Showing papers by "Geoffrey C. Gurtner published in 2020"

Laser Treatment of Traumatic Scars and Contractures: 2020 International Consensus Recommendations.

Abstract: Background and objectives There is currently intense multidisciplinary interest and a maturing body of literature regarding laser treatments for traumatic scars, but international treatment guidelines and reimbursement schemes have not yet caught up with current knowledge and practice in many centers. The authors intend to highlight the tremendous potential of laser techniques, offer recommendations for safe and efficacious treatment, and promote wider patient access guided by future high-quality research. Study design/materials and methods An international panel of 26 dermatologists and plastic and reconstructive surgeons from 13 different countries and a variety of practice backgrounds was self-assembled to develop updated consensus recommendations for the laser treatment of traumatic scars. A three-step modified Delphi method took place between March 2018 and March 2019 consisting of two rounds of emailed questionnaires and supplementary face-to-face meetings. The panel members approved the final manuscript via email correspondence, and the threshold for consensus was at least 80% concurrence among the panel members. Results The manuscript includes extensive detailed discussion regarding a variety of laser platforms commonly used for traumatic scar management such as vascular lasers and ablative and non-ablative fractional lasers, special considerations such as coding and laser treatments in skin of color, and 25 summary consensus recommendations. Conclusions Lasers are a first-line therapy in the management of traumatic scars and contractures, and patients without access to these treatments may not be receiving the best available care after injury. Updated international treatment guidelines and reimbursement schemes, additional high-quality research, and patient access should reflect this status. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Mechanotransduction in Wound Healing and Fibrosis.

Abstract: Skin injury is a common occurrence and mechanical forces are known to significantly impact the biological processes of skin regeneration and wound healing. Immediately following the disruption of the skin, the process of wound healing begins, bringing together numerous cell types to collaborate in several sequential phases. These cells produce a multitude of molecules and initiate multiple signaling pathways that are associated with skin disorders and abnormal wound healing, including hypertrophic scars, keloids, and chronic wounds. Studies have shown that mechanical forces can alter the microenvironment of a healing wound, causing changes in cellular function, motility, and signaling. A better understanding of the mechanobiology of cells in the skin is essential in the development of efficacious therapeutics to reduce skin disorders, normalize abnormal wound healing, and minimize scar formation.

Consensus Conference Statement on the General Use of Near-Infrared Fluorescence Imaging and Indocyanine Green Guided Surgery: Results of a Modified Delphi Study.

Abstract: Fernando Dip, MD, y Luigi Boni, MD,z Michael Bouvet, MD,§ Thomas Carus, MD, Michele Diana, MD,jj Jorge Falco, MD, Geoffrey C. Gurtner, MD,yy Takeaki Ishizawa, MD, PhD,zz Norihiro Kokudo, MD, PhD,zz Emanuele Lo Menzo, MD,y Philip S. Low, PhD,§§ Jaume Masia, MD, Derek Muehrcke, MD,jjjj Francis A. Papay, MD, Carlo Pulitano, MD, PhD,yyy Sylke Schneider-Koraith, MD,zzz Danny Sherwinter, MD,§§§ Giuseppe Spinoglio, MD, Laurents Stassen, MD, PhD,jjjjjj Yasuteru Urano, PhD, Alexander Vahrmeijer, MD, Eric Vibert, MD, PhD,yyyy Jason Warram, MD,zzzz Steven D. Wexner, MD, PhD (Hon),y Kevin White, MD, PhD,§§§§ and Raul J. Rosenthal, MDyY

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

Abstract: 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.

Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice.

Abstract: Human mesenchymal stromal cells (hMSCs) are a promising source for engineered cell-based therapies in which genetic engineering could enhance therapeutic efficacy and install novel cellular functions. Here, we describe an optimized Cas9-AAV6-based genome editing tool platform for site-specific mutagenesis and integration of up to more than 3 kilobases of exogenous DNA in the genome of hMSCs derived from the bone marrow, adipose tissue, and umbilical cord blood without altering their ex vivo characteristics. We generate safe harbor-integrated lines of engineered hMSCs and show that engineered luciferase-expressing hMSCs are transiently active in vivo in wound beds of db/db mice. Moreover, we generate PDGF-BB- and VEGFA-hypersecreting hMSC lines as short-term, local wound healing agents with superior therapeutic efficacy over wildtype hMSCs in the diabetic mouse model without replacing resident cells long-term. This study establishes a precise genetic engineering platform for genetic studies of hMSCs and development of engineered hMSC-based therapies.

Hyperbaric Oxygen Therapy: Descriptive Review of the Technology and Current Application in Chronic Wounds.

Abstract: Hyperbaric oxygen therapy (HBOT) serves as "primary" or "adjunctive" therapy in a wide range of pathologies. It is considered the mainstay of management for potentially life-threatening conditions such as carbon monoxide poisoning, decompression illness, and gas embolisms. Moreover, HBOT has been utilized for decades as an adjunctive therapy in a variety of medical disciplines, including chronic wounds, which affect approximately 6.5 million Americans annually. In general, chronic wounds are characterized by hypoxia, impaired angiogenesis, and prolonged inflammation, all of which may theoretically be ameliorated by HBOT. Nonetheless, the cellular, biochemical, and physiological mechanisms by which HBOT achieves beneficial results in chronic wounds are not fully understood, and there remains significant skepticism regarding its efficacy. This review article provides a comprehensive overview of HBOT, and discusses its history, mechanisms of action, and its implications in management of chronic wounds. In particular, we discuss the current evidence regarding the use of HBOT in diabetic foot ulcers, while digging deeply into the roots of controversy surrounding its efficacy. We discuss how the paucity of high-quality research is a tremendous challenge, and offer future direction to address existing obstacles.

Characterization of Diabetic and Non-Diabetic Foot Ulcers Using Single-Cell RNA-Sequencing

Abstract: Background: Recent advances in high-throughput single-cell sequencing technologies have led to their increasingly widespread adoption for clinical applications. However, challenges associated with tissue viability, cell yield, and delayed time-to-capture have created unique obstacles for data processing. Chronic wounds, in particular, represent some of the most difficult target specimens, due to the significant amount of fibrinous debris, extracellular matrix components, and non-viable cells inherent in tissue routinely obtained from debridement. Methods: Here, we examined the feasibility of single cell RNA sequencing (scRNA-seq) analysis to evaluate human chronic wound samples acquired in the clinic, subjected to prolonged cold ischemia time, and processed without FACS sorting. Wound tissue from human diabetic and non-diabetic plantar foot ulcers were evaluated using an optimized 10X Genomics scRNA-seq platform and analyzed using a modified data pipeline designed for low-yield specimens. Cell subtypes were identified informatically and their distributions and transcriptional programs were compared between diabetic and non-diabetic tissue. Results: 139,000 diabetic and non-diabetic wound cells were delivered for 10X capture after either 90 or 180 min of cold ischemia time. cDNA library concentrations were 858.7 and 364.7 pg/µL, respectively, prior to sequencing. Among all barcoded fragments, we found that 83.5% successfully aligned to the human transcriptome and 68% met the minimum cell viability threshold. The average mitochondrial mRNA fraction was 8.5% for diabetic cells and 6.6% for non-diabetic cells, correlating with differences in cold ischemia time. A total of 384 individual cells were of sufficient quality for subsequent analyses; from this cell pool, we identified transcriptionally-distinct cell clusters whose gene expression profiles corresponded to fibroblasts, keratinocytes, neutrophils, monocytes, and endothelial cells. Fibroblast subpopulations with differing fibrotic potentials were identified, and their distributions were found to be altered in diabetic vs. non-diabetic cells. Conclusions: scRNA-seq of clinical wound samples can be achieved using minor modifications to standard processing protocols and data analysis methods. This simple approach can capture widespread transcriptional differences between diabetic and non-diabetic tissue obtained from matched wound locations.

Wound Center Without Walls: The New Model of Providing Care During the COVID-19 Pandemic

Abstract: The COVID-19 pandemic poses a major challenge in delivering care to wound patients. Due to multiple comorbidities, wound patients are at an increased risk for the most extreme complications of COVID-19 and providers must focus on reducing their exposure risk. The Federal, State, and local governments, as well as payers, have urged hospitals and providers to reduce utilization of nonessential health services, but they also have given more flexibility to shift the site of necessary care to lower risk environments. Providers must be prepared for disruption from this pandemic mode of health care for the next 18 months, at minimum. The wound provider must accept the new normal during the pandemic by adapting their care to meet the safety needs of the patient and the public. The Wound Center Without Walls is a strategy to untether wound care from a physical location and aggressively triage and provide care to patients with wounds across the spectrum of the health system utilizing technology and community-centered care.

Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis.

Abstract: Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.

Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model.

Abstract: Cryopreserved human skin allografts (CHSAs) are used for the coverage of major burns when donor sites for autografts are insufficiently available and have clinically shown beneficial effects on chronic non-healing wounds. However, the biologic mechanisms behind the regenerative properties of CHSA remain elusive. Furthermore, the impact of cryopreservation on the immunogenicity of CHSA has not been thoroughly investigated and raised concerns with regard to their clinical application. To investigate the importance and fate of living cells, we compared cryopreserved CHSA with human acellular dermal matrix (ADM) grafts in which living cells had been removed by chemical processing. Both grafts were subcutaneously implanted into C57BL/6 mice and explanted after 1, 3, 7, and 28 days (n = 5 per group). A sham surgery where no graft was implanted served as a control. Transmission electron microscopy (TEM) and flow cytometry were used to characterise the ultrastructure and cells within CHSA before implantation. Immunofluorescent staining of tissue sections was used to determine the immune reaction against the implanted grafts, the rate of apoptotic cells, and vascularisation as well as collagen content of the overlaying murine dermis. Digital quantification of collagen fibre alignment on tissue sections was used to quantify the degree of fibrosis within the murine dermis. A substantial population of live human cells with intact organelles was identified in CHSA prior to implantation. Subcutaneous pockets with implanted xenografts or ADMs healed without clinically apparent rejection and with a similar cellular immune response. CHSA implantation largely preserved the cellularity of the overlying murine dermis, whereas ADM was associated with a significantly higher rate of cellular apoptosis, identified by cleaved caspase-3 staining, and a stronger dendritic cell infiltration of the murine dermis. CHSA was found to induce a local angiogenic response, leading to significantly more vascularisation of the murine dermis compared with ADM and sham surgery on day 7. By day 28, aggregate collagen-1 content within the murine dermis was greater following CHSA implantation compared with ADM. Collagen fibre alignment of the murine dermis, correlating with the degree of fibrosis, was significantly greater in the ADM group, whereas CHSA maintained the characteristic basket weave pattern of the native murine dermis. Our data indicate that CHSAs promote angiogenesis and collagen-1 production without eliciting a significant fibrotic response in a xenograft model. These findings may provide insight into the beneficial effects clinically observed after treatment of chronic wounds and burns with CHSA.

Impaired Neovascularization in Aging

Abstract: Significance: The skin undergoes an inevitable degeneration as an individual ages. As intrinsic and extrinsic factors degrade the structural integrity of the skin, it experiences a critical loss of function and homeostatic stability. Thus, aged skin becomes increasingly susceptible to injury and displays a prolonged healing process. Recent Advances: Several studies have found significant differences during wound healing between younger and older individuals. The hypoxia-inducible factor 1-alpha (HIF-1α) signaling pathway has recently been identified as a major player in wound healing. Hypoxia-inducible factors (HIFs) are pleiotropic key regulators of oxygen homeostasis. HIF-1α is essential to neovascularization through its regulation of cytokines, such as SDF-1α (stromal cell-derived factor 1-alpha) and has been shown to upregulate the expression of genes important for a hypoxic response. Prolyl hydroxylase domain proteins (PHDs) and factor inhibiting HIF effectively block HIF-1α signaling in normoxia through hydroxylation, preventing the signaling cascade from activating, leading to impaired tissue survival. Critical Issues: Aged wounds are a major clinical burden, resisting modern treatment and costing millions in health care each year. At the molecular level, aging has been shown to interfere with PHD regulation, which in turn prevents HIF-1α from activating gene expression, ultimately leading to impaired healing. Other studies have identified loss of function in cells during aging, impeding processes such as angiogenesis. Future Directions: An improved understanding of the regulation of molecular mediators, such as HIF-1α and PHD, will allow for manipulation of the various factors underlying delayed wound healing in the aged. The findings highlighted in this may facilitate the development of potential therapeutic approaches involved in the alteration of cellular dynamics and aging.

Er:YAG laser vs. sharp debridement in management of chronic wounds: Effects on pain and bacterial load

Abstract: Chronic wounds affect roughly 6.5 million patients in the US annually. Current standard of therapy entails weekly sharp debridement. However, the sharp technique is associated with significant pain, while having minimal impact on the bioburden. Our study proposes the Er:YAG laser as an alternative method of debridement that may decrease procedural pain, reduce bioburden, and potentially improve overall healing. This pilot study was performed as a prospective, randomized, controlled, crossover clinical trial, containing two groups: (1) one group underwent single laser debridement session first, followed by single sharp debridement session one week later; and (2) the other group underwent single sharp debridement session first, followed by single laser debridement session one week later. Variables analyzed included pain during debridement, pre- and post-debridement wound sizes, pre- and post-debridement bacterial loads and patient preference. Twenty-two patients were enrolled (12 patients in Group 1, plus 10 patients in Group 2). The mean pain score for patients undergoing laser debridement was 3.0 ± 1.7 vs. 4.8 ± 2.6 for those undergoing sharp debridement (p = 0.003). The mean percent change in wound size 1-week post-laser debridement was -20.8% ± 80.1%, as compared with -36.7% ± 54.3% 1-week post-sharp debridement (p = 0.6). The percentage of patients who had a bacterial load in the low/negative category increased from 27.3% to 59.1% immediately after laser debridement (p = 0.04), vs. 54.5% to 68.2% immediately after sharp debridement (p = 0.38). Moreover, there was a sustained decrease in bacterial load 1-week post-laser debridement, as compared with no sustained decrease 1-week post-sharp debridement (p < 0.02). Overall, 52.9% of patients preferred laser debridement vs. 35.3% for sharp debridement. We believe that Er:YAG laser serves as a promising technology in chronic wounds, functioning as a potentially superior alternative to sharp debridement, the current standard of therapy.

Current and Emerging Topical Scar Mitigation Therapies for Craniofacial Burn Wound Healing.

Abstract: Burn injury in the craniofacial region causes significant health and psychosocial consequences and presents unique reconstructive challenges. Healing of severely burned skin and underlying soft tissue is a dynamic process involving many pathophysiological factors, often leading to devastating outcomes such as the formation of hypertrophic scars and debilitating contractures. There are limited treatment options currently used for post-burn scar mitigation but recent advances in our knowledge of the cellular and molecular wound and scar pathophysiology have allowed for development of new treatment concepts. Clinical effectiveness of these experimental therapies is currently being evaluated. In this review, we discuss current topical therapies for craniofacial burn injuries and emerging new therapeutic concepts that are highly translational.

Tissue Engineering of Axially Vascularized Soft-Tissue Flaps with a Poly-(ɛ-Caprolactone) Nanofiber-Hydrogel Composite.

Abstract: Objective: To develop a novel approach for tissue engineering of soft-tissue flaps suitable for free microsurgical transfer, using an injectable nanofiber hydrogel composite (NHC) vascularized by an arteriovenous (AV) loop. Approach: A rat AV loop model was used for tissue engineering of vascularized soft-tissue flaps. NHC or collagen-elastin (CE) scaffolds were implanted into isolation chambers together with an AV loop and explanted after 15 days. Saphenous veins were implanted into the scaffolds as controls. Neoangiogenesis, ultrastructure, and protein expression of SYNJ2BP, EPHA2, and FOXC1 were analyzed by immunohistochemistry and compared between the groups. Rheological properties were compared between the two scaffolds and native human adipose tissue. Results: A functional neovascularization was evident in NHC flaps with its amount being comparable with CE flaps. Scanning electron microscopy revealed a strong mononuclear cell infiltration along the nanofibers in NHC flaps and a trend toward higher fiber alignment compared with CE flaps. SYNJ2BP and EPHA2 expression in endothelial cells (ECs) was lower in NHC flaps compared with CE flaps, whereas FOXC1 expression was increased in NHC flaps. Compared with the stiffer CE flaps, the NHC flaps showed similar rheological properties to native human adipose tissue. Innovation: This is the first study to demonstrate the feasibility of tissue engineering of soft-tissue flaps with similar rheological properties as human fat, suitable for microsurgical transfer using an injectable nanofiber hydrogel composite. Conclusions: The injectable NHC scaffold is suitable for tissue engineering of axially vascularized soft-tissue flaps with a solid neovascularization, strong cellular infiltration, and biomechanical properties similar to human fat. Our data indicate that SYNJ2BP, EPHA2, and FOXC1 are involved in AV loop-associated angiogenesis and that the scaffold material has an impact on protein expression in ECs.

A multivariable miRNA signature delineates the systemic hemodynamic impact of arteriovenous shunt placement in a pilot study.

Abstract: Arteriovenous (AV) fistulas for hemodialysis can lead to cardiac volume loading and increased serum brain natriuretic peptide (BNP) levels. Whether short-term AV loop placement in patients undergoing microsurgery has an impact on cardiac biomarkers and circulating microRNAs (miRNAs), potentially indicating an increased hemodynamic risk, remains elusive. Fifteen patients underwent AV loop placement with delayed free flap anastomosis for microsurgical reconstructions of lower extremity soft-tissue defects. N-terminal pro-BNP (NT-proBNP), copeptin (CT-proAVP), and miRNA expression profiles were determined in the peripheral blood before and after AV loop placement. MiRNA expression in the blood was correlated with miRNA expression from AV loop vascular tissue. Serum NT-proBNP and copeptin levels exceeded the upper reference limit after AV loop placement, with an especially strong NT-proBNP increase in patients with preexistent cardiac diseases. A miRNA signature of 4 up-regulated (miR-3198, miR-3127-5p, miR-1305, miR-1288-3p) and 2 down-regulated miRNAs (miR30a-5p, miR-145-5p) which are related to cardiovascular physiology, showed a significant systemic deregulation in blood and venous tissue after AV loop placement. AV loop placement causes serum elevations of NT-proBNP, copeptin as well as specific circulating miRNAs, indicating a potentially increased hemodynamic risk for patients with cardiovascular comorbidities, if free flap anastomosis is delayed.

Divergent molecular signatures of regeneration and fibrosis during wound repair

Abstract: Summary Regeneration is the “holy grail” of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward either scarring or regenerative fates. We profile scarring versus YAP inhibition-induced wound regeneration at the transcriptional (single-cell RNA-sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell surface barcoding, we integrate these data to reveal fibrotic and regenerative “molecular trajectories” of healing. We show that disrupting YAP mechanical signaling yields regenerative repair orchestrated by fibroblasts with activated Trps1 and Wnt signaling. Our findings serve as a multimodal map of wound regeneration and could have therapeutic implications for pathologic fibroses.

Matched‐cohort study comparing bioactive human split‐thickness skin allograft plus standard of care to standard of care alone in the treatment of diabetic ulcers: A retrospective analysis across 470 institutions

Abstract: This retrospective, matched-cohort study analyzed 1,556 patients with diabetic ulcers treated at 470 wound centers throughout the United States to determine the effectiveness of a cryopreserved bioactive split-thickness skin allograft plus standard of care when compared to standard of care alone. There were 778 patients treated with the graft in the treatment cohort, who were paired with 778 patients drawn from a pool of 126,864 candidates treated with standard of care alone (controls), by using propensity matching to create nearly identical cohorts. Both cohorts received standard wound care, including surgical debridement, moist wound care, and offloading. Logistic regression analysis of healing rates according to wound size, wound location, wound duration, volume reduction, exposed deep structures, and Wagner grade was performed. Amputation rates and recidivism at 3 months, 6 months, and 1 year after wound closure were analyzed. Diabetic ulcers were 59% more likely to close in the treatment cohort compared to the control cohort (p = 0.0045). The healing rate with the graft was better than standard of care across multiple subsets, but the most significant improvement was noted in the worst wounds that had a duration of 90-179 days prior to treatment (p = 0.0073), exposed deep structures (p = 0.036), and/or Wagner Grade 4 ulcers (p = 0.04). Furthermore, the decrease in recidivism was statistically significant at 3 months, 6 months, and 1 year, with and without initially exposed deep structures (p < 0.05). The amputation rate in the treatment cohort was 41.7% less than that of the control cohort at 20 weeks (0.9% vs. 1.5%, respectively). This study demonstrated that diabetic ulcers treated with a cryopreserved bioactive split-thickness skin allograft were more likely to heal and remain closed compared to ulcers treated with standard of care alone.

Endothelial CXCL12 regulates neovascularization during tissue repair and tumor progression

Abstract: 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.

New Drugs for Scar Treatment

Abstract: Cutaneous scar formation following injury is an exuberant fibro-proliferative event and causes aesthetic distress associated with functional problems for those afflicted. Traditionally, surgical revision of excessive hypertrophic scars is commonly performed. However, scar recurrence rate is high and surgical treatments are often combined with radiation therapy, corticosteroid injections, or with other noninvasive therapies. Pharmacological intervention of scar-promoting cellular activities has recently gained traction based on the emerging scientific evidence proving efficacy and safety of new therapeutics in preclinical studies. Ideal new drug therapies would be noninvasive, inexpensive, safe-to-use, and effective in prevention of scar formation. Recently, cytokine-based therapies and modulators of mechanotransduction are being evaluated for their anti-fibrotic properties in the reduction and prevention of scarring. Therapeutic potential of evidence-based new scar therapeutics holds promise toward improving the current wound and scar management practice.

Mechanisms of Action and Chemical Origins of Biologically Active Antimicrobial Polymers

Abstract: The creation of synthetic tissues for patients with traumatic or debilitating injuries and diseases has proven to be a rapidly growing field. Scaffold design plays a crucial role in determining the biocompatibility, function and longevity of these engineered tissues. Biodegradable polymers with high levels of biocompatibility and functional flexibility are currently the primary choice for scaffold construction. Due to the fiscal and healthcare-related costs of replacing scaffolds during the healing process, manufacturing transplants with the ability to withstand foreign infection is tantamount to the success of the field. Antimicrobial polymers (AMPs) can serve as materials for such synthetic transplants. A variety of AMPs bearing different chemical motifs and biological effects have been studied with regard to their viability as biocompatible engineering materials. This review discusses the merits and faults of AMPs in their potential applications toward tissue scaffold design.

Abstract 175: Single Cell RNA-Seq Reveals Molecular Signatures Of Heterogeneous Populations Of Dendritic Cells And Macrophages In Murine Wound Healing And Hypertrophic Scarring

Abstract: Methods: Murine hypertrophic scar (HTS) model and porcine deep partial-thickness excisional wound model were studied to investigate the effects of FAK inhibition on regeneration of intradermal adipocytes. 1) Mouse model: For HTS model, full-thickness dorsal incisional wounds (2 cm) were immediately suture closed and left untreated until D4. On D4, sutures were removed and the healing tissue was subject to consistent mechanical loading until D14 to induce HTS. A small molecule FAK inhibitor (FAK-I; VS-6062, Verastem Oncology) was locally injected to the wound site daily until the animals were euthanized on D14. 2) Red Duroc model: Female red Duroc swine was used to create deep partial-thickness excisions (25 cm in size and 0.07 inches in depth). Wounds were immediately treated with FAK-I-releasing hydrogel for 90 days. FAK-I-releasing hydrogels were replenished twice a week until D90. Animals were euthanized on D180. 3) Tissue analyses: Specimens were collected at various time points after the initial injury. The presence of intradermal adipose tissue, hair follicles, and other skin appendages were visualized by histology and immunofluorescent techniques.

Therapeutic Breast Reconstruction Using Gene Therapy–Delivered IFNγ Immunotherapy

Abstract: After mastectomy, breast reconstruction is increasingly performed using autologous tissue with the aim of improving quality of life. During this procedure, autologous tissue is excised, relocated, and reattached using microvascular anastomoses at the site of the extirpated breast. The period during which the tissue is ex vivo may allow genetic modification without any systemic exposure to the vector. Could such access permit delivery of therapeutic agents using the tissue flap as a vehicle? Such delivery may be more targeted and oncologically efficient than systemic therapy, and avoid systemic complications. The cytokine IFNγ has antitumor effects, and systemic toxicity could be circumvented by localized delivery of the IFNγ gene via gene therapy to autologous tissue used for breast reconstruction, which then releases IFNγ and exerts antitumor effects. In a rat model of loco-regional recurrence (LRR) with MADB-106-Luc and MAD-MB-231-Luc breast cancer cells, autologous tissue was transduced ex vivo with an adeno-associated viral vector encoding IFNγ. The "Therapeutic Reconstruction" released IFNγ at the LRR site and eliminated cancer cells, significantly decreased tumor burden, and increased survival compared with sham reconstruction (P <0.05). Mechanistically, localized IFNγ immunotherapy stimulated M1 macrophages to target cancer cells within the regional confines of the modified tumor environment. This concept of "Therapeutic Breast Reconstruction" using ex vivo gene therapy of autologous tissue offers a new application for immunotherapy in breast cancer with a dual therapeutic effect of both reconstructing the ablative defect and delivering local adjuvant immunotherapy.

Topical and transdermal delivery of an iron chelator to prevent and treat chronic wounds

Abstract: A transdermal patch for the treatment of Sickle Cell Ulcers is provided. The patch can facilitate the delivery of an iron chelator, such as DFO. The DFO can be encapsulated in a reverse micelle to enhance penetration into and absorption by the dermis. The patch can be used to accelerate healing and reduce pain associated with Sickle Cell Ulcers.

Therapeutic Interventions to Reduce Radiation Induced Dermal Injury in a Murine Model of Tissue Expander Based Breast Reconstruction.

Abstract: Background Radiation therapy (XRT) induced dermal injury disrupts type I collagen architecture. This impairs cutaneous viscoelasticity, which may contribute to the high rate of complications in expander-based breast reconstruction with adjuvant XRT. The objective of this study was to further elucidate the mechanism of radiation-induced dermal injury and to determine if amifostine (AMF) or deferoxamine (DFO) mitigates type I collagen injury in an irradiated murine model of expander-based breast reconstruction. Methods Female Lewis rats (n = 20) were grouped: expander (control), expander-XRT (XRT), expander-XRT-AMF (AMF), and expander-XRT-DFO (DFO). Expanders were surgically placed. All XRT groups received 28 Gy of XRT. The AMF group received AMF 30 minutes before XRT, and the DFO group used a patch for delivery 5 days post-XRT. After a 20-day recovery period, skin was harvested. Atomic force microscopy and Raman spectroscopy were performed to evaluate type I collagen sheet organization and tissue compositional properties, respectively. Results Type I collagen fibril disorganization was significantly increased in the XRT group compared with the control (83.8% vs 22.4%; P = 0.001). Collagen/matrix ratios were greatly reduced in the XRT group compared with the control group (0.49 ± 0.09 vs 0.66 ± 0.09; P = 0.017). Prophylactic AMF demonstrated a marked reduction in type I collagen fibril disorganization on atomic force microscopy (15.9% vs 83.8%; P = 0.001). In fact, AMF normalized type I collagen organization in irradiated tissues to the level of the nonirradiated control (P = 0.122). Based on Raman spectroscopy, both AMF and DFO demonstrated significant differential protective effects on expanded-irradiated tissues. Collagen/matrix ratios were significantly preserved in the AMF group compared with the XRT group (0.49 ± 0.09 vs 0.69 ± 0.10; P = 0.010). β-Sheet/α-helix ratios were significantly increased in the DFO group compared with the XRT group (1.76 ± 0.03 vs 1.86 ± 0.06; P = 0.038). Conclusions Amifostine resulted in a significant improvement in type I collagen fibril organization and collagen synthesis, whereas DFO mitigated abnormal changes in collagen secondary structure in an irradiated murine model of expander-based breast reconstruction. These therapeutics offer the ability to retain the native microarchitecture of type I collagen after radiation. Amifostine and DFO may offer clinical utility to reduce radiation induced dermal injury, potentially decreasing the high complication rate of expander-based breast reconstruction with adjuvant XRT and improving surgical outcomes.

Device and methods for skin tightening

Abstract: Devices, kits and methods are used for wound healing, including but not limited to the treatment, amelioration, or prevention of scars and/or keloids, and include packaging, manipulation elements, applicator and/or tensioning device that are used to apply and/or maintain a strain in an elastic dressing.

Medical device for joining materials

Abstract: A medical device for joining materials is provided. The device comprises a piercing element configured to penetrate materials to be joined. The piercing element is sufficiently sharp to penetrate materials to be joined and comprises a hollow interior along at least a portion of its length configured to distal advancement of a fastener therethrough; and an open tip through which the fastener can be pushed. The device can be used for fastening materials including tissue, synthetic mesh, and biologic mesh (e.g., ADM).