Testosterone Promotes Nerve Tethering and Acellular Biomaterial Perineural Fibrosis in a Rat Wound Repair Model.

Objective: Nerve scarring after traumatic or iatrogenic exposure can lead to impaired function and pain. Nerve-adjacent biomaterials promoting a regenerative tissue response may help reduce perineural fibrosis. Our prior work suggests that testosterone may promote fibrotic skin scarring, but it is unknown how testosterone alters nerve fibrosis or shifts the response to biomaterials. Approach: Sterilized Lewis rats received either testosterone cypionate (+T) or placebo (-T) biweekly. Fifteen days later, wounds were created over the sciatic nerve and covered with an acellular matrix (AM) or closed via primary closure (PC). At day 42, force gauge testing measured the force required to mobilize the nerve, and wound tissue was analyzed. Results: Nerve mobilization force was greater in +T versus -T wounds (p < 0.01). Nerves tore before gliding in 60% of +T versus 6% of -T rats. Epidermal gap (p < 0.01), scar width (p < 0.01), and cross-sectional scar tissue area (p = 0.02) were greater in +T versus -T rats. +T versus -T rats expressed less Col-3 (p = 0.02) and CD68 (p = 0.02). Nerve mobilization force trended nonsignificantly higher for PC versus AM wounds and for +T versus -T wounds within the AM cohort. Innovation: Testosterone increases nerve tethering in the wound healing milieu, altering repair and immune cell balances. Conclusion: Testosterone significantly increases the force required to mobilize nerves in wound beds and elevates histological markers of scarring, suggesting that testosterone-induced inflammation may increase perineural adhesion. Testosterone may reduce the potential anti-tethering protective effect of AM. Androgen receptor antagonism may represent a therapeutic target to reduce scar-related nerve morbidity.

Androgenic steroids induce pathologic scarring in a preclinical porcine model via dysfunctional extracellular matrix deposition.

Hypertrophic scarring is a major source of morbidity. Sex hormones are not classically considered modulators of scarring. However, based on increased frequency of hypertrophic scarring in patients on testosterone, we hypothesized that androgenic steroids induce abnormal scarring and developed a preclinical porcine model to explore these effects. Mini-swine underwent castration, received no testosterone (noT) or biweekly testosterone therapy (+T), and underwent excisional wounding. To create a delayed wound healing model, a subset of wounds were re-excised at 2 weeks. Scars from postoperative day 42 (POD42) and delayed wounds (POD28) were harvested 6 weeks after initial wounding for analysis via histology, bulk RNA-seq, and mechanical testing. Histologic analysis of scars from +T animals showed increased mean fibrosis area (16 mm2noT, 28 mm2+T; p = .007) and thickness (0.246 mm2noT, 0.406 mm2+T; p < .001) compared to noT. XX+T and XY+T scars had greater tensile burst strength (p = .024 and p = .013, respectively) compared to noT swine. Color deconvolution analysis revealed greater deposition of type I and type III collagen as well as increased collagen type I:III ratio in +T scars. Dermatopathologist histology scoring showed that +T exposure was associated with worse overall scarring (p < .05). Gene ontology analysis found that testosterone exposure was associated with upregulation of cellular metabolism and immune response gene sets, while testosterone upregulated pathways related to keratinization and laminin formation on pathway analysis. In conclusion, we developed a preclinical porcine model to study the effects of the sex hormone testosterone on scarring. Testosterone induces increased scar tissue deposition and appears to increase physical strength of scars via supraphysiologic deposition of collagen and other ECM factors. The increased burst strength seen in both XX and XY animals suggests that hormone administration has a strong influence on scar mechanical properties independent of chromosomal sex. Anti-androgen topical therapies may be a promising future area of research.

"Revision Phalloplasty: Evaluation, Algorithms and Techniques for Salvage After Major Complications".

BACKGROUND: Phalloplasty is among the most complex and technically demanding reconstructive surgeries. As a larger pool of surgeons perform this difficult procedure, more patients will present with major complications. There is little published on the comprehensive evaluation and management of these patients, particularly those needing correction of multiple ongoing complications, which may require consideration of starting over with a new microsurgical procedure versus salvage of the existing flap. METHODS: A literature review on complications of phalloplasty was conducted in combination with drawing upon the experience of two high-volume phalloplasty teams (Johns Hopkins/Brigham & Women's Hospital and GU Recon/Buncke Clinic) in treating patients with severe post-surgical issues. The purpose was to analyze critical factors and develop algorithms for secondary revision. RESULTS: Common complications of phalloplasty include urethral strictures and fistulae, diverticula, excess bulk, phalloplasty malposition, hypertrophic/keloidal scarring, and partial/total flap loss. In severe cases, local flaps or free flaps may be required for reconstruction. The decision to revise the existing neophallus or start over with a new flap for phalloplasty is particularly critical. Multidisciplinary team collaboration is essential to develop comprehensive plans that will resolve multiple concomitant problems while meeting patient goals for a functional and aesthetic neophallus. CONCLUSIONS: Preserving the original flap for phalloplasty is ideal when feasible. Additional local or free flaps are sometimes necessary in situations of significant tissue loss. In severe cases, complete redo phalloplasty is required. The algorithms proposed provide a conceptual framework to guide surgeons in analyzing and managing severe complications following phalloplasty.

A Novel Mouse Model for Investigating the Effects of Gender-affirming Hormone Therapy on Surgical Healing.

Wound healing problems are a major cause of morbidity for gender-affirming surgery (GAS) patients. Prior studies have shown sex differences in wound healing may exist. We hypothesized exogenous testosterone supplementation may impair post-GAS wound healing and developed a model to investigate this phenomenon. Mice were randomized by hormone regimen and gonadectomy (OVX). Gonadectomy or sham occurred on day 0 and mice were assigned to no testosterone (-T), mono- or bi-weekly (T/2T) testosterone groups. Dorsal splinted wounding occurred on day 14 and harvest on day 21. Serum testosterone levels were quantified with mass spectrometry. Tissue underwent analysis with planimetry, qPCR, ELISA, and immunofluorescence. Mean testosterone trough levels for bi-weekly regimen were higher compared to mono-weekly (397 versus 272 ng/dL; P = 0.027). At POD5, 2T injections led to 24.9% and 24.7% increases in mean wound size relative to SHAM and OVX/-T, respectively (P = 0.004; 0.001). Wounds in OVX/+2T mice demonstrated increased gene expression for inflammatory cytokines and macrophage marker F4/80 (P < 0.05). ELISA confirmed elevated wound TNFα levels (P < 0.05). Quantitative multiplex immunofluorescence with F4/80/NOS2/ARG1 showed significant increases in macrophage prevalence in OVX/+2T (P < 0.05). We developed a novel model of GAS hormonal milieu to study effects of exogenous testosterone on wound healing. Optimized twice-weekly dosing yielded serum levels comparable to clinical therapy. We showed exogenous testosterone administered to XX/OVX mice significantly impairs wound healing. A hyperinflammatory wound environment results in increased macrophage proliferation and elevated cytokines. Future efforts are directed toward mechanistic investigation and clinical validation.

Outcomes of Patients with Burns Associated with Home Oxygen Therapy: An Institutional Retrospective Review.

Home oxygen therapy (HOT) burns carry high morbidity and mortality. Many patients are active smokers, which is the most frequent cause of oxygen ignition. We conducted a retrospective review at our institution to characterize demographics and outcomes in this patient population. An IRB-approved single-institution retrospective review was conducted for home oxygen therapy burn patients between July 2016 and January 2021. Demographic and clinical outcome data were compared between groups. We identified 100 patients with oxygen therapy burns. Mean age was 66.6 years with a male to female ratio of 1.3:1 and median burn surface area of 1%. In these patients, 97% were on oxygen for COPD and smoking caused 83% of burns. Thirteen were discharged from the emergency department, 35 observed for less than 24 hours, and 52 admitted. For admitted patients, 69.2% were admitted to the ICU, 37% required intubation, and 11.5% required debridement and grafting. Inhalational injury was found in 26.9% of patients, 3.9% underwent tracheostomy, and 17.3% experienced hospital complications. In-hospital mortality was 9.6% and 7.7% were discharged to hospice. 13.5% required readmission within 30 days. Admitted patients had significantly higher rates of admission to the ICU, intubation, and inhalational injury compared to those that were not admitted (P < .01). Most HOT-related burns are caused by smoking and can result in significant morbidity and mortality. Efforts to educate and encourage smoking cessation with more judicious HOT allocation would assist in preventing these unnecessary highly morbid injuries.

Plasmin drives burn-induced systemic inflammatory response syndrome.

Severe injuries, such as burns, provoke a systemic inflammatory response syndrome (SIRS) that imposes pathology on all organs. Simultaneously, severe injury also elicits activation of the fibrinolytic protease plasmin. While the principal adverse outcome of plasmin activation in severe injury is compromised hemostasis, plasmin also possesses proinflammatory properties. We hypothesized that, following a severe injury, early activation of plasmin drives SIRS. Plasmin activation was measured and related to injury severity, SIRS, coagulopathy, and outcomes prospectively in burn patients who are not at risk of hemorrhage. Patients exhibited early, significant activation of plasmin that correlated with burn severity, cytokines, coagulopathy, and death. Burn with a concomitant, remote muscle injury was employed in mice to determine the role of plasmin in the cytokine storm and inflammatory cascades in injured tissue distant from the burn injury. Genetic and pharmacologic inhibition of plasmin reduced the burn-induced cytokine storm and inflammatory signaling in injured tissue. These findings demonstrate (a) that severe injury-induced plasmin activation is a key pathologic component of the SIRS-driven cytokine storm and SIRS-activated inflammatory cascades in tissues distant from the inciting injury and (b) that targeted inhibition of plasmin activation may be effective for limiting both hemorrhage and tissue-damaging inflammation following injury.

Tradeoffs in Implant Selection for Reconstructive Surgery and Adjuncts Utilized to Maximize Aesthetic Outcomes.

BACKGROUND: With many US Food and Drug Administration-approved cohesive gel implant styles currently available in the United States, surgeons and patients may feel overwhelmed by the implant-selection process. We discuss the relative merits of the most commonly used silicone cohesive gel implants and associated adjuncts, particularly in the reconstructive setting. METHODS: A literature review was conducted in PubMed to identify articles that assessed the clinical impact of differing cohesive silicone gel implants and associated adjuncts on aesthetic outcomes and complications profile. RESULTS: First, we review how the shape, cohesivity, and texture of cohesive gel implants impact breast aesthetics and complications after implant-based breast reconstruction (IBBR). Second, we review common adjuncts used in IBBR, including fat grafting and acellular dermal matrix (ADM), and we explore their roles in prepectoral IBBR. Finally, we review future directions in IBBR, including nanoscale implant surface modifications. CONCLUSIONS: In the absence of data showing that shaped implants are aesthetically preferable over round implants, we turn to a risk-benefit analysis of the complication profile of each type of implant. In selecting a smooth, round cohesive silicone implant that offers a variety of cohesivity levels, the patient can enjoy the benefits of smooth shells and avoid the drawbacks of textured shells, all without sacrificing clinically significant visual aesthetics. In the era of the bioengineered breast, this remains even more true.

Implementation of a Trauma Quality Improvement Program Communications Package Decreases Time-to-Operation for Facial Trauma.

INTRODUCTION: Facial trauma is common and carries significant morbidity and cost. Suboptimal interdisciplinary communication is associated with negative health outcomes. This study evaluates the clinical impact of implementation of American College of Surgeons Trauma Quality Improvement Program (TQIP) interdisciplinary communication guidelines between facial surgery and trauma teams. METHODS: Patients with facial trauma presenting to our level 1 trauma center between May and December 2017 were included (N = 812) and split into 3 groups, each anonymously representing a service that treats facial trauma. Services 1 and 2 were controls, and service 3 adopted TQIP communication guidelines. Mean and slope of time-to-operation (TTO) and mean length of stay were assessed 106 days before (n = 95) and 107 days after (n = 77) implementation. RESULTS: For service 3, mean TTO decreased significantly from 6.2 to 2.9 days (P = 0.005) after implementation of the communication intervention. There was no significant difference in mean TTO preimplementation versus postimplementation in either control cohort, including service 1 (4.6 vs 4.9 days; P = 0.59) and service 2 (4.2 vs 4.5 days; P = 0.62). Average length of stay did not differ significantly between the preintervention versus postintervention in any service (service 1: 9.0 vs 8.3 days, P = 0.43; service 2: 4.6 vs 6.6 days, P = 0.85; service 3: 6.7 vs 6.4 days, P = 0.45). CONCLUSION: Our study demonstrates that cost-free TQIP-guided improvement in interdisciplinary communication between the trauma service and a consulting surgical specialist decreases TTO for patients with operative facial trauma. Health care providers should develop strong well-defined communication channels between collaborating teams involved in patient care to optimize patient clinical outcomes.

Diffusion tensor tractography to visualize axonal outgrowth and regeneration in a 4-cm reverse autograft sciatic nerve rabbit injury model.

BACKGROUND: Diffusion tensor tractography (DTT) has recently been shown to accurately detect nerve injury and regeneration. This study assesses whether 7-tesla (7T) DTT imaging is a viable modality to observe axonal outgrowth in a 4 cm rabbit sciatic nerve injury model fixed by a reverse autograft (RA) surgical technique. METHODS: Transection injury of unilateral sciatic nerve (4 cm long) was performed in 25 rabbits and repaired using a RA surgical technique. Analysis of the nerve autograft was performed at 3, 6, and 11 weeks postoperatively and compared to normal contralateral sciatic nerve, used as control group. High-resolution DTT from ex vivo sciatic nerves were obtained using 3D diffusion-weighted spin-echo acquisitions at 7-T. Total axons and motor and sensory axons were counted at defined lengths along the graft. RESULTS: At 11 weeks, histologically, the total axon count of the RA group was equivalent to the contralateral uninjured nerve control group. Similarly, by qualitative DTT visualization, the 11-week RA group showed increased fiber tracts compared to the 3 and 6 weeks counterparts. Upon immunohistochemical evaluation, 11-week motor axon counts did not significantly differ between RA and control; but significantly decreased sensory axon counts remained. Nerves explanted at 3 weeks and 6 weeks showed decreased motor and sensory axon counts. DISCUSSION: 7-T DTT is an effective imaging modality that may be used qualitatively to visualize axonal outgrowth and regeneration. This has implications for the development of technology that non-invasively monitors peripheral nerve regeneration in a variety of clinical settings.

Posttraumatic Proximal Radioulnar Synostosis after Closed Reduction for a Radial Neck and Olecranon Fracture.

Posttraumatic proximal radioulnar synostosis (PPRUS) is a severe complication of radial head and neck fractures known to occur after severe injury or operative fixation. Cases of PPRUS occurring after minimally displaced, nonoperatively treated radial neck injuries are, by contrast, extremely rare. Here, we present a pediatric case of PPRUS that developed after a nonoperatively treated minimally displaced radial neck fracture with concomitant olecranon fracture. While more cases are needed to establish the association between this pattern of injury and PPRUS, we recommend that when encountering patients with a minimally displaced radial neck fracture and a concomitant elbow injury, the rare possibility of developing proximal radioulnar synostosis should be considered.