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Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients., Abdominal adhesions are a common cause of bowel obstruction, but knowledge regarding adhesion biology and anti-adhesion therapies remains limited. Here the authors report a systematic analysis of mouse and human adhesion tissues demonstrating that visceral fibroblast JUN and associated PDGFRA expression promote adhesions, and JUN suppression can prevent adhesion formation.

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.

Significance In the skin, tissue injury results in fibrosis in the form of a scar composed of dense extracellular matrix deposited by fibroblasts. Therapies that promote tissue regeneration rather than fibrosis remain elusive because principles of fibroblast programming and response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the study of cell populations in complex tissue, which has allowed us to characterize wound healing fibroblasts across both time and space. We identify functionally distinct fibroblast subpopulations and track cell fate during the response to wounding. We demonstrate that populations of fibroblasts migrate, proliferate, and differentiate in an adaptive response to disruption of their environment. These results illustrate fundamental principles underlying the cellular response to tissue injury., 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.

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., Humans and other large mammals heal wounds by forming fibrotic scar tissue with diminished function. Here, the authors show that disrupting mechanotransduction through the focal adhesion kinase pathway in large animals accelerates healing, prevents fibrosis, and enhances skin regeneration.

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.

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. 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. 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. 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. 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.

Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1α) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery. We recently published a preclinical proof of concept drug delivery system (TDDS) which showed that transdermally applied DFO is effective in improving chronic wound healing. Here we present an enhanced TDDS (eTDDS) comprised exclusively of FDA-compliant constituents to optimize drug release and expedite clinical translation. We evaluate the eTDDS to the original TDDS and compare this with other commonly used delivery methods including DFO drip-on and polymer spray applications. The eTDDS displayed excellent physicochemical characteristics and markedly improved DFO delivery into human skin when compared to other topical application techniques. We demonstrate an accelerated wound healing response with the eTDDS treatment resulting in significantly increased wound vascularity, dermal thickness, collagen deposition and tensile strength. Together, these findings highlight the immediate clinical potential of DFO eTDDS to treating diabetic wounds. Further, the topical drug delivery platform has important implications for targeted pharmacologic therapy of a wide range of cutaneous diseases.

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. 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. 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. 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. 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 .

In diabetes, stromal cell-derived factor-1 (SDF-1) expression and progenitor cell recruitment are reduced. Dipeptidyl peptidase-4 (DPP-4) inhibits SDF-1 expression and progenitor cell recruitment. Here we examined the impact of the DPP-4 inhibitor, MK0626, on progenitor cell kinetics in the context of wound healing. Wildtype (WT) murine fibroblasts cultured under high-glucose to reproduce a diabetic microenvironment were exposed to MK0626, glipizide, or no treatment, and SDF-1 expression was measured with ELISA. Diabetic mice received MK0626, glipizide, or no treatment for 6 weeks and then were wounded. Immunohistochemistry was used to quantify neovascularization and SDF-1 expression. Gene expression was measured at the RNA and protein level using quantitative polymerase chain reaction and ELISA, respectively. Flow cytometry was used to characterize bone marrow-derived mesenchymal progenitor cell (BM-MPC) population recruitment to wounds. BM-MPC gene expression was assayed using microfluidic single cell analysis. WT murine fibroblasts exposed to MK0626 demonstrated increased SDF-1 expression. MK0626 treatment significantly accelerated wound healing and increased wound vascularity, SDF-1 expression, and dermal thickness in diabetic wounds. MK0626 treatment increased the number of BM-MPCs present in bone marrow and in diabetic wounds. MK0626 had no effect on BM-MPC population dynamics. BM-MPCs harvested from MK0626-treated mice exhibited increased chemotaxis in response to SDF-1 when compared to diabetic controls. Treatment with a DPP-4 inhibitor significantly improved wound healing, angiogenesis, and endogenous progenitor cell recruitment in the setting of diabetes.

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 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 define the mechanisms controlling cell fate during migration, proliferation, and differentiation following tissue 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.

CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1 [SDF-1]), primarily known for its role in embryogenesis and hematopoiesis, has also been implicated in tumor biology and neovascularization. However, its specific role and mechanism of action remain poorly understood. We previously demonstrated that CXCL12 expression is Hypoxia-Inducible Factor (HIF)-1 responsive. Here we use a conditional CXCL12 knockout mouse to show that endothelial-specific deletion of CXCL12 (eKO) does not affect embryogenesis, but reduces the survival of ischemic tissue, altering tissue repair and tumor progression. Loss of vascular endothelial CXCL12 disrupts endothelial – fibroblast crosstalk necessary for stromal growth and vascularization. Single-cell gene expression analysis in combination with a parabiosis model reveals a specific population of non-inflammatory circulating cells, defined by genes regulating neovascularization, which is recruited by endothelial CXCL12. These findings indicate an essential role for endothelial CXCL12 expression during the adult neovascular response in tissue injury and tumor progression.

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.

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.

CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1 [SDF-1]), primarily known for its role in embryogenesis and hematopoiesis, has also been implicated in tumor biology and neovascularization. However, its specific role and mechanism of action remain poorly understood. We previously demonstrated that CXCL12 expression is Hypoxia-Inducible Factor (HIF)-1 responsive. Here we use a conditional CXCL12 knockout mouse to show that endothelial-specific deletion of CXCL12 (eKO) does not affect embryogenesis, but reduces the survival of ischemic tissue, altering tissue repair and tumor progression. Loss of vascular endothelial CXCL12 disrupts endothelial – fibroblast crosstalk necessary for stromal growth and vascularization. Single-cell gene expression analysis in combination with a parabiosis model reveals a specific population of non-inflammatory circulating cells, defined by genes regulating neovascularization, which is recruited by endothelial CXCL12. These findings indicate an essential role for endothelial CXCL12 expression during the adult neovascular response in tissue injury and tumor progression.

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.

Background:Acute wound healing is a dynamic process that results in the formation of scar tissue. The mechanisms of this process are not well understood; numerous signaling pathways are thought to play a major role. Here, the authors have identified β-catenin–dependent Wnt signaling as an early acut

Significance: Scarring of the skin from burns, surgery, and injury constitutes a major burden on the healthcare system. Patients affected by major scars, particularly children, suffer from long-term functional and psychological problems. Recent Advances: Scarring in humans is the end result of the wound healing process, which has evolved to rapidly repair injuries. Wound healing and scar formation are well described on the cellular and molecular levels, but truly effective molecular or cell-based antiscarring treatments still do not exist. Recent discoveries have clarified the role of skin stem cells and fibroblasts in the regeneration of injuries and formation of scar. Critical Issues: It will be important to show that new advances in the stem cell and fibroblast biology of scarring can be translated into therapies that prevent and reduce scarring in humans without major side effects. Future Directions: Novel therapies involving the use of purified human cells as well as agents that target specific cells...

Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the wound environment enable us to target mechanical forces to minimize scar formation. Fetal wounds experience much lower resting stress when compared with adult wounds, and they heal without scars. Therapies that modulate mechanical forces in the wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless-type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance adult wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed.

Cutaneous wound repair is a highly coordinated cascade of cellular responses to injury which restores the epidermal integrity and its barrier functions. Even under optimal healing conditions, normal wound repair of adult human skin is imperfect and delayed healing and scarring are frequent occurrences. Dysregulated wound healing is a major concern for global healthcare, and, given the rise in diabetic and aging populations, this medicoeconomic disease burden will continue to rise. Therapies to reliably improve nonhealing wounds and reduce scarring are currently unavailable. Mesenchymal stromal cells (MSCs) have emerged as a powerful technique to improve skin wound healing. Their differentiation potential, ease of harvest, low immunogenicity, and integral role in native wound healing physiology make MSCs an attractive therapeutic remedy. MSCs promote cell migration, angiogenesis, epithelialization, and granulation tissue formation, which result in accelerated wound closure. MSCs encourage a regenerative, rather than fibrotic, wound healing microenvironment. Recent translational research efforts using modern bioengineering approaches have made progress in creating novel techniques for stromal cell delivery into healing wounds. This paper discusses experimental applications of various stromal cells to promote wound healing and discusses the novel methods used to increase MSC delivery and efficacy.

Objective: Fetuses early in gestation heal skin wounds without forming scars. The biological mechanisms behind this process are largely unknown. Fibroblasts, however, are cells known to be intimately involved in wound healing and scar formation. We examined fibroblasts in different stages of development to characterize differences in gene expression that may result in the switch from regenerative wound repair to repair with scarring.

BACKGROUND Cell therapy with mesenchymal stromal cells is a promising strategy for tissue repair. Restoration of blood flow to ischemic tissues is a key step in wound repair, and mesenchymal stromal cells have been shown to be proangiogenic. Angiogenesis is critically regulated by the hypoxia-inducible factor (HIF) superfamily, consisting of transcription factors targeted for degradation by prolyl hydroxylase domain (PHD)-2. The aim of this study was to enhance the proangiogenic capability of mesenchymal stromal cells and to use these modified cells to promote wound healing. METHODS Mesenchymal stromal cells harvested from mouse bone marrow were transduced with short hairpin RNA (shRNA) against PHD-2; control cells were transduced with scrambled shRNA (shScramble) construct. Gene expression quantification, human umbilical vein endothelial cell tube formation assays, and wound healing assays were used to assess the effect of PHD knockdown mesenchymal stromal cells on wound healing dynamics. RESULTS PHD-2 knockdown mesenchymal stromal cells overexpressed HIF-1α and multiple angiogenic factors compared to control (p < 0.05). Human umbilical vein endothelial cells treated with conditioned medium from PHD-2 knockdown mesenchymal stromal cells exhibited increased formation of capillary-like structures and enhanced migration compared with human umbilical vein endothelial cells treated with conditioned medium from shScramble-transduced mesenchymal stromal cells (p < 0.05). Wounds treated with PHD-2 knockdown mesenchymal stromal cells healed at a significantly accelerated rate compared with wounds treated with shScramble mesenchymal stromal cells (p < 0.05). Histologic studies revealed increased blood vessel density and increased cellularity in the wounds treated with PHD-2 knockdown mesenchymal stromal cells (p < 0.05). CONCLUSIONS Silencing PHD-2 in mesenchymal stromal cells augments their proangiogenic potential in wound healing therapy. This effect appears to be mediated by overexpression of HIF family transcription factors and up-regulation of multiple downstream angiogenic factors.

Hand injuries often result in significant functional impairments and are rarely completely restored. The spontaneous regeneration of injured appendages, which occurs in salamanders and newts, for example, has been reported in human fingertips after distal amputation, but this type of regeneration is rare in mammals and is incompletely understood. Here, we study fingertip regeneration by amputating murine digit tips, either distally to initiate regeneration, or proximally, causing fibrosis. Using an unbiased microarray analysis, we found that digit tip regeneration is significantly associated with hair follicle differentiation, Wnt, and sonic hedgehog (SHH) signaling pathways. Viral over-expression and genetic knockouts showed the functional significance of these pathways during regeneration. Using transgenic reporter mice, we demonstrated that, while both canonical Wnt and HH signaling were limited to epidermal tissues, downstream hedgehog signaling (through Gli) occurred in mesenchymal tissues. These findings reveal a mechanism for epidermal/mesenchyme interactions, governed by canonical hedgehog signaling, during digit regeneration. Further research into these pathways could lead to improved therapeutic outcomes after hand injuries in humans.

Chronic Granulomatous Disease (CGD) is a rare, inherited disorder due to an X-linked or autosomal genetic defect, in which patients experience a high rate of lymphadenitis. To date, no studies have examined the best treatment for severe lymphadenitis in this patient population. We present a nine CGD patient retrospective case series, examining surgical treatment of cervical lymphadenitis. Our evolving surgical strategy shows that an initially more aggressive surgical approach (selective neck dissection) can help prevent recurrent infection. The results found within this patient population may be relevant to other multi-nodal disease, including cancers of the head and neck region, while preserving functional and cosmetically acceptable outcomes. This article is protected by copyright. All rights reserved.

Background:A hallmark of diabetes mellitus is the breakdown of almost every reparative process in the human body, leading to critical impairments of wound healing. Stabilization and activity of the transcription factor hypoxia-inducible factor (HIF)-1α is impaired in diabetes, leading to deficits in

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.

Summary Introduction Diabetes mellitus remains a significant public health problem, consuming over $400 billion every year. While Diabetes itself can be controlled effectively, impaired wound healing still occurs frequently in diabetic patients. Adipose-derived mesenchymal stem cells (ASCs) provide an especially appealing source for diabetic wound cell therapy. With autologous approaches, the functionality of ASCs largely underlie patient-dependent factors. Diabetes is a significant diminishing factor of MSC functionality. Here, we explore a novel strategy to enhance diabetic ASC functionality through deferoxamine (DFO) preconditioning. Material and Methods Human diabetic ASCs have been preconditioned with 150 µM and 300 µM DFO in vitro and analyzed for regenerative cytokine expression. Murine diabetic ASCs have been preconditioned with 150 µM DFO examined for their in vitro and in vivo vasculogenic capacity in Matrigel assays. Additionally, a diabetic murine wound healing model has been performed to assess the regenerative capacity of preconditioned cells. Results DFO preconditioning enhances the VEGF expression of human diabetic ASCs through hypoxia-inducible factor upregulation. The use of 150 µM of DFO was an optimal concentration to induce regenerative effects. The vasculogenic potential of preconditioned diabetic ASCs is significantly greater in vitro and in vivo. The enhanced regenerative functionality of DFO preconditioned ASCs was further confirmed in a model of diabetic murine wound healing. Conclusion These results demonstrate that DFO significantly induced the upregulation of hypoxia-inducible factor-1 alpha and VEGF in diabetic ASCs and showed efficacy in the treatment of diabetes-associated deficits of wound healing. The favorable status of DFO as a small molecule drug approved since decades for multiple indications makes this approach highly translatable.

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.

Sanativo is an over-the-counter Brazilian product derived from Amazon rainforest plant extract that is purported to improve the healing of skin wounds. Two experimental studies have shown accelerated closure of nonsplinted excisional wounds in rat models. However, these models allow for significant contraction of the wound and do not approximate healing in the tight skin of humans.Full-thickness excisional wounds were created on the dorsal skin of mice and were splinted with silicone rings, a model that forces the wound to heal by granulation and reepithelialization. Sanativo or a control solution was applied either daily or every other day to the wounds. Photographs were taken every other day, and the degree of reepithelialization of the wounds was determined.With both daily and every-other-day applications, Sanativo delayed reepithelialization of the wounds. Average time to complete healing was faster with control solution versus Sanativo in the daily application group (9.4 versus 15.2 days; p0.0001) and the every-other-day application group (11 versus 13 days; p = 0.017). The size of visible scar at the last time point of the study was not significantly different between the groups, and no differences were found on histologic examination.Sanativo wound healing compound delayed wound reepithelialization in a mouse splinted excisional wound model that approximates human wound healing. The size of visible scar after complete healing was not improved with the application of Sanativo. These results should cast doubt on claims that this product can improve wound healing in humans.

Surgical manipulation of skin may result in undesired puckering of excess tissue, which is generally assumed to settle over time. In this article, the authors address the novel question of how this excess tissue remodels.Purse-string sutures (6-0 nylon) were placed at the midline dorsum of 22 wild-type BALB/c mice in a circular pattern marked with tattoo ink. Sutures were cinched and tied under tension in the treatment group, creating an excess tissue deformity, whereas control group sutures were tied without tension. After 2 or 4 weeks, sutures were removed. The area of tattooed skin was measured up to 56 days after suture removal. Histologic analysis was performed on samples harvested 14 days after suture removal.The majority of excess tissue deformities flattened within 2 days after suture removal. However, the sutured skin in the treatment group decreased in area by an average of 18 percent from baseline (n = 9), compared to a 1 percent increase in the control group (n = 10) at 14 days after suture removal (p0.05). This was similarly observed at 28 days (treatment, -11.7 percent; control, 4.5 percent; n = 5; p = 0.0243). Despite flattening, deformation with purse-string suture correlated with increased collagen content of skin, in addition to increased numbers of myofibroblasts. Change in area did not correlate with duration of suture placement.Excess dermal tissue deformities demonstrate the ability to remodel with gross flattening of the skin, increased collagen deposition, and incomplete reexpansion to baseline area. Further studies will reveal whether our findings in this mouse model translate to humans.

Scarring and fibrosis are an enormous public health concern, resulting in excessive morbidity and mortality in addition to countless lost health care dollars. Recent advances in cell and developmental biology promise a better understanding of scarring and fibrosis and may translate to new clinical therapies.

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/β-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).

Bone has the capacity to regenerate and repair itself. However, this capacity may be impaired or lost depending on the size of the defect or the presence of certain disease states. In this review, we discuss the key principles underlying bone healing, efforts to characterize bone stem and progenitor cell populations, and the current status of translational and clinical studies in cell-based bone tissue engineering. Though barriers to clinical implementation still exist, the application of stem and progenitor cell populations to bone engineering strategies has the potential to profoundly impact regenerative medicine.

A new group of blood-derived CD34+ progenitor cells (BDPCs) with the ability to expand and differentiate into functional hepatocyte-like cells and promote liver regeneration is reported. With their ease of access, application through the peripheral blood, and the capability of rapid expansion and hepatic differentiation, BDPCs have great potential as a cell-based therapy for liver disease., The low availability of functional hepatocytes has been an unmet demand for basic scientific research, new drug development, and cell-based clinical applications for decades. Because of the inability to expand hepatocytes in vitro, alternative sources of hepatocytes are a focus of liver regenerative medicine. We report a new group of blood-derived CD34+ progenitor cells (BDPCs) that have the ability to expand and differentiate into functional hepatocyte-like cells and promote liver regeneration. BDPCs were obtained from the peripheral blood of an adult mouse with expression of surface markers CD34, CD45, Sca-1, c-kit, and Thy1.1. BDPCs can proliferate in vitro and differentiate into hepatocyte-like cells expressing hepatocyte markers, including CK8, CK18, CK19, α-fetoprotein, integrin-β1, and A6. The differentiated BDPCs (dBDPCs) also display liver-specific functional activities, such as glycogen storage, urea production, and albumin secretion. dBDPCs have cytochrome P450 activity and express specific hepatic transcription factors, such as hepatic nuclear factor 1α. To demonstrate liver regenerative activity, dBDPCs were injected into mice with severe acute liver damage caused by a high-dose injection of carbon tetrachloride (CCl4). dBDPC treatment rescued the mice from severe acute liver injury, increased survival, and induced liver regeneration. Because of their ease of access and application through peripheral blood and their capability of rapid expansion and hepatic differentiation, BDPCs have great potential as a cell-based therapy for liver disease. Significance Hematopoietic stem/progenitor cell expansion and tissue-specific differentiation in vitro are challenges in regenerative medicine, although stem cell therapy has raised hope for the treatment of liver diseases by overcoming the scarcity of hepatocytes. This study identified and characterized a group of blood-derived progenitor cells (BDPCs) from the peripheral blood of an adult mouse. The CD34+ progenitor-dominant BDPCs were rapidly expanded and hepatically differentiated into functional hepatocyte-like cells with our established coculture system. BDPC treatment increased animal survival and produced full regeneration in a severe liver injury mouse model caused by CCl4. BDPCs could have potential for liver cell therapies.

The craniofacial region comprises the most complex and intricate anatomical structures in the human body. As a result of developmental defects, traumatic injury, or neoplastic tissue formation, the functional and aesthetic intricacies of the face and cranium are often disrupted. While reconstructive techniques have long been innovated in this field, there are crucial limitations to the surgical restoration of craniomaxillofacial form and function. Fortunately, the rise of regenerative medicine and surgery has expanded the possibilities for patients affected with hard and soft tissue deficits, allowing for the controlled engineering and regeneration of patient-specific defects. In particular, stem cell therapy has emerged in recent years as an adjuvant treatment for the targeted regeneration of craniomaxillofacial structures. This review outlines the current state of the art in stem cell therapies utilized for the engineered restoration and regeneration of skeletal defects in the craniofacial region.

Adult cutaneous wounds repair through a fibroproliferative response which results in a scar. Early-gestation fetal skin has the ability to regenerate damaged skin without the formation of a scar in a process that resembles regeneration. The fetal and adult wound healing phenotypes are characterized by differences in the degree of inflammation, molecular signaling, extracellular matrix composition, and biomechanical properties. Significant advancements in understanding scarless fetal mammalian wound healing have led to the development of therapeutic applications with the potential to reduce scarring in the healing of adult cutaneous wounds. This chapter outlines the molecular and cellular processes involved in scarless fetal wound healing and the progress that has been made in recapitulating this process in adult wounds.

Objective: In early gestation, fetal wounds heal without fibrosis in a process resembling regeneration. Elucidating this remarkable mechanism can result in tremendous benefits to prevent scarring. Fetal mouse cutaneous wounds before embryonic day (E)18 heal without scar. Herein, we analyze expression profiles of fetal and postnatal wounds utilizing updated gene annotations and pathway analysis to further delineate between repair and regeneration.

Acute wound healing is a dynamic process that results in the formation of scar tissue. The mechanisms of this process are not well understood; numerous signaling pathways are thought to play a major role. Here, the authors have identified β-catenin-dependent Wnt signaling as an early acute-phase reactant in acute wound healing and scar formation.The authors created 6-mm full-thickness excisional cutaneous wounds on adult β-catenin-dependent Wnt signal (BAT-gal) reporter mice. The expression of canonical Wnt after wounding was analyzed using X-gal staining and quantitative real-time polymerase chain reaction. Next, recombinant mouse Wnt3a (rmWnt3a) was injected subcutaneously to the wound edge, daily. The mice were killed at stratified time points, up to 15 days after injury. Histologic analysis, quantitative real-time polymerase chain reaction, and Western blot were performed.Numerous individual Wnt ligands increased in expression after wounding, including Wnt3a, Wnt4, Wnt10a, and Wnt11. A specific pattern of Wnt activity was observed, localized to the hair follicle and epidermis. Mice injected with rmWnt3a exhibited faster wound closure, increased scar size, and greater expression of fibroblast growth factor receptor-2 and type I collagen.The authors' data suggest that β-catenin-dependent Wnt signaling expression increases shortly after cutaneous wounding, and exogenous rmWnt3a accelerates reepithelialization, wound matrix maturation, and scar formation. Future experiments will focus on the intersection of Wnt signaling and other known profibrotic cytokines.