Faculty Bibliography

The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1

Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system and its dysfunction has been implicated in numerous pathologies. Here, we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor, Keap1, and the subsequent changes in Nrf2 signaling. We also developed a topical siRNA-based therapy to restore redox homeostasis within diabetic wounds. Western blot demonstrated that chronic hyperglycemia-associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.

Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.

BACKGROUND/UNASSIGNED:In vascularized composite allotransplantation, face transplantation stands as a transformative intervention for patients with severe facial disfigurement. Monitoring of graft rejection, however, remains a critical challenge. This study aimed to investigate the role of lymphocyte subsets in the early detection and monitoring of graft rejection in face transplantation. METHODS/UNASSIGNED:We conducted a retrospective chart review of 3 face transplant recipients who underwent face transplantation at our institution. Peripheral blood samples were analyzed for lymphocyte subsets at multiple time points posttransplantation. A linear mixed-effects model was used, aiming to identify any upregulation associated with episodes of graft rejection. RESULTS/UNASSIGNED:= 0.0015, respectively). CONCLUSIONS/UNASSIGNED:Our study demonstrates that monitoring specific lymphocyte subsets offers a promising adjunct for graft surveillance that is less invasive when compared with traditionally used punch biopsies. This approach not only enhances the precision of rejection monitoring but also improves patient comfort and compliance, thereby contributing to better long-term graft outcomes.

INTRODUCTION/BACKGROUND:The aging neck is a prevalent aesthetic concern, with over 160,000 neck procedures performed in 2020. It is characterized by increased soft tissue laxity and displacement of cervical structures. While nonsurgical interventions like cryoablation and laser resurfacing show promise, their variable responses highlight the necessity for surgical solutions. Traditional neck lifts address superficial structures but often neglect the subplatysmal plane. Recently, deep plane neck lifts have gained attention for addressing deeper anatomical structures. This paper systematically reviews the literature on subplatysmal modifications in cervicoplasty, aiming to clarify the risks and benefits of these evolving surgical techniques. METHODS:On February 20, 2024, a systematic review adhering to Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 guidelines was performed. MEDLINE, PubMed, Cochrane, and Scopus databases were searched for terms related to neck rejuvenation. Independent reviewers screened titles, abstracts, and full texts, including all relevant studies. Data extracted included patient numbers, procedures, outcomes, and complications. RESULTS:From an initial 771 articles, 57 studies encompassing 8648 patients met inclusion criteria. The most commonly altered anatomical structures during "deep plane" neck lift (DPNL) were the submandibular gland (69.9%), digastric muscles (58.6%), and subplatysmal fat (48.6%). Postoperative complications were reported in 59.6% of studies, with nerve palsy (0.2%-12%) and hematoma (0.2%-4%) being most common. Aesthetic outcomes were less frequently reported (56% of studies); patient satisfaction ranged from 81.6% to 98.6%, while objective measures were reported in only 12% of studies. CONCLUSIONS:Recent surveys indicate a growing concern over excess laxity under the chin, with patients increasingly seeking neck rejuvenation. Our review found that DPNL techniques vary widely, with the submandibular gland and digastric muscles being the most frequently altered structures. Despite a general lack of standardized outcome measures, patient satisfaction was high. However, DPNL showed a higher rate of postoperative nerve palsy compared to traditional neck lift. Overall, while DPNL demonstrates potential aesthetic benefits, the increased risk necessitates thorough patient counseling and further studies for standardization and comparison.

IMPORTANCE/UNASSIGNED:Catastrophic facial injury with globe loss remains a formidable clinical problem with no previous reports of reconstruction by whole eye or combined whole eye and facial transplant. OBJECTIVE/UNASSIGNED:To develop a microsurgical strategy for combined whole eye and facial transplant and describe the clinical findings during the first year following transplant. DESIGN, SETTING, AND PARTICIPANT/UNASSIGNED:A 46-year-old man who sustained a high-voltage electrical injury with catastrophic tissue loss to his face and left globe underwent combined whole eye and face transplant using personalized surgical devices and a novel microsurgical strategy at a specialized center for vascularized composite allotransplantation. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Reperfusion and viability of the whole eye and facial allografts, retinal function, and incidence of acute rejection. RESULTS/UNASSIGNED:The patient underwent a combined whole eye and face transplant from an immunologically compatible donor with primary optic nerve coaptation and conventional postoperative immunosuppression. Globe and retinal perfusion were maintained throughout the immediate postoperative period, evidenced by fluorescein angiography. Optical coherence tomography demonstrated atrophy of inner retinal layers and attenuation and disruption of the ellipsoid zone. Serial electroretinography confirmed retinal responses to light in the transplanted eye. Using structural and functional magnetic resonance imaging, the integrity of the transplanted visual pathways and potential occipital cortical response to light stimulation of the transplanted eye was demonstrated. At 1 year post transplant (postoperative day 366), there was no perception of light in the transplanted eye. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This is the first report of whole eye transplant combined with facial transplant, demonstrating allograft survival including rejection-free graft survival and electroretinographic measurements indicating retinal response to light stimuli. These data highlight the potential for clinical allotransplantation for globe loss.

BACKGROUND/UNASSIGNED:A deeper understanding of acute rejection in vascularized composite allotransplantation is paramount for expanding its utility and longevity. There remains a need to develop more precise and accurate tools for diagnosis and prognosis of these allografts, as well as alternatives to traditional immunosuppressive regimens. METHODS/UNASSIGNED:Twenty-seven skin biopsies collected from 3 vascularized composite allotransplantation recipients, consisting of face and hand transplants, were evaluated by histology, immunohistochemistry staining, and gene expression profiling. RESULTS/UNASSIGNED:significantly predicted inflammation specific to vascularized composite allografts that required therapeutic intervention. CONCLUSIONS/UNASSIGNED:The mechanism of vascularized composite allograft-specific inflammation and rejection appears to be conserved across different patients and skin on different anatomical sites. A concise gene signature can be utilized to ascertain graft status along with a continuous scale, providing valuable diagnostic and prognostic information to supplement current gold standards of graft evaluation.

BACKGROUND/UNASSIGNED:Vascularized composite allotransplantation (VCA) has become a viable option for restoration of devastating injuries that are not amenable to conventional reconstructive techniques. However, the relative scarcity of procedures performed worldwide, as well as the potential for iatrogenic injury with biopsies, makes studying the immunopathogenesis of acute rejection challenging. Translational VCA research focuses on developing strategies to overcome these barriers with the use of animal models can be technically challenging and difficult to replicate without highly trained microsurgeons. METHODS/UNASSIGNED:We describe a modified model of a femur-based composite tissue allograft using an adapted vascular cuff anastomotic technique with a tunneled skin flap in a rodent model. RESULTS/UNASSIGNED:The use of a heterotopic osteomyocutaneous flap with a subcutaneously tunneled-skin paddle to the posterolateral aspect of the recipient rodent allows for ease of flap monitoring and reduces the risk of self-mutilation. A total of six transplantations were conducted with no signs of self-mutilation. Operative time decreased as our surgical technique improved, and long-term graft tolerance was possible under our immunosuppressive regimen. Additionally, we demonstrate cases of successful transplantation in both an allogeneic and syngeneic rodent model. CONCLUSION/UNASSIGNED:Animal models, although technically challenging, are a reliable and reproducible modality that has been used to investigate various aspects of VCA immunology. We describe the success of an osteomyocutaneous flap with a modified vascular cuff anastomosis that can be used by investigators with less experience in microsurgical techniques to further our understanding of VCA physiology. Furthermore, tunneling of the skin paddle reduces the risk of self-mutilation and other external factors affecting the graft.

STUDY DESIGN/UNASSIGNED:Retrospective observational study. OBJECTIVE/UNASSIGNED:This study analyzes the epidemiology of pediatric Le Fort fractures and assesses the incidence of concomitant injuries and acute-level hospital course using the largest, national pediatric trauma database to date. METHODS/UNASSIGNED:Pediatric midface and Le Fort fractures from 2016-2019 were identified in the National Trauma Data Bank. Descriptive analyses of Le Fort compared to non-Le Fort midface fractures were performed. Multivariable regression assessed whether Le Fort fractures were risk factors for ICU admission, intracranial injury, cervical spine (C-spine) fracture, tracheostomy, and mortality. RESULTS/UNASSIGNED:< 0.001). Incidence of all the above increased with higher-grade Le Fort fractures. Le Fort III fractures had higher rates of mortality than non-Le Fort midface fractures (7.6% vs 3.2%). Multivariable regression showed that all Le Fort patterns were independent risk factors for tracheostomy and ICU admission, but only Le Fort I for C-spine fractures. CONCLUSIONS/UNASSIGNED:The incidence of Le Fort fractures appears to increase with age. Higher category Le Fort fractures are associated with greater morbidity.

PURPOSE/OBJECTIVE:The pediatric craniofacial trauma literature is limited to single institutions or short study periods. Herein, this study analyzes a national database over 10 years to delineate the epidemiology of pediatric craniofacial fractures and to identify risk factors for acute-level hospital course in the largest series to date. METHODS:Utilizing the National Trauma Data Bank, pediatric craniofacial fractures admitted between 2010 and 2019 were identified. Descriptive analyses and multivariable regression were performed to identify risk factors for acute-level hospital course. RESULTS:A total of 155,136 pediatric craniofacial fracture cases were reviewed, including cranial vault (49.0%), nasal (22.4%), midface (21.0%), mandibular (20.2%), and orbital floor fractures (13.7%). Midface and orbital floor fractures occurred commonly as multicraniofacial fractures. Cranial vault fractures were the most common among all age groups, but frequency declined with age. In contrast, facial fractures increased with age. Despite the inherent complexity of multicraniofacial trauma, isolated fractures remained a concern for acute-level hospital course.Cranial vault and midface fractures had an increased risk of intracranial injury and intensive care unit admission (P<0.001). Mandibular and midface fractures had an increased risk for cervical spine fracture and tracheostomy (P<0.001). Patient and injury-specific risk factors among the fractures with the strongest association for each outcome-cranial vault and mandible-were identified. CONCLUSIONS:The inherent limitations of prior studies-geographical biases, small cohorts, and short-term study periods-were addressed. Describing the independent contribution of each craniofacial fracture to the risk of acute-level hospital course outcomes can be employed to better optimize risk stratification, counseling, and management.