent mandate from the Food and Drug Administration restricting the marketing and direct indication of acellular dermal matrices (ADMs) in breast reconstruction, we sought to highlight the overall safety and efficacy demonstrated in the existing literature surrounding all alloplastic materials in nipple-areola complex reconstruction. In this study, the authors conduct a systematic review and pooled outcomes analysis on allogenic and alloplastic implant materials utilized to achieve long-lasting nipple projection stratified by specific material used and respective outcomes. METHODS: A comprehensive systematic review on allogenic and synthetic materials data utilized in nipple reconstruction was conducted utilizing Medline/PubMed database. Articles were stratified by (1) alloplastic material, as well as (2) objective and patient-reported outcomes. RESULTS: A total of 592 nipple-areola complexes on 482 patients were featured in 15 case series. In all studies, alloplastic or allograft material was utilized to achieve and maintain nipple projection. Subjective measurements revealed a patient satisfaction rate of 93.3% or higher with the majority of patients being very satisfied with their reconstruction. The alloplastic and allograft implants analyzed had an overall complication rate of 5.3% across all materials used. The most common complication reported was flap or graft necrosis with a pooled rate of 2.5%. Overall, the Ceratite implant presented with the highest complication rate (18%) including flap/graft necrosis (13%) and extrusion of the artificial bone (5%). Other rigid implants such as the biodesign nipple reconstruction cylinder reported complications of extrusion (3.6%), projection loss requiring revision (2.5%), wound dehiscence/drainage (1.5%), flap or graft necrosis (1.0%) and excessive bleeding (0.5%). ADM implants had reported complications of both insufficient projection (0.8%) and excessive projection (1.6%), which required surgical revision. Injectable materials had minimal reported complications of pain during injection (0.8%) with Radiesse and a false-positive PET scan result (0.8%) with DermaLive. CONCLUSIONS: Allogeneic and alloplastic grafts are a reliable means of achieving satisfactory nipple projection, with a relatively low overall complication profile. The use of Ceratite (artificial bone) led to the highest complication rates. Further clinical studies are necessary to better understand the feasibility and longer-term outcomes of the use of allogeneic and synthetic augmentation grafts to improve nipple projection. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Functioning Free Muscle Transfer for Brachial Plexus Injury: A Systematic Review and Pooled Analysis Comparing Functional Outcomes of Intercostal Nerve and Spinal Accessory Nerve Grafts.

BACKGROUND: The aim of this study was to compare postoperative elbow flexion outcomes in patients receiving functioning free muscle transplantation (FFMT) innervated by either intercostal nerve (ICN) or spinal accessory nerve (SAN) grafts. METHODS: A comprehensive systematic review on FFMT for brachial plexus reconstruction was conducted utilizing Medline/PubMed database. Analysis was designed to compare functional outcomes between (1) nerve graft type (ICN vs. SAN) and (2) different free muscle graft types to biceps tendon (gracilis vs. rectus femoris vs. latissimus dorsi). RESULTS: A total of 312 FFMTs innervated by ICNs (169) or the SAN (143) are featured in 10 case series. The mean patient age was 28 years. Patients had a mean injury to surgery time of 31.5 months and an average follow-up time of 39.1 months with 18 patients lost to follow-up. Muscles utilized included the gracilis (275), rectus femoris (28), and latissimus dorsi (8). After excluding those lost to follow-up or failures due to vascular compromise, the mean success rates of FFMTs innervated by ICNs and SAN were 64.1 and 65.4%, respectively. CONCLUSION: This analysis did not identify any difference in outcomes between FFMTs via ICN grafts and those innervated by SAN grafts in restoring elbow flexion in traumatic brachial plexus injury patients.

Wound healing and fibrosis: current stem cell therapies.

Scarring is a result of the wound healing response and causes tissue dysfunction after injury. This process is readily evident in the skin, but also occurs internally across organ systems in the form of fibrosis. Stem cells are crucial to the innate tissue healing response and, as such, present a possible modality to therapeutically promote regenerative healing while minimizing scaring. In this review, the cellular basis of scaring and fibrosis is examined. Current stem cell therapies under exploration for skin wound healing and internal organ fibrosis are discussed. While most therapeutic approaches rely on the direct application of progenitor-type cells to injured tissue to promote healing, novel strategies to manipulate the scarring response are also presented. As our understanding of developmental and stem cell biology continues to increase, therapies to encourage regeneration of healthy functional tissue after damage secondary to injury or disease will continue to expand.

Macrophage Transplantation Fails to Improve Repair of Critical-Sized Calvarial Defects.

INTRODUCTION: Over 500,000 bone grafting procedures are performed every year in the United States for neoplastic and traumatic lesions of the craniofacial skeleton, costing $585 million in medical care. Current bone grafting procedures are limited, and full-thickness critical-sized defects (CSDs) of the adult human skull thus pose a substantial reconstructive challenge for the craniofacial surgeon. Cell-based strategies have been shown to safely and efficaciously accelerate the rate of bone formation in CSDs in animals. The authors recently demonstrated that supraphysiological transplantation of macrophages seeded in pullalan-collagen composite hydrogels significantly accelerated wound healing in wild type and diabetic mice, an effect mediated in part by enhancing angiogenesis. In this study, the authors investigated the bone healing effects of macrophage transplantation into CSDs of mice. METHODS: CD1 athymic nude mice (60 days of age) were anesthetized, and unilateral full-thickness critical-sized (4 mm in diameter) cranial defects were created in the right parietal bone, avoiding cranial sutures. Macrophages were isolated from FVB-L2G mice and seeded onto hydroxyapatite-poly (lactic-co-glycolic acid) (HA-PLGA) scaffolds (1.0 × 10 cells per CSD). Scaffolds were incubated for 24 hours before they were placed into the CSDs. Macrophage survival was assessed using three-dimensional in vivo imaging system (3D IVIS)/micro-CT. Micro-CT at 0, 2, 4, 6, and 8 weeks was performed to evaluate gross bone formation, which was quantified using Adobe Photoshop. Microscopic evidence of bone regeneration was assessed at 8 weeks by histology. Bone formation and macrophage survival were compared at each time point using independent samples t tests. RESULTS: Transplantation of macrophages at supraphysiological concentration had no effect on the formation of bones in CSDs as assessed by either micro-CT data at any time point analyzed (all P > 0.05). These results were corroborated by histology. 3D IVIS/micro-CT demonstrated survival of macrophages through 8 weeks. CONCLUSION: Supraphysiologic delivery of macrophages to CSDs of mice had no effect on bone formation despite survival of transplanted macrophages through to 8 weeks posttransplantation. Further research into the physiological effects of macrophages on bone regeneration is needed to assess whether recapitulation of these conditions in macrophage-based therapy can promote the healing of large cranial defects.

Alloplastic Facial Implants: A Systematic Review and Meta-Analysis on Outcomes and Uses in Aesthetic and Reconstructive Plastic Surgery.

BACKGROUND: Alloplastic materials in facial surgery have been used successfully for various applications in the reconstructive restoration or aesthetic augmentation of the facial skeleton. The objective of this study was to conduct a comprehensive systematic review of alloplastic implant materials utilized to augment the facial skeleton stratified by anatomical distribution, indication, specific material used, and respective outcomes. METHODS: A comprehensive systematic review on alloplastic facial implant data was conducted utilizing Medline/PubMed database. Articles were stratified by (1) anatomic localization in the face, as well as (2) alloplastic material. RESULTS: A total of 17 studies (n = 2100 patients, follow-up range = 1 month-27 years) were included. Overall, mersilene mesh implants were associated with the highest risk of infection (3.38%). Methyl methacrylate implants were associated with the highest rate of hematoma (5.98%). Implants placed in the malar region (2.67%) and frontal bones (2.50%) were associated with the highest rates of infection. Implants placed in the periorbital region were associated with the highest rate of inflammation (8.0%), explantation (8.0%), and poor cosmetic outcome (17.0%). Porous implants were shown to be more likely to potentiate infection than non-porous implant types. CONCLUSIONS: Alloplastic facial implants are a reliable means of restoring facial symmetry and achieving facial skeletal augmentation with a relatively low complication profile. It is important for plastic surgeons to understand the relative risks for each type of implant to develop postoperative complications or poor long-term cosmetic results. Interestingly, porous implants were shown to be more likely to potentiate infection than non-porous implant types. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Local Pro- and Anti-Coagulation Therapy in the Plastic Surgical Patient: A Literature Review of the Evidence and Clinical Applications.

The risks of systemic anti-coagulation or its reversal are well known but accepted as necessary under certain circumstances. However, particularly in the plastic surgical patient, systemic alteration to hemostasis is often unnecessary when local therapy could provide the needed adjustments. The aim of this review was to provide a summarized overview of the clinical applications of topical anti- and pro-coagulant therapy in plastic and reconstructive surgery. While not a robust field as of yet, local tranexamic acid (TXA) has shown promise in achieving hemostasis under various circumstances, hemostats are widely used to halt bleeding, and local anticoagulants such as heparin can improve flap survival. The main challenge to the advancement of local therapy is drug delivery. However, with increasingly promising innovations underway, the field will hopefully expand to the betterment of patient care.

Cell-Assisted Lipotransfer Improves Volume Retention in Irradiated Recipient Sites and Rescues Radiation-Induced Skin Changes.

Radiation therapy is not only a mainstay in the treatment of many malignancies but also results in collateral obliteration of microvasculature and dermal/subcutaneous fibrosis. Soft tissue reconstruction of hypovascular, irradiated recipient sites through fat grafting remains challenging; however, a coincident improvement in surrounding skin quality has been noted. Cell-assisted lipotransfer (CAL), the enrichment of fat with additional adipose-derived stem cells (ASCs) from the stromal vascular fraction, has been shown to improve fat volume retention, and enhanced outcomes may also be achieved with CAL at irradiated sites. Supplementing fat grafts with additional ASCs may also augment the regenerative effect on radiation-damaged skin. In this study, we demonstrate the ability for CAL to enhance fat graft volume retention when placed beneath the irradiated scalps of immunocompromised mice. Histologic metrics of fat graft survival were also appreciated, with improved structural qualities and vascularity. Finally, rehabilitation of radiation-induced soft tissue changes were also noted, as enhanced amelioration of dermal thickness, collagen content, skin vascularity, and biomechanical measures were all observed with CAL compared to unsupplemented fat grafts. Supplementation of fat grafts with ASCs therefore shows promise for reconstruction of complex soft tissue defects following adjuvant radiotherapy.

Ultrasound-assisted liposuction provides a source for functional adipose-derived stromal cells.

BACKGROUND AIMS: Regenerative medicine employs human mesenchymal stromal cells (MSCs) for their multi-lineage plasticity and their pro-regenerative cytokine secretome. Adipose-derived mesenchymal stromal cells (ASCs) are concentrated in fat tissue, and the ease of harvest via liposuction makes them a particularly interesting cell source. However, there are various liposuction methods, and few have been assessed regarding their impact on ASC functionality. Here we study the impact of the two most popular ultrasound-assisted liposuction (UAL) devices currently in clinical use, VASER (Solta Medical) and Lysonix 3000 (Mentor) on ASCs. METHODS: After lipoaspirate harvest and processing, we sorted for ASCs using fluorescent-assisted cell sorting based on an established surface marker profile (CD34+CD31-CD45-). ASC yield, viability, osteogenic and adipogenic differentiation capacity and in vivo regenerative performance were assessed. RESULTS: Both UAL samples demonstrated equivalent ASC yield and viability. VASER UAL ASCs showed higher osteogenic and adipogenic marker expression, but a comparable differentiation capacity was observed. Soft tissue healing and neovascularization were significantly enhanced via both UAL-derived ASCs in vivo, and there was no significant difference between the cell therapy groups. CONCLUSIONS: Taken together, our data suggest that UAL allows safe and efficient harvesting of the mesenchymal stromal cellular fraction of adipose tissue and that cells harvested via this approach are suitable for cell therapy and tissue engineering applications.

Suction assisted liposuction does not impair the regenerative potential of adipose derived stem cells.

BACKGROUND: Adipose-derived stem cells (ASCs) have been identified as a population of multipotent cells with promising applications in tissue engineering and regenerative medicine. ASCs are abundant in fat tissue, which can be safely harvested through the minimally invasive procedure of liposuction. However, there exist a variety of different harvesting methods, with unclear impact on ASC regenerative potential. The aim of this study was thus to compare the functionality of ASCs derived from the common technique of suction-assisted lipoaspiration (SAL) versus resection. METHODS: Human adipose tissue was obtained from paired abdominoplasty and SAL samples from three female donors, and was processed to isolate the stromal vascular fraction. Fluorescence-activated cell sorting was used to determine ASC yield, and cell viability was assayed. Adipogenic and osteogenic differentiation capacity were assessed in vitro using phenotypic staining and quantification of gene expression. Finally, ASCs were applied in an in vivo model of tissue repair to evaluate their regenerative potential. RESULTS: SAL specimens provided significantly fewer ASCs when compared to excised fat tissue, however, with equivalent viability. SAL-derived ASCs demonstrated greater expression of the adipogenic markers FABP-4 and LPL, although this did not result in a difference in adipogenic differentiation. There were no differences detected in osteogenic differentiation capacity as measured by alkaline phosphatase, mineralization or osteogenic gene expression. Both SAL- and resection-derived ASCs enhanced significantly cutaneous healing and vascularization in vivo, with no significant difference between the two groups. CONCLUSION: SAL provides viable ASCs with full capacity for multi-lineage differentiation and tissue regeneration, and is an effective method of obtaining ASCs for cell-based therapies.

Scarless wound healing: finding the right cells and signals.

From the moment we are born, every injury to the skin has the potential to form a scar, many of which can impair form and/or function. As such, scar management constitutes a billion-dollar industry. However, effectively promoting scarless wound healing remains an elusive goal. The complex interactions of wound healing contribute to our inability to recapitulate scarless wound repair as it occurs in nature, such as in fetal skin and the oral mucosa. However, many new advances have occurred in recent years, some of which have translated scientific findings from bench to bedside. In vivo lineage tracing has helped establish a variety of novel cellular culprits that may act as key drivers of the fibrotic response. These newly characterized cell populations present further targets for therapeutic intervention, some of which have previously demonstrated promising results in animal models. Here, we discuss several recent studies that identify exciting approaches for diminishing scar formation. Particular attention will also be paid to the canonical Wnt/ß-catenin signaling pathway, which plays an important role in both embryogenesis and tissue repair. New insights into the differential effects of Wnt signaling on heterogeneous fibroblast and keratinocyte populations within the skin further demonstrate methods by which wound healing can be re-directed to a more fetal scarless phenotype. Graphical abstract Recent approaches to reducing scar formation. Representation showing novel scientific approaches for decreasing scar formation, including the targeting of pro-fibrotic cell populations based on surface molecule expression (e.g. DPP4(+) fibroblasts, ADAM12(+) pericytes). Modulation of cellular mechanotransduction pathways are another means to reduce scar formation, both at the molecular level or, macroscopically with dressings designed to offload tension, at cutaneous wound sites (ADAM12 a disintegrin and metalloprotease 12, DPP4 dipeptidyl peptidase-4, FAK focal adhesion kinase).

Emerging drugs for the treatment of wound healing.

INTRODUCTION: Wound healing can be characterized as underhealing, as in the setting of chronic wounds, or overhealing, occurring with hypertrophic scar formation after burn injury. Topical therapies targeting specific biochemical and molecular pathways represent a promising avenue for improving and, in some cases normalizing, the healing process. AREAS COVERED: A brief overview of both normal and pathological wound healing has been provided, along with a review of the current clinical guidelines and treatment modalities for chronic wounds, burn wounds and scar formation. Next, the major avenues for wound healing drugs, along with drugs currently in development, are discussed. Finally, potential challenges to further drug development, and future research directions are discussed. EXPERT OPINION: The large body of research concerning wound healing pathophysiology has provided multiple targets for topical therapies. Growth factor therapies with the ability to be targeted for localized release in the wound microenvironment are most promising, particularly when they modulate processes in the proliferative phase of wound healing.

Nanotechnology in bone tissue engineering.

Nanotechnology represents a major frontier with potential to significantly advance the field of bone tissue engineering. Current limitations in regenerative strategies include impaired cellular proliferation and differentiation, insufficient mechanical strength of scaffolds, and inadequate production of extrinsic factors necessary for efficient osteogenesis. Here we review several major areas of research in nanotechnology with potential implications in bone regeneration: 1) nanoparticle-based methods for delivery of bioactive molecules, growth factors, and genetic material, 2) nanoparticle-mediated cell labeling and targeting, and 3) nano-based scaffold construction and modification to enhance physicochemical interactions, biocompatibility, mechanical stability, and cellular attachment/survival. As these technologies continue to evolve, ultimate translation to the clinical environment may allow for improved therapeutic outcomes in patients with large bone deficits and osteodegenerative diseases. FROM THE CLINICAL EDITOR: Traditionally, the reconstruction of bony defects has relied on the use of bone grafts. With advances in nanotechnology, there has been significant development of synthetic biomaterials. In this article, the authors provided a comprehensive review on current research in nanoparticle-based therapies for bone tissue engineering, which should be useful reading for clinicians as well as researchers in this field.

Gene expression in fetal murine keratinocytes and fibroblasts.

BACKGROUND: Early fetuses heal wounds without the formation of a scar. Many studies have attempted to explain this remarkable phenomenon. However, the exact mechanism remains unknown. Herein, we examine the predominant cell types of the epidermis and dermis--the keratinocyte and fibroblast--during different stages of fetal development to better understand the changes that lead to scarring wound repair versus regeneration. MATERIALS AND METHODS: Keratinocytes and fibroblasts were harvested and cultured from the dorsal skin of time-dated BALB/c fetuses. Total RNA was isolated and microarray analysis was performed using chips with 42,000 genes. Significance analysis of microarrays was used to select genes with >2-fold expression differences with a false discovery rate<2. Enrichment analysis was performed on significant genes to identify differentially expressed pathways. RESULTS: By comparing the gene expression profile of keratinocytes from E16 versus E18 fetuses, we identified 24 genes that were downregulated at E16. Analysis of E16 and E18 fibroblasts revealed 522 differentially expressed genes. Enrichment analysis showed the top 20 signaling pathways that were downregulated in E16 keratinocytes and upregulated or downregulated in E16 fibroblasts. CONCLUSIONS: Our data reveal 546 differentially expressed genes in keratinocytes and fibroblasts between the scarless and scarring transition. In addition, a total of 60 signaling pathways have been identified to be either upregulated or downregulated in these cell types. The genes and pathways recognized by our study may prove to be essential targets that may discriminate between fetal wound regeneration and adult wound repair.

Disrupting biological sensors of force promotes tissue regeneration in large organisms.

Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

A single-center blinded randomized clinical trial to evaluate the anti-aging effects of a novel HSF™-based skin care formulation.

BACKGROUND: Similar to chronic wounds, skin aging is characterized by dysfunction of key cellular regulatory pathways. The hypoxia-inducible factor-1 alpha (HIF-1α) pathway was linked to both conditions. Recent evidence suggests that modulating this pathway can rejuvenate aged fibroblasts and improve skin regeneration. Here, we describe the application of a novel HIF stimulating factor (HSF™)-based formulation for skin rejuvenation. METHODS: Over a period of 6 weeks using a split-face study design, the effects on skin surface profile, skin moisture, and transepidermal water loss were determined in 32 female subjects (mean age 54, range 32-67 years) by Fast Optical in vivo Topometry of Human Skin (FOITSHD ), Corneometer, and Tewameter measurements. In addition, a photo documentation was performed for assessment by an expert panel and a survey regarding subject satisfaction was conducted. RESULTS: No negative skin reactions of dermatological relevance were documented for the test product. A significant reduction in skin roughness could be demonstrated. The clinical evaluation of the images using a validated method confirmed significant improvement of wrinkles, in particular of fine wrinkles, lip wrinkles, and crow's feet. A significant skin moisturizing effect was detected while skin barrier function was preserved. The HSF™-based skin care formulation resulted in a self-reported 94% satisfaction rate. CONCLUSION: With no negative skin reactions and highly significant effects on skin roughness, wrinkles, and moisturization, the HSF™-based skin care formulation achieved very satisfying outcomes in this clinical trial. Given the favorable results, this approach represents a promising innovation in aesthetic and regenerative medicine.