Current Treatment Landscape for Dystrophic Epidermolysis Bullosa: From Surgical Management to Emerging Gene Therapies and Novel Skin Grafts.

Epidermolysis bullosa is a genetic skin disorder characterized by blister formation from mechanical trauma. Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the COL7A1 gene presenting as generalized blisters from birth, which can result in extensive scarring, alopecia, esophageal stenosis, corneal erosions, and nail dystrophy. This disease also often leads to pseudosyndactyly of the digits from the closure of webspaces, progressing to a "mitten hand" deformity. Although traditional and current treatment for DEB is largely supportive with wound care and iterative surgical pseudosyndactyly release, emerging gene therapies and novel skin grafts may offer promising treatment. Studies published in the early 2020s have used HSV-1 vectors expressing missing COL7A1 genes to restore collagen function. One of these treatments, B-VEC, is an HSV-1-based topical gene therapy designed to restore collagen 7 by delivering the COL7A1 gene, leveraging a differentiated HSV-1 vector platform that evades the patient's immune system response. Other work has been performed to retrovirally modify autologous keratinocytes, but limitations of this process include increased labor in harvesting and engineering autologous cells. This article provides an overview of DEB treatment with an emphasis on emerging gene therapies and novel skin grafts, especially as they pertain to pseudosyndactyly treatment.

Prolymphangiogenic Effects of 9-cis Retinoic Acid Are Enhanced at Sites of Lymphatic Injury and Dependent on Treatment Duration in Experimental Postsurgical Lymphedema.

Background: Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged lymphatic vessels fail to adequately regenerate and lymphatic obstruction leads to fluid and protein accumulation in the interstitial space and chronic lymphedema develops as a result. There are currently no effective pharmacological agents that reduce the risk of developing lymphedema or treat pre-existing lymphedema, and management is largely palliative. The present study investigated the efficacy of various 9-cis retinoic acid (9-cis RA) dosing strategies in reducing postsurgical lymphedema by utilizing a well-established mouse tail lymphedema model. Methods and Results: Short-duration treatment with 9-cis RA did not demonstrate a significant reduction in postoperative tail volume, nor an improvement in lymphatic clearance. However, long-term treatment with 9-cis RA resulted in decreased overall tail volume, dermal thickness, and epidermal thickness, with an associated increase in functional lymphatic clearance and lymphatic vessel density, assessed by LYVE-1 immunostaining, compared with control. These effects were seen at the site of lymphatic injury, with no significant changes observed in uninjured sites such as ear skin and the diaphragm. Conclusions: Given the reported results indicating that 9-cis RA is a potent promoter of lymphangiogenesis and improved lymphatic clearance at sites of lymphatic injury, investigation of postoperative 9-cis RA administration to patients at high risk of developing lymphedema may demonstrate positive efficacy and reduced rates of postsurgical lymphedema.

Reinforced Biologic Mesh Reduces Postoperative Complications Compared to Biologic Mesh after Ventral Hernia Repair.

BACKGROUND: The use of biologic mesh to reinforce the abdominal wall in ventral hernia repair has been proposed as a viable alternative to synthetic mesh, particularly for high-risk patients and in contaminated settings. However, a comparison of clinical outcomes between the currently available biologic mesh types has yet to be performed. METHODS: We performed a retrospective analysis of 141 patients who had undergone ventral hernia repair with biologic mesh, including noncross-linked porcine ADM (NC-PADM) (n = 51), cross-linked porcine ADM (C-PADM) (n = 17), reinforced biologic ovine rumen (RBOR) (n = 36), and bovine ADM (BADM) (n = 37) at the Stanford University Medical Center between 2002 and 2020. Postoperative donor site complications and rates of hernia recurrence were compared between patients with different biologic mesh types. RESULTS: Abdominal complications occurred in 47.1% of patients with NC-PADM, 52.9% of patients with C-PADM, 16.7% of patients with RBOR, and 43.2% of patients with BADM (P = 0.015). Relative risk for overall complications was higher in patients who had received NC-PADM (RR = 2.64, P = 0.0182), C-PADM (RR = 3.19, P = 0.0127), and BADM (RR = 2.11, P = 0.0773) compared with those who had received RBOR. Furthermore, relative risk for hernia recurrence was also higher in all other mesh types compared with RBOR. CONCLUSION: Our data indicate that RBOR decreases abdominal complications and recurrence rates after ventral hernia repair compared with NC-PADM, C-PADM, and BADM.

Inhibiting Fibroblast Mechanotransduction Modulates Severity of Idiopathic Pulmonary Fibrosis.

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear to be important. Given the dynamic environment of the lung, we examined the significance of mechanotransduction on both inflammatory and fibrotic signaling during IPF. Innovation: Mechanotransduction pathways have not been thoroughly examined in the context of lung disease, and pharmacologic approaches for IPF do not currently target these pathways. The interplay between mechanical strain and inflammation in pulmonary fibrosis remains incompletely understood. Approach: In this study, we used conditional KO mice to block mechanotransduction by knocking out Focal Adhesion Kinase (FAK) expression in fibroblasts, followed by induction of pulmonary fibrosis using bleomycin. We examined both normal human and human IPF fibroblasts and used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western Blot to evaluate the effects of FAK inhibitor (FAK-I) on modulating fibrotic and inflammatory genes. Results: Our data indicate that the deletion of FAK in mice reduces expression of fibrotic and inflammatory genes in lungs. Similarly, mechanical straining in normal human lung fibroblasts activates inflammatory and fibrotic pathways. The FAK inhibition decreases these signals but has a less effect on IPF fibroblasts as compared with normal human fibroblasts. Conclusion: Administering FAK-I at early stages of fibrosis may attenuate the FAK-mediated fibrotic response pathway in IPF, potentially mediating disease progression.

The Impact of Plastic Surgery Volume on Inpatient Burn Outcomes.

BACKGROUND: Acute burn care involves multiple types of physicians. Plastic surgery offers the full spectrum of acute burn care and reconstructive surgery. The authors hypothesize that access to plastic surgery will be associated with improved inpatient outcomes in the treatment of acute burns. METHODS: Acute burn encounters with known percentage total body surface area were extracted from the National Inpatient Sample from 2012 to 2014 based on International Classification of Diseases, Ninth Edition, codes. Plastic surgery volume per facility was determined based on procedure codes for flaps, breast reconstruction, and complex hand reconstruction. Outcomes included odds of receiving a flap, patient safety indicators, and mortality. Regression models included the following variables: age, percentage total body surface area, gender, inhalation injury, comorbidities, hospital size, and urban/teaching status of hospital. RESULTS: The weighted sample included 99,510 burn admissions with a mean percentage total body surface area of 15.5 percent. The weighted median plastic surgery volume by facility was 245 cases per year. Compared with the lowest quartile, the upper three quartiles of plastic surgery volume were associated with increased likelihood of undergoing flap procedures (p < 0.03). The top quartile of plastic surgery volume was also associated with decreased odds of patient safety indicator events (p < 0.001). Plastic surgery facility volume was not significantly associated with a difference in the likelihood of inpatient death. CONCLUSIONS: Burn encounters treated at high-volume plastic surgery facilities were more likely to undergo flap operations. High-volume plastic surgery centers were also associated with a lower likelihood of inpatient complications. Therefore, where feasible, acute burn patients should be triaged to high-volume centers. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Risk Factors for Wound Complications After Soft Tissue Sarcoma Resection.

ABSTRACT: Soft tissue sarcomas are a heterogenous group of malignant tumors that represent approximately 1% of adult malignancies. Although these tumors occur throughout the body, the majority involved the lower extremity. Management may involve amputation but more commonly often includes wide local resection by an oncologic surgeon and involvement of a plastic surgeon for reconstruction of larger and more complex defects. Postoperative wound complications are challenging for the surgeon and patient but also impact management of adjuvant chemotherapy and radiation therapy. To explore risk factors for wound complications, we reviewed our single-institution experience of lower-extremity soft tissue sarcomas from April 2009 to September 2016. We identified 127 patients for retrospective review and analysis. The proportion of patients with wound complications in the cohort was 43.3%. Most notably, compared with patients without wound complications, patients with wound complications had a higher proportion of immediate reconstruction (34.5% vs 15.3%; P = 0.05) and a marginally higher proportion who received neoadjuvant radiation (30.9% vs 16.7%; P = 0.06).

Human Acellular Dermis as Spacer for Small-Joint Arthroplasty: Analysis of Revascularization in a Rabbit Trapeziectomy Model.

BACKGROUND: Carpometacarpal joint osteoarthritis affects 8 to 12 percent of the general population. Surgical management provides symptomatic relief for 78 percent of patients who fail conservative therapy, but little consensus exists regarding which surgical procedure provides superior patient outcomes. Recent human trials substituted exogenous acellular dermal matrices in the bone space, but there are no quantitative histologic data on the outcome of acellular dermal matrices in this environment. The authors aimed to quantify the revascularization and recellularization of acellular dermal matrices in the joint space using a rabbit model. METHODS: Bilateral lunate carpal bones were surgically removed in New Zealand rabbits. Acellular dermal matrix and autologous tissue were implanted in place of the lunate of the right and left wrists, respectively. Acellular dermal matrix was also implanted subcutaneously as a nonjoint control. Histologic and immunofluorescence analysis was performed after collection at 0, 6, and 12 weeks. RESULTS: Quantitative analysis of anti-α-smooth muscle actin and CD31 immunofluorescence revealed a sequential and comparable increase of vascular lumens in joint space and subcutaneous acellular dermal matrices. In contrast, autologous tissue implanted in the joint space did not have a similar increase in α-smooth muscle actin-positive or CD31-positive lumens. Semiquantitative analysis revealed increased cellularity in both autologous and acellular dermal matrix wrist implants at each time point, whereas average cellularity of subcutaneous acellular dermal matrix peaked at 6 weeks and regressed by 12 weeks. Trichrome and Sirius red staining revealed abundant collagen at all time points. CONCLUSION: The trapeziectomy joint space supports both cellular and vascular ingrowth into human acellular dermal matrix.

Local Administration of Interleukin-1 Receptor Antagonist Improves Diabetic Wound Healing.

Impaired healing of the skin is a notable cause of patient morbidity and mortality. In diabetic individuals, dysregulated inflammation contributes to delayed wound healing. Specific immunomodulatory agents may have a role in the treatment of diabetic wounds. One of these molecules is interleukin-1 receptor antagonist (Anakinra; Amgen Corp.). Although interleukin-1 receptor antagonist (Anakinra; Amgen Corp.) is approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, little is known about the local use this drug in cutaneous wound healing. Therefore, the aim of this study is to determine the effect of locally administered interleukin-1 receptor antagonist on delayed wound healing, specifically, in a diabetic mouse model. Two 6-mm full-thickness wounds were created on the dorsa of diabetic (db/db) mice and stented. One-hour postwounding, wound margins were subcutaneously injected with either (1) low-dose interleukin-1 receptor antagonist in a gelatin-transglutaminase gel vehicle or (2) the gel vehicle only. Wounds were imaged on days 0, 7, 14, and 21 postwounding, and wound area was determined. Wound biopsies were collected on day 21 and immunohistochemically stained for neutrophil and macrophage infiltration. Wounds treated with interleukin-1 receptor antagonist had significantly smaller wound area than nontreated wounds on day 7 and day 14 postwounding. Treated wounds also showed significantly less neutrophil and macrophage infiltration. These findings support the hypothesis that interleukin-1 receptor antagonist may have an important role in cutaneous wound healing, possibly by promoting successful resolution of acute inflammation and hence accelerating wound closure. Thereby, administration of IL-1Ra may be useful in the treatment of nonhealing wounds.

Porcine Mesothelium-Wrapped Diced Cartilage Grafts for Nasal Reconstruction.

BACKGROUND: Fascia-wrapped diced cartilage grafts have become a useful tool in modern rhinoplasty surgery. Unfortunately, fascial harvest is associated with donor site morbidity; therefore, a nonautologous alternative to fascia would be ideal. Decellularized porcine mesothelium (PM), Meso BioMatrix™, is an acellular scaffold that could potentially fill this need. To determine if PM could serve as an acceptable alternative, we histologically compared diced cartilage grafts wrapped in fascia versus PM. METHODS: Human rib cartilage and temporoparietal fascia were obtained under an IRB-approved protocol. Cartilage was diced into 0.5 mm pieces and implanted in subcutaneous pockets in nude rats. Implanted materials included cartilage alone, cartilage wrapped in fascia, cartilage wrapped in PM, fascia alone, or PM alone. Specimens were harvested at 8 weeks and stained with hematoxylin and eosin, Masson's trichrome, Safranin-O, and Verhoeff's stain to assess cartilage viability, architecture, and regenerative potential. RESULTS: Unwrapped diced cartilage showed the highest cartilage viability, but was associated with loss of contour and dispersion of the cartilage pieces. Meso BioMatrix-wrapped grafts maintained contour and cartilage pieces had not dispersed; however, there was a significantly lower number of nucleated lacunae and a greater amount of basophilia than both fascia-wrapped cartilage and unwrapped cartilage. There was no significant difference in cartilage resorption between fascia-wrapped cartilage and Meso BioMatrix-wrapped cartilage or in the proteoglycan or collagen content between all groups. CONCLUSION: Off-the-shelf decellularized PM was associated with lower cartilage viability than unprocessed fascial allograft. No cartilage piece dispersion, fibrosis, resorption, or a foreign body reaction to Meso BioMatrix was observed. PM, although not equivalent to autologous tissue, may be utilized to achieve acceptable clinical results and be a viable alternative that limits donor side morbidity. This experimental study supports further clinical investigation of this material in rhinoplasty procedures.

Risk Factors Associated with Reconstructive Complications Following Sacrectomy.

BACKGROUND: Sacral pathology requiring partial or total sacrectomy is rare, and reconstructing the ensuing defects requires careful decision-making to minimize morbidity. The purpose of this study was to review the experience of a single institution with reconstructing large sacral defects, to identify risk factors for suboptimal outcomes. METHODS: A retrospective chart review was conducted of all patients who underwent sacrectomy over a 10-year period. Univariate analysis of differences in risk factors between patients with and without various postoperative complications was performed. Multivariate logistic regression was used to identify predictive variables. RESULTS: Twenty-eight patients were identified. The most common diagnosis leading to sacrectomy was chordoma (39%). Total sacrectomy was performed on 4 patients, whereas 24 patients underwent partial resection. Reconstructive modalities included 15 gluteal advancement flaps, 4 pedicled rectus abdominis myocutaneous flaps, and 9 paraspinous muscle or other flap types. There was an overall complication rate of 57.1% (n = 12) and a 28.6% (n = 8) incidence of major complications. There were significantly more flap-related complications in patients who underwent total sacrectomy (P = 0.02). Large defect size resulted in significantly more unplanned returns to the operating room (P < 0.01). CONCLUSION: Consistent with other published series', the overall complication rate exceeded 50%. Defect volume and sacrectomy type were the strongest predictors of postoperative complications and return to the operating room, while reconstructive strategy showed limited power to predict patient outcomes. We recommend that patients anticipated to have large sacral defects should be appropriately counseled regarding the incidence of wound complications, regardless of reconstructive approach.

Development and Characterization of A Novel Prox1-EGFP Lymphatic and Schlemm's Canal Reporter Rat.

The lymphatic system plays a key role in tissue fluid homeostasis, immune cell trafficking, and fat absorption. We previously reported a bacterial artificial chromosome (BAC)-based lymphatic reporter mouse, where EGFP is expressed under the regulation of the Prox1 promoter. This reporter line has been widely used to conveniently visualize lymphatic vessels and other Prox1-expressing tissues such as Schlemm's canal. However, mice have a number of experimental limitations due to small body size. By comparison, laboratory rats are larger in size and more closely model the metabolic, physiological, and surgical aspects of humans. Here, we report development of a novel lymphatic reporter rat using the mouse Prox1-EGFP BAC. Despite the species mismatch, the mouse Prox1-EGFP BAC enabled a reliable expression of EGFP in Prox1-expressing cells of the transgenic rats and allowed a convenient visualization of all lymphatic vessels, including those in the central nervous system, and Schlemm's canal. To demonstrate the utility of this new reporter rat, we studied the contractile properties and valvular functions of mesenteric lymphatics, developed a surgical model for vascularized lymph node transplantation, and confirmed Prox1 expression in venous valves. Together, Prox1-EGFP rat model will contribute to the advancement of lymphatic research as a valuable experimental resource.

Topical Fibronectin Improves Wound Healing of Irradiated Skin.

Wound healing is significantly delayed in irradiated skin. To better understand global changes in protein expression after radiation, we utilized a reverse phase protein array (RPPA) to identify significant changes in paired samples of normal and irradiated human skin. Of the 210 proteins studied, fibronectin was the most significantly and consistently downregulated in radiation-damaged skin. Using a murine model, we confirmed that radiation leads to decreased fibronectin expression in the skin as well as delayed wound healing. Topically applied fibronectin was found to significantly improve wound healing in irradiated skin and was associated with decreased inflammatory infiltrate and increased angiogenesis. Fibronectin treatment may be a useful adjunctive modality in the treatment of non-healing radiation wounds.