Showing papers by "Geoffrey C. Gurtner published in 2014"

The Role of Hypoxia-Inducible Factor in Wound Healing.

Abstract: Significance: Poor wound healing remains a significant health issue for a large number of patients in the United States. The physiologic response to local wound hypoxia plays a critical role in determining the success of the normal healing process. Hypoxia-inducible factor-1 (HIF-1), as the master regulator of oxygen homeostasis, is an important determinant of healing outcomes. HIF-1 contributes to all stages of wound healing through its role in cell migration, cell survival under hypoxic conditions, cell division, growth factor release, and matrix synthesis throughout the healing process. Recent Advances: Positive regulators of HIF-1, such as prolyl-4-hydroxylase inhibitors, have been shown to be beneficial in enhancing diabetic ischemic wound closure and are currently undergoing clinical trials for treatment of several human-ischemia-based conditions. Critical Issues: HIF-1 deficiency and subsequent failure to respond to hypoxic stimuli leads to chronic hypoxia, which has been shown to contribute to the formation of nonhealing ulcers. In contrast, overexpression of HIF-1 has been implicated in fibrotic disease through its role in increasing myofibroblast differentiation leading to excessive matrix production and deposition. Both positive and negative regulators of HIF-1 therefore provide important therapeutic targets that can be used to manipulate HIF-1 expression where an excess or deficiency in HIF-1 is known to correlate with pathogenesis. Future Directions: Targeting HIF-1 during wound healing has many important clinical implications for tissue repair. Counteracting the detrimental effects of excessive or deficient HIF-1 signaling by modulating HIF-1 expression may improve future management of poorly healing wounds.

Angiogenic properties of dehydrated human amnion/chorion allografts: therapeutic potential for soft tissue repair and regeneration

Abstract: Background: Chronic wounds are associated with a number of deficiencies in critical wound healing processes, including growth factor signaling and neovascularization. Human-derived placental tissues are rich in regenerative cytokines and have been shown in randomized clinical trials to be effective for healing chronic wounds. In this study, PURION® Processed (MiMedx Group, Marietta, GA) dehydrated human amnion/chorion membrane tissue allografts (dHACM, EpiFix®, MiMedx) were evaluated for properties to support wound angiogenesis. Methods: Angiogenic growth factors were identified in dHACM tissues using enzyme-linked immunosorbent assays (ELISAs), and the effects of dHACM extract on human microvascular endothelial cell (HMVEC) proliferation and production of angiogenic growth factors was determined in vitro. Chemotactic migration of human umbilical vein endothelial cells (HUVECs) toward pieces of dHACM tissue was determined using a standard in vitro transwell assay. Neovascularization of dHACM in vivo was determined utilizing a murine subcutaneous implant model. Results: Quantifiable levels of the angiogenic cytokines angiogenin, angiopoietin-2 (ANG-2), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), heparin binding epidermal growth factor (HB-EGF), hepatocyte growth factor (HGF), platelet derived growth factor BB (PDGF-BB), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) were measured in dHACM. Soluble cues promoted HMVEC proliferation in vitro and increased endogenous production of over 30 angiogenic factors by HMVECs, including granulocyte macrophage colony-stimulating factor (GM-CSF), angiogenin, transforming growth factor β 3( TGF-β3), and HB-EGF. 6.0 mm disks of dHACM tissue were also found to recruit migration of HUVECs in vitro. Moreover, subcutaneous dHACM implants displayed a steady increase in microvessels over a period of 4 weeks, indicative of a dynamic intra-implant neovascular process. Conclusions: Taken together, these results demonstrate that dHACM grafts: 1) contain angiogenic growth factors retaining biological activity; 2) promote amplification of angiogenic cues by inducing endothelial cell proliferation and migration and by upregulating production of endogenous angiogenic growth factors by endothelial cells; and 3) support the formation of blood vessels in vivo. dHACM grafts are a promising wound care therapy with the potential to promote revascularization and tissue healing within poorly vascularized, non-healing wounds.

Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellular subpopulations

Abstract: Pathophysiologic changes associated with diabetes impair new blood vessel formation and wound healing. Mesenchymal stem cells derived from adipose tissue (ASCs) have been used clinically to promote healing, although it remains unclear whether diabetes impairs their functional and therapeutic capacity. In this study, we examined the impact of diabetes on the murine ASC niche as well as on the potential of isolated cells to promote neovascularization in vitro and in vivo. A novel single-cell analytical approach was used to interrogate ASC heterogeneity and subpopulation dynamics in this pathologic setting. Our results demonstrate that diabetes alters the ASC niche in situ and that diabetic ASCs are compromised in their ability to establish a vascular network both in vitro and in vivo. Moreover, these diabetic cells were ineffective in promoting soft tissue neovascularization and wound healing. Single-cell transcriptional analysis identified a subpopulation of cells which was diminished in both type 1 and type 2 models of diabetes. These cells were characterized by the high expression of genes known to be important for new blood vessel growth. Perturbations in specific cellular subpopulations, visible only on a single-cell level, represent a previously unreported mechanism for the dysfunction of diabetic ASCs. These data suggest that the utility of autologous ASCs for cell-based therapies in patients with diabetes may be limited and that interventions to improve cell function before application are warranted.

Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension

Abstract: Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34–PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)–positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.

Studies in fat grafting: Part III. Fat grafting irradiated tissue--improved skin quality and decreased fat graft retention.

Abstract: Background Following radiation therapy, skin becomes fibrotic and can present a difficult problem for reconstructive surgeons. There is an increasing belief that fat grafting under radiated skin can reverse the damage caused by radiation. The present study evaluated the effect of fat grafting on irradiated skin, along with fat graft quality and retention rates in irradiated tissue.

Paracrine mechanism of angiogenesis in adipose-derived stem cell transplantation.

Abstract: Introduction Adipose-derived stem cells (ASCs) have shown potential for cell-based therapy in the field of plastic surgery. However, the fate of ASCs after transplantation and the mechanism(s) of their biologic capabilities remain unclear.

Capillary Force Seeding of Hydrogels for Adipose-Derived Stem Cell Delivery in Wounds

Abstract: Effective skin regeneration therapies require a successful interface between progenitor cells and biocompatible delivery systems. We previously demonstrated the efficiency of a biomimetic pullulan-collagen hydrogel scaffold for improving bone marrow-derived mesenchymal stem cell survival within ischemic skin wounds by creating a “stem cell niche” that enhances regenerative cytokine secretion. Adipose-derived mesenchymal stem cells (ASCs) represent an even more appealing source of stem cells because of their abundance and accessibility, and in this study we explored the utility of ASCs for hydrogel-based therapies. To optimize hydrogel cell seeding, a rapid, capillary force-based approach was developed and compared with previously established cell seeding methods. ASC viability and functionality following capillary hydrogel seeding were then analyzed in vitro and in vivo. In these experiments, ASCs were seeded more efficiently by capillary force than by traditional methods and remained viable and functional in this niche for up to 14 days. Additionally, hydrogel seeding of ASCs resulted in the enhanced expression of multiple stemness and angiogenesis-related genes, including Oct4, Vegf, Mcp-1, and Sdf-1. Moving in vivo, hydrogel delivery improved ASC survival, and application of both murine and human ASC-seeded hydrogels to splinted murine wounds resulted in accelerated wound closure and increased vascularity when compared with control wounds treated with unseeded hydrogels. In conclusion, capillary seeding of ASCs within a pullulan-collagen hydrogel bioscaffold provides a convenient and simple way to deliver therapeutic cells to wound environments. Moreover, ASC-seeded constructs display a significant potential to accelerate wound healing that can be easily translated to a clinical setting.

Challenges and Opportunities in Drug Delivery for Wound Healing

Abstract: Significance: Chronic wounds remain a significant public health problem. Alterations in normal physiological processes caused by aging or diabetes lead to impaired tissue repair and the development of chronic and nonhealing wounds. Understanding the unique features of the wound environment will be required to develop new therapeutics that impact these disabling conditions. New drug-delivery systems (DDSs) may enhance current and future therapies for this challenging clinical problem. Recent Advances: Historically, physical barriers and biological degradation limited the efficacy of DDSs in wound healing. In aiming at improving and optimizing drug delivery, recent data suggest that combinations of delivery mechanisms, such as hydrogels, small molecules, RNA interference (RNAi), as well as growth factor and stem cell-based therapies (biologics), could offer exciting new opportunities for improving tissue repair. Critical Issues: The lack of effective therapeutic approaches to combat the significant disability associated with chronic wounds has become an area of increasing clinical concern. However, the unique challenges of the wound environment have limited the development of effective therapeutic options for clinical use. Future Directions: New platforms presented in this review may provide clinicians and scientists with an improved understanding of the alternatives for drug delivery in wound care, which may facilitate the development of new therapeutic approaches for patients.

Tracking the elusive fibrocyte: identification and characterization of collagen-producing hematopoietic lineage cells during murine wound healing

Abstract: Fibrocytes are a unique population of circulating cells reported to exhibit characteristics of both hematopoietic and mesenchymal cells, and play an important role in wound healing However, putative fibrocytes have been found to lose expression of hematopoietic surface markers such as CD45 during differentiation, making it difficult to track these cells in vivo with conventional methodologies In this study, to distinguish hematopoietic and nonhematopoietic cells without surface markers, we took advantage of the gene vav 1, which is expressed solely on hematopoietic cells but not on other cell types, and established a novel transgenic mouse, in which hematopoietic cells are irreversibly labeled with green fluorescent protein and nonhematopoietic cells with red fluorescent protein Use of single-cell transcriptional analysis in this mouse model revealed two discrete types of collagen I (Col I) expressing cells of hematopoietic lineage recruited into excisional skin wounds We confirmed this finding on a protein level, with one subset of these Col I synthesizing cells being CD45+ and CD11b+, consistent with the traditional definition of a fibrocyte, while another was CD45- and Cd11b-, representing a previously unidentified population Both cell types were found to initially peak, then reduce posthealing, consistent with a disappearance from the wound site and not a loss of identifying surface marker expression Taken together, we have unambiguously identified two cells of hematopoietic origin that are recruited to the wound site and deposit collagen, definitively confirming the existence and natural time course of fibrocytes in cutaneous healing

Wound healing: an update

Abstract: Wounds, both chronic and acute, continue to be a tremendous socioeconomic burden. As such, technologies drawn from many disciplines within science and engineering are constantly being incorporated into innovative wound healing therapies. While many of these therapies are experimental, they have resulted in new insights into the pathophysiology of wound healing, and in turn the development of more specialized treatments for both normal and abnormal wound healing states. Herein, we review some of the emerging technologies that are currently being developed to aid and improve wound healing after cutaneous injury.

A randomized controlled trial of the embrace advanced scar therapy device to reduce incisional scar formation

Abstract: Background Scarring represents a significant biomedical burden in clinical medicine. Mechanomodulation has been linked to scarring through inflammation, but until now a systematic approach to attenuate mechanical force and reduce scarring has not been possible.

The embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial.

Abstract: More than 200 million incisions are made in the world each year, all of which result in scarring, which is the body’s natural response to cutaneous tissue injury.1,2 Scarring creates both functional and aesthetic impairments and is associated with considerable psychosocial stress. Although there is currently no level I evidence for scar mitigation therapy, several procedures are widely used to reduce the impact of postsurgical scars. Revision surgery is the traditional treatment for improving scar appearance, generally focusing on either making the scar less noticeable or reframing the scar geometry so that it appears more like a natural anatomical crease.3,4 In the United States alone, more than 170,000 scar revision procedures were performed in 2011.5 Laser treatments have become increasingly popular in the past two decades, including carbon dioxide and pulsed dye lasers, and dermabrasion therapy is frequently used to smooth scars with irregular topology.6,7 Silicone gels, sheets, and tapes have also been used to minimize scarring postoperatively.8–10 Similarly, topical creams containing ingredients such as retinoic acid and onion extract have been used to reduce scar intensity, as have intralesional therapies containing corticosteroids or biomolecules.11,12 However, even the most scientifically grounded of these approaches, the human transforming growth factor-β3 drug Juvista (Renovo, Manchester, United Kingdom), failed to achieve efficacy in a phase III clinical trial.13 The impact of mechanical forces on fibrosis and scar formation has been known for over 100 years. Surgeons routinely strive to make incisions parallel to the Langer lines, corresponding to the orientation of native collagen fibers in the dermis, to minimize tension across the wound. Despite this intuitive knowledge of the relationship between mechanical force and scar formation, until recently, few studies had thoroughly explored the physiologic mechanisms underlying this interaction, and therapeutics aimed at reducing scarring through mechanomodulation have not been widely available. A recent report involving both pig and human incisions treated with a tension-shielding device postoperatively showed a highly significant reduction in scarring.14 Furthermore, the biology underlying mechanomodulation to reduce fibrosis in scarring of cutaneous wounds has been rigorously studied in a transgenic mouse model.15 These basic science and clinical studies strongly support a strategy for shielding healing wounds from mechanical forces to reduce scarring. In this article, we report clinical data using the embrace (Neodyne Biosciences, Inc., Menlo Park, Calif.) device following scar revision and potentially address the large unmet clinical need for significantly improving scar appearance following revision surgery. The embrace device creates a tension shield around the healing wound, which results in a reduced-stress environment conducive to wound healing with minimal fibrosis and scarring.14 We demonstrate the efficacy of this device through a randomized controlled trial of scar revision in 12 patients evaluated by four independent surgeons using a visual analogue scale system.

Intraoperative imaging of nipple perfusion patterns and ischemic complications in nipple-sparing mastectomies.

Abstract: Background Nipple-sparing mastectomies (NSM) have gained acceptance in the field of breast oncology. Ischemic complications involving the nipple–areolar complex (NAC) occur in 3–37 % of cases. Skin perfusion can be monitored intraoperatively using indocyanine green (IC-GREEN™, ICG) and a specialized infrared camera–computer system (SPY Elite™). The blood flow pattern to the breast skin and the NAC were evaluated and a classification scheme was developed.

Diabetes Irreversibly Depletes Bone Marrow–Derived Mesenchymal Progenitor Cell Subpopulations

Abstract: Diabetic vascular pathology is largely attributable to impairments in tissue recovery from hypoxia. Circulating progenitor cells have been postulated to play a role in ischemic recovery, and deficiencies in these cells have been well described in diabetic patients. Here, we examine bone marrow–derived mesenchymal progenitor cells (BM-MPCs) that have previously been shown to be important for new blood vessel formation and demonstrate significant deficits in the context of diabetes. Further, we determine that this dysfunction is attributable to intrinsic defects in diabetic BM-MPCs that are not correctable by restoring glucose homeostasis. We identify two transcriptionally distinct subpopulations that are selectively depleted by both type 1 and type 2 diabetes, and these subpopulations have provasculogenic expression profiles, suggesting that they are vascular progenitor cells. These results suggest that the clinically observed deficits in progenitor cells may be attributable to selective and irreversible depletion of progenitor cell subsets in patients with diabetes.

The Stanford Microsurgery and Resident Training (SMaRT) Scale: Validation of an on-line global rating scale for technical assessment

Abstract: INTRODUCTION We previously reported results of our on-line microsurgery training program, showing that residents who had access to our website significantly improved their cognitive and technical skills. In this study, we report an objective means for expert evaluators to reliably rate trainees' technical skills under the microscope, with the use of our novel global rating scale. METHODS "Microsurgery Essentials" (http://smartmicrosurgery.com) is our on-line training curriculum. Residents were randomly divided into 2 groups: 1 group reviewed this online resource and the other did not. Pre- and post-tests consisted of videotaped microsurgical sessions in which the trainee performed "microsurgery" on 3 different models: latex glove, penrose drain, and the dorsal vessel of a chicken foot. The SMaRT (Stanford Microsurgery and Resident Training) scale, consisting of 9 categories graded on a 5-point Likert scale, was used to assess the trainees. Results were analyzed with ANOVA and Student t test, with P less than 0.05 indicating statistical significance. RESULTS Seventeen residents participated in the study. The SMaRT scale adequately differentiated the performance of more experienced senior residents (PGY-4 to PGY-6, total average score=3.43) from less experienced junior residents (PGY-1 to PGY-3, total average score=2.10, P 0.05). Additionally, junior residents who had access to our website showed a significant increase in their graded technical performance by 0.7 points when compared to residents who did not have access to the website who showed an improvement of only 0.2 points (P=0.01). CONCLUSIONS Our SMaRT scale is valid and reliable in assessing the microsurgical skills of residents and other trainees. Current trainees are more likely to use self-directed on-line education because of its easy accessibility and interactive format. Our global rating scale can help ensure residents are achieving appropriate technical milestones.

Studies in fat grafting: Part I. Effects of injection technique on in vitro fat viability and in vivo volume retention.

Abstract: Background:Fat grafting has become increasingly popular for the correction of soft-tissue deficits at many sites throughout the body. Long-term outcomes, however, depend on delivery of fat in the least traumatic fashion to optimize viability of the transplanted tissue. In this study, the authors com

Noncontact, low-frequency ultrasound therapy enhances neovascularization and wound healing in diabetic mice.

Abstract: Background Chronic wounds are a major source of morbidity for patients and represent a significant health burden. Implementing noninvasive techniques that accelerate healing of these wounds would provide great benefit. Ultrasound appears to be an effective modality for the treatment of chronic wounds in humans. MIST Therapy is a noncontact, low-frequency ultrasound treatment delivered through a saline mist. A variety of mechanisms have been proposed to explain the efficacy of ultrasound therapy, but the underlying molecular and cellular pathways impacted by this technique remain unclear. The in vivo effect of noncontact, low-frequency ultrasound was therefore examined in a humanized excisional wound model.

Transcriptional profiling of rapamycin-treated fibroblasts from hypertrophic and keloid scars.

Abstract: Excess scar formation after cutaneous injury can result in hypertrophic scar (HTS) or keloid formation. Modern strategies to treat pathologic scarring represent nontargeted approaches that produce suboptimal results. Mammalian target of rapamycin (mTOR), a central mediator of inflammation, has been proposed as a novel target to block fibroproliferation. To examine its mechanism of action, we performed genomewide microarray on human fibroblasts (from normal skin, HTS, and keloid scars) treated with the mTOR inhibitor, rapamycin. Hypertrophic scar and keloid fibroblasts demonstrated overexpression of collagen I and III that was effectively abrogated with rapamycin. Blockade of mTOR specifically impaired fibroblast expression of the collagen biosynthesis genes PLOD, PCOLCE, and P4HA, targets significantly overexpressed in HTS and keloid scars. These data suggest that pathologic scarring can be abrogated via modulation of mTOR pathways in procollagen and collagen processing.

Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing.

Abstract: Objective:To investigate how epithelial mechanotransduction pathways impact wound repair.Background:Mechanical forces are increasingly recognized to influence tissue repair, but their role in chronic wound pathophysiology remains unknown. Studies have shown that chronic wounds exhibit high levels of

The Role of Stem Cells in Aesthetic Surgery: Fact or Fiction?

Abstract: Background Stem cells are attractive candidates for the development of novel therapies, targeting indications that involve functional restoration of defective tissue. Although most stem cell therapies are new and highly experimental, there are clinics around the world that exploit vulnerable patients with the hope of offering supposed stem cell therapies, many of which operate without credible scientific merit, oversight, or other patient protection. Methods The authors review the potential and the drawbacks of incorporation of stem cells in cosmetic procedures. A review of U.S. Food and Drug Administration-approved indications and ongoing clinical trials with adipose stem cells is provided. Furthermore, a "snapshot" analysis of Web sites using the search terms "stem cell therapy" or "stem cell treatment" or "stem cell facelift" was performed. Results Despite the protective net cast by regulatory agencies such as the U.S. Food and Drug Administration and professional societies such as the American Society of Plastic Surgeons, the authors are witnessing worrying advertisements for procedures such as stem cell face lifts, stem cell breast augmentations, and even stem cell vaginal rejuvenation. The marketing and promotion of stem cell procedures in aesthetic surgery is not adequately supported by clinical evidence in the majority of cases. Conclusions Stem cells offer tremendous potential, but the marketplace is saturated with unsubstantiated and sometimes fraudulent claims that may place patients at risk. With plastic surgeons at the forefront of stem cell-based regenerative medicine, it is critically important that they provide an example of a rigorous approach to research, data collection, and advertising of stem cell therapies.

Mechanical offloading of incisional wounds is associated with transcriptional downregulation of inflammatory pathways in a large animal model.

Abstract: Cutaneous scarring is a major source of morbidity and current therapies to mitigate scar formation remain ineffective. Although wound fibrosis and inflammation are highly linked, only recently have mechanical forces been implicated in these pathways. Our group has developed a topical polymer device that significantly reduces post-injury scar formation via the manipulation of mechanical forces. Here we extend these studies to examine the genomewide transcriptional effects of mechanomodulation during scar formation using a validated large animal model, the red Duroc pig. We demonstrate that mechanical loading of incisional wounds upregulates expression of genes associated with inflammatory and fibrotic pathways, and that device-mediated offloading of these wounds reverses these effects. Validation studies are needed to clarify the clinical significanceof these findings.

Studies in fat grafting: Part II. Effects of injection mechanics on material properties of fat.

Abstract: Although fat grafting can address many soft-tissue deficits, results remain inconsistent. In this study, the authors compared physical properties of fat following injection using an automated, low-shear device or the modified Coleman technique.Lipoaspirate was obtained from nine patients and processed for injection using either a modified Coleman technique or an automated, low-shear device. Fat was passed through a 2-mm cannula and compared with minimally processed fat. A rheometer was used to measure the storage modulus and shear rate at which tissues began to lose their solid-like properties. Viscosity was also measured, and gross properties of treatment groups were evaluated qualitatively with a glass slide test.Fat injected through an automated, low-shear device closely matched physical properties of minimally processed fat. The storage modulus (G') of fat for the device group was greater than for the modified Coleman group, and the onset of breakdown was delayed. Similarly, viscosity measurement of fat from the automated device closely matched minimally processed fat and was greater than that of othe modified Coleman group.The physical properties of lipoaspirate processed using an automated, low-shear device with a 2-mm cannula preserved the intactness of fat more than the modified Coleman technique. The authors' rheologic data demonstrate less damage using an automated device compared with the modified Coleman technique and potentially support its use for improved fat graft integrity.

Epidermal or dermal specific knockout of PHD-2 enhances wound healing and minimizes ischemic injury.

Abstract: Introduction: Hypoxia-inducible factor (HIF)-1α, part of the heterodimeric transcription factor that mediates the cellular response to hypoxia, is critical for the expression of multiple angiogenic growth factors, cell motility, and the recruitment of endo

Abstract 10: Global and Endothelial Cell Specific Deletion of SDF-1 Results in Delayed Wound Healing.

Abstract: Zeshaan N Maan, MBBS, MS, MRCS1; Natalie Ho, High school1; Robert C Rennert, BA1; Dominik Duscher, MD1; Michael Sorkin, MD1; Melanie Rodrigues, PhD1; Jerry Chen, MD1; Ivan N Vial, MD2; Michael Januszyk, MD1; Michael Findlay, MBBS, PhD1; Michael Hu, MD1; Graham Walmsley, BA1; Michael T Longaker, MD, MBA1; Geoffrey C Gurtner, MD, FACS1 1Stanford University School of Medicine, Stanford, CA, University of Pittsburgh, Pittsburgh, PA

Reply: tension shielding with the embrace device: does it really improve scars?

Abstract: Reply: Tension Shielding with the embrace Device: Does It Really Improve Scars? Sir: We are grateful to Dr. Swanson for his thoughtful comments. We are gratified that Dr. Swanson believes that decreasing scar formation is an “extraordinary claim” and that the “implications are mind-boggling.” We are confident that the body of published scientific and clinical work supporting mechanomodulation as a safe and effective approach to decrease scar formation easily meets the bar as “extraordinary evidence.” We wholeheartedly agree with the concept of “science before marketing.” We would respectfully point out that the embrace device (Neodyne Biosciences, Inc., Menlo Park, Calif.) represents the culmination of a 20-year journey to develop scientifically based and clinically validated technologies to improve scars. This work began with the earliest human fetal surgery experience1 and initial observation of scarless fetal wound healing,2–21 extended across adult wound healing, including smalland large-animal models,22–30 and has been subjected to three clinical trials.31–33 It has been funded by grants from the National Institutes of Health, the U.S. Department of Defense, and numerous private foundations. It has been conducted at the leading academic medical centers in the world and has been published in the highest impact scientific and surgical journals, including Nature (impact factor, 38), Science (impact factor, 31), The New England Journal of Medicine (impact factor, 51), Nature Medicine (impact factor, 24), Annals of Surgery (impact factor, 6) and, of course, Plastic and Reconstructive Surgery (impact factor, 3). Possibly, even a cursory read of this substantial literature will convince Dr. Swanson that a lot of science was performed before marketing was even a glimmer in our eyes. Dr. Swanson raises concerns about the small sample size (10 patients) and our use of photographs for analysis of the scars. The analysis was performed by three board-certified plastic surgeons evaluating the photographs in a blinded fashion. Despite our sample size of 10 patients, the observed “difference” between the half of the revised scar treated with the embrace device versus the control-treated side was highly significant (p < 0.005). Dr. Swanson also had concerns with the scar revisions performed at different anatomical sites. Scars occur all over the body and, thus, the embrace device was tested on scars in several locations. Dr. Swanson also stated that “primary abdominoplasties would have provided a similar amount of tissue removal and similar tension from the same part of the body with symmetrical scars—ideal for side-by-side comparisons.” What Dr. Swanson could not have known is that we have performed a soon-to-be-published randomized controlled trial on primary abdominoplasties33: one side was treated with the embrace device, and the other side received the therapy that worked best in the experience of the treating surgeons. The results were again highly significant in favor of the embrace device. Furthermore, the difference in favor of the embracetreated side was more significant at 1 year than it was near the end of the treatment, demonstrating that the results were durable. The article describing this randomized controlled trial has recently been accepted for publication by Plastic and Reconstructive Surgery. Dr. Swanson also voiced concerns that “Patients seeking scar revisions are a selected patient group (obviously not good scar formers) that may not be comparable to first-time surgical patients.” The concerns raised about scar revisions are precisely the reasons we conducted this study. Whether or not these patients are considered “obviously not good scar-formers” is not the issue. The issue is whether a revision followed DISCLOSURE The author has no financial interest in any of the products or devices mentioned in this communication. The author has no conflicts of interest to disclose. There was no outside funding for this study.

Impaired Angiogenesis: A Critical Contributor to Problematic Fracture Healing in Diabetes

Abstract: RESULTS: Aging is associated with cell intrinsic changes in the skeletal stem cell population and a decline in their regenerative potential. Heterochronic parabiosis rejuvenates aged bones by altering osteoclastogenesis. Transcriptional and metabolomic changes are associated with the age-related functional decline of skeletal stem cells. Manipulation of BMP and Wnt signaling pathways can rejuvenate aged bone by stimulating their innate regenerative capacity.