Denver M. Lough

Stimulation of the follicular bulge LGR5+ and LGR6+ stem cells with the gut-derived human alpha defensin 5 results in decreased bacterial presence, enhanced wound healing, and hair growth from tissues devoid of adnexal structures.

Background: Discovery of leucine-rich repeat-containing G-protein–coupled receptors 5 and 6 (LGR5 and LGR6) as markers of adult epithelial stem cells of the skin and intestine permits researchers to draw on the intrinsic cellular fundamentals of wound healing and proliferation dynamics of epithelial surfaces. In this study, the authors use the intestine-derived human alpha defensin 5 to stimulate epithelial proliferation, bacterial reduction, and hair production in burn wound beds to provide the field with initial insight on augmenting wound healing in tissues devoid of adnexal stem cells. Methods: Murine third-degree burn wound beds were treated with (1) intestine-derived human alpha defensin 5, (2) skin-derived human beta defensin 1, and (3) sulfadiazine to determine their roles in wound healing, bacterial reduction, and hair growth. Results: The human alpha defensin 5 peptide significantly enhanced wound healing and reduced basal bacterial load compared with human beta defensin 1 and sulfadiazine. Human alpha defensin 5 was the only therapy to induce LGR stem cell migration into the wound bed. In addition, gene heat mapping showed significant mRNA up-regulation of key wound healing and Wnt pathway transcripts such as Wnt1 and Wisp1. Ex vivo studies showed enhanced cell migration in human alpha defensin 5–treated wounds compared with controls. Conclusions: Application of human alpha defensin 5 increases LGR stem cell migration into wound beds, leading to enhanced healing, bacterial reduction, and hair production through the augmentation of key Wnt and wound healing transcripts. These findings can be used to derive gut protein–based therapeutics in wound healing.

Transplantation of the LGR6+ epithelial stem cell into full-thickness cutaneous wounds results in enhanced healing, nascent hair follicle development, and augmentation of angiogenic analytes.

Background: The recently discovered leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6+) epithelial stem cell located within the follicular bulge of the adnexal compartment is capable of producing all cellular lineages of the skin. In this study, the authors sought to determine whether these cells can be transplanted for use as a type of cellular therapy for the repair of full-thickness wounds in which the native stem cell niche has been obliterated. Methods: Full-thickness murine skin was harvested and LGR6+GFP epithelial stem cells were isolated using fluorescence-activated cell sorting. This enriched epithelial stem cell population was then transplanted by means of local injection into wound beds on the dorsum of nude mice. Viability, migration, healing, the development of nascent hair follicles, and gene and proteomic expression studies were performed to determine whether the engraftment of LGR6+GFP epithelial stem cells enhanced healing when compared with controls. Results: Wound beds receiving LGR6+GFP epithelial stem cells showed enhanced healing; nascent follicle growth; and augmentation of the Wnt, vascular endothelial growth factor, epidermal growth factor, and platelet-derived growth factor pathways when compared with controls. Conclusions: The LGR6+ epithelial stem cells appear to hold great promise for the development of a clinically useful stem cell–based therapy for the repair of full-thickness wounds and hair regeneration. These results indicate that transplantation of LGR6+ epithelial stem cells promotes epithelialization, hair growth, and angiogenesis in tissues destined for scar formation.

Current concepts and systematic review of vascularized composite allotransplantation of the abdominal wall

Abdominal wall vascularized composite allotransplantation (AW‐VCA) is a rarely utilized technique for large composite abdominal wall defects. The goal of this article is to systematically review the literature and current concepts of AW‐VCA, outline the challenges ahead, and provide an outlook for the future.

What Effect Does Self-Citation Have on Bibliometric Measures in Academic Plastic Surgery?

BackgroundResearch productivity plays a significant role in academic promotions. Currently, various bibliometric measures utilizing citation counts are used to judge an authors work. With increasing numbers of journals, numbers of open access publications, ease of online submission, and expedited indexing of accepted manuscripts, it is plausible that an author could influence his/her own bibliometric measures through self-citation. The purpose of this study was to determine the impact of self-citation in academic plastic surgery. MethodsA cohort of full-time academic plastic surgeons was identified from 9 U.S. plastic surgery training programs. For all included faculty, academic rank was retrieved from department/division websites, and bibliometric measures were assessed using a subscription bibliographic citation database (Scopus, Reed Elsevier, London, UK). Bibliometric measures included the Hirsch index (h-index, the number of publications h which are cited ≥ h times), total number of publications, and total number of citations. The h-index and total number of citations were collected with and without self-citations. Percent changes in the h-index and total citations were calculated after removal of self-citations and compared across academic ranks and levels of research productivity (total publications, h-index, and total citations). ResultsThe study cohort consisted of 169 full-time academic plastic surgeons. The h-index and total citations experienced decreases of 2.8 ± 5.0% (P < 0.0001) and 4.5 ± 4.6% (P < 0.0001), respectively, after correction for self-citation. More than half of the cohort (n = 113, 67%) did not experience a change in the h-index after removal of self-citations. These decreases did not vary across academic rank. Surgeons who self-cited at rates greater than 5% were 9.8 times more likely (95% confidence interval, 4.5–21.9; P < 0.001) to have their h-index change as a result of self-citation (after adjusting for academic rank). There were weak correlations between percent decreases in the h-index and total citations and various biblimoteric measures (total publications, h-index, total citations; r < 0.32). ConclusionsSelf-citation has a minor impact on common bibliometric measures in academic plastic surgery. The influence of self-citation is consistent across academic ranks and increasing levels of bibliometric measures, suggesting that authors are not manipulating the system with increasing experience.

Transplantation of an LGR6+ Epithelial Stem Cell-Enriched Scaffold for Repair of Full-Thickness Soft-Tissue Defects: The In Vitro Development of Polarized Hair-Bearing Skin.

Background: Recent literature has shown that full-thickness wounds, devoid of the stem cell niche, can subsequently be reconstructed with functional skin elements following migration of the LGR6+ epithelial stem cell into the wound bed. In this study, the authors use a variety of LGR6+ epithelial stem cell–seeded scaffolds to determine therapeutic utility and regenerative potential in the immediate reconstruction of full-thickness wounds. Methods: Isolated LGR6+ epithelial stem cells were seeded onto a spectrum of acellular matrices and monitored in both in vitro and in vivo settings to determine their relative capacity to regenerate tissues and heal wounds. Results: Wound beds containing LGR6+ stem cell–seeded scaffolds showed significantly augmented rates of healing, epithelialization, and hair growth compared with controls. Gene and proteomic expression studies indicate that LGR6+ stem cell–seeded constructs up-regulate WNT, epidermal growth factor, and angiogenesis pathways. Finally, the addition of stromal vascular fraction to LGR6+ stem cell–seeded constructs induces polarized tissue formation, nascent hair growth, and angiogenesis within wounds. Conclusions: LGR6+ stem cells are able to undergo proliferation, differentiation, and migration following seeding onto a variety of collagen-based scaffolding. In addition, deployment of these constructs induces epithelialization, hair growth, and angiogenesis within wound beds. The addition of stromal vascular fraction to LGR6+ stem cell–containing scaffolds initiated an early form of tissue polarization, providing for the first time a clinically applicable stem cell–based construct that is capable of the repair of full-thickness wounds and hair regeneration. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Penile Transplantation: An Emerging Option for Genitourinary Reconstruction

Penile transplantation is an emerging option for patients with severe genital defects not amenable to traditional reconstructive options. In this article, we discuss the burgeoning problem of severe male genitourinary trauma in the military, the limitations of traditional reconstructive options in addressing these problems, and the potential for penile transplantation to provide improved outcomes. We also review the preclinical research and limited worldwide experience with penile transplantation to date, including lessons learned, and discuss the many important technical, logistical, and ethical considerations pertaining to penile transplantation that must be addressed to maximize the likelihood of successful implementation.

Incisional Negative Pressure Wound Therapy Following Ventral Hernia Repair Reduces Wound Complications and Hernia Recurrence: A Meta-Analysis.

BACKGROUND: Ventral hernia repair (VHR) is associated with postoperative wound complications and hernia recurrence, resulting in morbidity and significant healthcare costs. The purpose of this study was to identify whether postoperative wound complications and hernia recurrence are reduced by the application of negative pressure wound therapy to closed incisions (iNPWT) following VHR through systematic review and meta-analysis.

A Novel Method for the Repair of Critically Sized Bone Defects: Utilization of a Muscle Derived Stem Cell-Seeded Scaffold Augments Proliferation, Migration and Osteogenic Induction.

PURPOSE: Contemporary surgical reconstruction of large craniofacial defects, commonly suffered during trauma and lifesaving decompressive craniectomies, has seen tremendous evolution with the development of custom alloplast implants and rigid fixation elements. Although these implants and fixation devices are often capable of providing coverage and stabilization to smaller or less complex defects, they remain prone to infection, extrusion, migration and failure with larger complicated wounds. Within this study, we aim to assess the functionality and osteo-inductive capacity of an easily deliverable osteo-enriched scaffold construct containing hBMP-2 and traceable muscle derived stem cells (MDSCs). We hope to determine a pragmatic regenerative application of this system to civilian and military patients suffering from complex craniofacial defects which current methods cannot address. METHODS: Utilizing a murine model, C57BL/6 (n=60) mice received two identical 5mm full-thickness craniectomy defects using a standardized micro-drill core bit. At 8 weeks, defects were imaged using a mini-CT, laser scanning confocal microscopy and tissues collected for downstream assays including: focused osteo-induction gene and proteome arrays. Concurrently, in vitro studies utilizing baclovirus Premo Fucci® transduced MDSCs (fluorescent correlation to cell cycle stage) were monitored using a FV10i-LIV® live cell confocal imaging system. Quantitative data was extracted from confocal multi-sequence 3D-imaging of daily and real-time cell migration assays as well as cell cycle proliferation kinetic studies. Additionally cell-to-cell interaction and correlative osteo-differentiation characteristics were analyzed following scaffold substrate and hBMP-2 variation.

Cleft and Craniofacial Care During Military Pediatric Plastic Surgery Humanitarian Missions.

Background:Military pediatric plastic surgery humanitarian missions in the Western Hemisphere have been initiated and developed since the early 1990 s using the Medical Readiness Education and Training Exercise (MEDRETE) concept. Despite its initial training mission status, the MEDRETE has developed into the most common and advanced low level medical mission platform currently in use. The objective of this study is to report cleft- and craniofacial-related patient outcomes after initiation and evolution of a standardized treatment protocol highlighting lessons learned which apply to civilian plastic surgery missions. Methods:A review of the MEDRETE database for pediatric plastic surgery/cleft and craniofacial missions to the Dominican Republic from 2005 to 2009 was performed. A multidisciplinary team including a craniofacial surgeon evaluated all patients with a cleft/craniofacial and/or pediatric plastic condition. A standardized mission time line included predeployment site survey and predeployment checklist, operational brief, and postdeployment after action report. Deployment data collection, remote patient follow-up, and coordination with larger land/amphibious military operations was used to increase patient follow-up data. Data collected included sex, age, diagnosis, date and type of procedure, surgical outcomes including speech scores, surgical morbidity, and mortality. Results:Five hundred ninety-four patients with cleft/craniofacial abnormalities were screened by a multidisciplinary team including craniofacial surgeons over 4 years. Two hundred twenty-three patients underwent 330 surgical procedures (cleft lip, 53; cleft palate, 73; revision cleft lip/nose, 73; rhinoplasty, 15; speech surgery, 24; orthognathic/distraction, 21; general pediatric plastic surgery, 58; fistula repair, 12). Average follow-up was 30 months (range, 1–60). The complication rate was 6% (n = 13) (palate fistula, lip revision, dental/alveolar loss, revision speech surgery rate). The average pre-surgical (Pittsburgh Weighted Speech Score) speech score was 12 (range, 6–24). The average postsurgical speech score was 6 (range, 0–21). Average hospital stay was 3 days for cleft surgery. There were no major complications or mortality, 1 reoperation for bleeding or infection, and 12 patients required secondary operations for palatal fistula, unsatisfactory aesthetic result, malocclusion, or velopharygeal dysfunction. Conclusions:Military pediatric plastic surgery humanitarian missions can be executed with similar home institution results after the initiation and evolution of a standardized approach to humanitarian missions. The incorporation of a dedicated logistics support unit, a dedicated operational specialist (senior noncommissioned officer), a speech language pathologist, remote internet follow up, an liaison officer (host nation liaison physician participation), host nation surgical resident participation, and support from the embassy, Military Advisory Attachment Group, and United States Aid and International Development facilitated patient accurate patient evaluation and posttreatment follow-up. Movement of the mission site from a remote more austere environment to a centralized better equipped facility with host nation support to transport patients to the site facilitated improved patient safety and outcomes despite increasing the complexity of surgery performed.

Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle-Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects

Background: Regeneration of functional bone substrate remains a priority in reconstructive surgery especially for patients suffering from complex skeletal defects. Efforts to develop implantable osteoinductive constructs and novel osteoconductive materials remain at the forefront of industry forces and product line development. Despite advancement in clinical practice and bone biology, cancellous autograft remains the gold standard for procedures requiring osteogenic mechanisms of healing. This study investigates the utility of muscle-derived stem cells as a cellular therapy for definitive bone regeneration through a form of neo-osteogenesis. Methods: Adipose-derived stem cell, bone marrow–derived mesenchymal stem cell, and muscle-derived stem cell populations were isolated separately from C57BL/6 murine tissues and supplemented with collagen scaffolding with or without bone morphogenetic protein-2 to compare relative osteogenic potency and ultrastructure organization in both two- and three-dimensional systems. Parallel populations were bound to a deployable collagen implant within a syngeneic murine cranial defect model. Results: Although all populations provided and maintained mesenchymal stem cell multilineage capacity, adipose-derived stem cell– and bone marrow–derived mesenchymal stem cell–enriched constructs were capable of forming small bone aggregates. Defects receiving muscle-derived stem cells self-assembled a form of organized corticocancellous structures within two- and three-dimensional in vitro systems and within the in vivo model. Muscle-derived stem cells also augmented healing, implant angiogenesis, and diploic space formation. Conclusion: Muscle-derived stem cell–enriched implants appear to provide an autologous response to current industry-derived products and an attractive alternative to mesenchymal stem cells for the regeneration of corticocancellous bone and a vascularized diploic space.