Showing papers by "Geoffrey C. Gurtner published in 2009"

Human skin wounds: a major and snowballing threat to public health and the economy.

Abstract: In the United States, chronic wounds affect 6.5 million patients. An estimated excess of US$25 billion is spent annually on treatment of chronic wounds and the burden is rapidly growing due to increasing health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity worldwide. The annual wound care products market is projected to reach $15.3 billion by 2010. Chronic wounds are rarely seen in individuals who are otherwise healthy. In fact, chronic wound patients frequently suffer from "highly branded" diseases such as diabetes and obesity. This seems to have overshadowed the significance of wounds per se as a major health problem. For example, NIH's Research Portfolio Online Reporting Tool (RePORT; http://report.nih.gov/), directed at providing access to estimates of funding for various disease conditions does list several rare diseases but does not list wounds. Forty million inpatient surgical procedures were performed in the United States in 2000, followed closely by 31.5 million outpatient surgeries. The need for post-surgical wound care is sharply on the rise. Emergency wound care in an acute setting has major significance not only in a war setting but also in homeland preparedness against natural disasters as well as against terrorism attacks. An additional burden of wound healing is the problem of skin scarring, a $12 billion annual market. The immense economic and social impact of wounds in our society calls for allocation of a higher level of attention and resources to understand biological mechanisms underlying cutaneous wound complications.

The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues

Abstract: Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1α (HIF-1α), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1α functional activity was specifically caused by impaired HIF-1α binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1α/p300 interaction and transactivation by HIF-1α. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention.

IFATS collection: Adipose stromal cells adopt a proangiogenic phenotype under the influence of hypoxia.

Abstract: Evolving evidence suggests a possible role for adipose stromal cells (ASCs) in adult neovascularization, although the specific cues that stimulate their angiogenic behavior are poorly understood. We evaluated the effect of hypoxia, a central mediator of new blood vessel development within ischemic tissue, on proneovascular ASC functions. Murine ASCs were exposed to normoxia (21% oxygen) or hypoxia (5%, 1% oxygen) for varying lengths of time. Vascular endothelial growth factor (VEGF) secretion by ASCs increased as an inverse function of oxygen tension, with progressively higher VEGF expression at 21%, 5%, and 1% oxygen, respectively. Greater VEGF levels were also associated with longer periods in culture. ASCs were able to migrate towards stromal cell-derived factor (SDF)-1, a chemokine expressed by ischemic tissue, with hypoxia augmenting ASC expression of the SDF-1 receptor (CXCR4) and potentiating ASC migration. In vivo, ASCs demonstrated the capacity to proliferate in response to a hypoxic insult remote from their resident niche, and this was supported by in vitro studies showing increasing ASC proliferation with greater degrees of hypoxia. Hypoxia did not significantly alter the expression of endothelial surface markers by ASCs. However, these cells did assume an endothelial phenotype as evidenced by their ability to tubularize when seeded with differentiated endothelial cells on Matrigel. Taken together, these data suggest that ASCs upregulate their proneovascular activity in response to hypoxia, and may harbor the capacity to home to ischemic tissue and function cooperatively with existing vasculature to promote angiogenesis. STEM CELLS 2009;27:266–274

Aging and Diabetes Impair the Neovascular Potential of Adipose-Derived Stromal Cells

Abstract: Multipotent mesenchymal stromal cells are capable of osteogenic, chondrogenic, myogenic, and adipogenic differentiation.1,2 Although mesenchymal stromal cells have been harvested primarily from bone marrow, these cells can also be isolated from several other tissue compartments, particularly adipose tissue.3 A comparative analysis of mesenchymal stromal cells obtained from bone marrow and adipose tissue clearly demonstrated that adipose-derived stromal cells are equivalent to bone marrow–derived mesenchymal stromal cells with regard to morphology, cell surface receptor profile, and differentiation capacity.4–6 In addition, adipose-derived stromal cells offer distinct advantages over bone marrow–derived mesenchymal stromal cells because they are readily accessible, plentiful, and expandable. Therefore, the accessibility, abundance, and multilineage differentiation capacity of adipose-derived stromal cells has stimulated tremendous interest in using this cell population for regeneration and replacement of mesenchymal-derived tissues such as bone, cartilage, and muscle.7 Recent reports describing the ability of adipose-derived stromal cells to differentiate into vascular/endothelial cells has inspired many researchers to investigate the use of adipose-derived stromal cells to enhance neovascularization for the treatment of ischemic disorders.8 Postnatal neovascularization was previously thought to occur only by angiogenesis, which is the formation of new blood vessels through the proliferation and remodeling of differentiated endothelial cells derived from existing blood vessels.9 It is now well established that postnatal neovascularization also occurs by vasculogenesis, which is the de novo formation of blood vessels through the recruitment, proliferation, and differentiation of stem/progenitor cells.10,11 A significant amount of data have been published regarding the neovascular potential of bone marrow–derived mesenchymal stromal cells, and recently adipose-derived stromal cells have also been reported to possess similar vascular capabilities.12,13 Human and murine adipose-derived stromal cells have been shown to release many potent angiogenic factors, differentiate into endothelial cells, and form tubules on Matrigel in vitro.14–16 Similarly, in vivo studies have demonstrated that human and murine adipose-derived stromal cells can incorporate into blood vessels by differentiating into endothelial cells and subsequently enhance the recovery of perfusion in a murine model of hind-limb ischemia.14–16 However, these previous reports have studied only wild-type adipose-derived stromal cells and have not yet explored adipose-derived stromal cells derived from aged or diabetic populations, as would be important for human clinical application. Advanced age17,18 and diabetes19 are major risk factors for vascular complications such as cardiovascular disease, peripheral vascular disease, and impaired wound healing. The extent of ischemic damage resulting from these complications is greatly increased by the impaired ability to form new blood vessels by means of angiogenesis and vasculogenesis following a hypoxic injury.20–22 Our study aims to explore the in vitro vascular biology of adipose-derived stromal cells and investigate whether the intrinsic neovascular potential of adipose-derived stromal cells is altered with advanced age or diabetes mellitus type 1 or 2.

Comparative healing of surgical incisions created by the PEAK PlasmaBlade, conventional electrosurgery, and a scalpel.

Abstract: Background: The PEAK PlasmaBlade is a new electrosurgical device that uses pulsed radiofrequency to generate a plasma-mediated discharge along the exposed rim of an insulated blade, creating an effective cutting edge while the blade stays near body temperature. Methods: Full-thickness incisions were made on the dorsums of pigs with the PlasmaBlade,aconventionalelectrosurgicaldevice,andascalpel,andbloodloss was quantified. Wounds were harvested at designated time points, tested for wound tensile strength, and examined histologically for scar formation and tissue damage. Results: Bleeding was reduced significantly (59 percent) in PlasmaBlade incisions compared with scalpel incisions, and acute thermal damage from the PlasmaBlade (66 5 m) was significantly less than both cut and coagulation mode electrosurgical incisions (456 35 m and 615 22 m, respectively). Histologic scoring for injury and wound strength was equivalent between the PlasmaBlade and scalpel incisions. By 6 weeks, the healed PlasmaBlade and scalpel incisions were approximately three times stronger, and scar cosmetic appearance was significantly better compared with electrosurgical incisions. Conclusions: The PlasmaBlade is a promising new surgical instrument that provides atraumatic, scalpel-like cutting precision and electrosurgical-like hemostasis, resulting in minimal bleeding, tissue injury, and scar formation. (Plast. Reconstr. Surg. 124: 1849, 2009.)

SDF-1α expression during wound healing in the aged is HIF dependent

Abstract: Background:Age-related impairments in wound healing are associated with decreased neovascularization, a process that is regulated by hypoxia-responsive cytokines, including stromal cell–derived factor (SDF)-1α. Interleukin-1β is an important inflammatory cytokine involved in wound healing and is bel

Mesenchymal stem cells can participate in ischemic neovascularization.

Abstract: Background:Cells from the bone marrow contribute to ischemic neovascularization, but the identity of these cells remains unclear. The authors identify mesenchymal stem cells as a bone marrow–derived progenitor population that is able to engraft into peripheral tissue in response to ischemia.Methods:

Tissue engineering using autologous microcirculatory beds as vascularized bioscaffolds

Abstract: Classic tissue engineering paradigms are limited by the incorporation of a functional vasculature and a reliable means for reimplantation into the host circulation. We have developed a novel approach to overcome these obstacles using autologous explanted microcirculatory beds (EMBs) as bioscaffolds for engineering complex three-dimensional constructs. In this study, EMBs consisting of an afferent artery, capillary beds, efferent vein, and surrounding parenchymal tissue are explanted and maintained for 24 h ex vivo in a bioreactor that preserves EMB viability and function. Given the rapidly advancing field of stem cell biology, EMBs were subsequently seeded with three distinct stem cell populations, multipotent adult progenitor cells (MAPCs), and bone marrow and adipose tissue-derived mesenchymal stem cells (MSCs). We demonstrate MAPCs, as well as MSCs, are able to egress from the microcirculation into the parenchymal space, forming proliferative clusters. Likewise, human adipose tissue-derived MSCs were a...

Threads of Hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof

Abstract: The present invention provides threads of hyaluronic acid, and/or derivatives thereof, methods of making thereof and uses thereof, for example, in aesthetic applications (e.g., dermal fillers), surgery (sutures), drug delivery, etc.

A recommended protocol for the immediate postoperative care of lower extremity free-flap reconstructions.

Abstract: The success of lower extremity microsurgical reconstructions may be compromised postoperatively secondary to several factors, including thrombosis, infection, bleeding, and edema. To address edema, surgeons may use protocols for gradually dangling and/or wrapping the affected extremity. Such protocols vary widely among surgeons and are typically based on training and/or prior experience. To that end, we distributed surveys to five plastic surgeons who are experienced in microvascular lower extremity reconstruction at five different institutions. The surveys inquired about postoperative management protocols for lower extremity free flaps with regard to positioning, compression, initiation and progression of postoperative mobilization, nonweightbearing and weightbearing ambulation, assessment of flap viability, and flap success rate. These protocols were then evaluated for similarities to create a consensus of postoperative management guidelines. Progressive periods of leg dependency and compression therapy emerged as important elements. Although the consensus protocol developed in this study is considered safe by each participant, we do not intend for these recommendations to serve as a standard of care, nor do we suggest that any one particular protocol leads to improved outcomes. However, these recommendations may serve as a guide for less experienced surgeons or those without a protocol in place.

Osteoblasts stimulated with pulsed electromagnetic fields increase HUVEC proliferation via a VEGF-A independent mechanism.

Abstract: The clinically beneficial effect of low frequency pulsed electromagnetic fields (ELF-PEMF) on bone healing has been described, but the exact mechanism of action remains unclear. A recent study suggests that there is a direct autocrine mitogenic effect of ELF-PEMF on angiogenesis. The hypothesis of this study is that ELF-PEMF also has an indirect effect on angiogenesis by manipulation of vascular endothelial growth factor (VEGF)-A-based paracrine intercellular communication with neighboring osteoblasts. Conditioned media experiments measured fetal rat calvarial cell (FRC) and human umbilical vein endothelial cell (HUVEC) proliferation using tritiated thymidine uptake. We demonstrate that ELF-PEMF (15 Hz, 1.8 mT, for 8 h) has an indirect effect on the proliferation rate of both endothelial cells and osteoblasts in vitro by altering paracrine mediators. Conditioned media from osteoblast cells stimulated with ELF-PEMF increased endothelial proliferation 54-fold, whereas media from endothelial cells stimulated with ELF-PEMF did not affect osteoblast proliferation. We examined the role of the pro-angiogenic mediator VEGF-A in the mitogenic effect of ELF-PEMF-stimulated osteoblast media on endothelial cells. The production of VEGF-A by FRC as measured by ELISA was not changed by exposure to PEMF, and blocking experiments demonstrated that the ELF-PEMF-induced osteoblast-derived endothelial mitogen observed in these studies was not VEGF-A, but some other soluble angiogenic mediator.

Methods for the treatment or prevention of scars and/or keloids

Abstract: Devices, bandages, kits and methods are described that can control or regulate the mechanical environment of a wound to ameliorate scar and/or keloid formation. The mechanical environment of a wound includes stress, strain, and any combination of stress and strain. The control of a wound's mechanical environment can be active, passive, dynamic, or static. The devices are configured to be removably secured to a skin surface in proximity to the wound site and shield the wound from endogenous and/or exogenous stress.

Treating chronic wound infections with genetically modified free flaps

Abstract: Background: The success of antimicrobial therapy has been impaired by the emergence of resistant bacterial strains. Antimicrobial peptides are ubiquitous proteins that are part of the innate immune system and are successful against such antibiotic-resistant microorganisms. The authors have previously demonstrated the feasibility of protein delivery via microvascular free flap gene therapy and here they examine this approach for recalcitrant infections. Methods: The authors investigated the production of the human cathelicidin antimicrobial peptide-LL37, delivered by ex vivo transduction of the rodent superficial inferior epigastric free flap with Ad/CMV-LL37. The vascular permeabilizing agent vascular endothelial growth factor ( VEGF) was co-administered during ex vivo transduction with adenoviral vectors in an attempt to augment transduction efficiency. A rodent model of chronic wound/foreign body infection seeded with bioluminescent Staphylococcus aureus was used to assess the biological efficacy of delivering therapeutic antimicrobial genes using this technology. Results: The authors were successful in demonstrating significant LL37 expression, which persisted for 14 days after ex vivo transduction with Ad/CMV-LL37. Transduction efficiency was significantly improved with the co-administration of 5 mu g of VEGF during transduction without significantly increasing systemic dissemination of adenovirus or systemic toxicity. They were able to demonstrate in the rodent model of chronic wound/foreign body infections a significant reduction in bacterial loads from infected catheters following transduction with Ad/CMV-LL37 and increased bacterial clearance. Conclusion: This study demonstrates for the first time that microbicidal gene therapy via microvascular free flaps is able to clear chronic infections such as occurs with osteomyelitis resulting from trauma or an infected foreign body. ( Plast. Reconstr. Surg. 123: 1157, 2009.)

From bedside to bench and back again: technology innovation in plastic surgery.

Abstract: Innovation is the primary driver for success in industry and medicine. Plastic surgery’s roots lie in devising innovative solutions to difficult clinical problems. It is likely that clinical innovation will be the key to our ongoing success and survival as a specialty. Unlike neurosurgery or cardiology, plastic surgery does not “own” any part of the human body, and our continued growth depends on the development of new solutions to unmet medical needs. Fortunately, we have an illustrious history of innovation, with advancements such as microsurgery, muscle flaps, tissue expansion, craniofacial surgery, transplantation, liposuction, and laser technology all being driven by practicing plastic surgeons. Unfortunately, medical innovation in 2009 is far different from how it was in the 1950s and 1960s. Today, there is increased scrutiny by the U.S. Food and Drug Administration on new products, increasing regulatory complexity in human trials, and an exponential growth in the number of patents filed. What this means for plastic surgeons is that we need to develop a systematic way to innovate and change our specialty in the same way our predecessors did. This will require a fresh platform that will be provided by a new meeting supported by our Plastic Surgery Educational Foundation, Plastic Surgery Research Council, and American Society of Plastic Surgeons taking place in the spring 2010, in Monterey, California, called Technology Innovation in Plastic Surgery. This meeting will be held immediately before the Plastic Surgery Research Council meeting in the same location. All new technologies begin with an unmet need. To develop a new technology, it is also important to understand the scientific knowledge base in a given area (e.g., what causes cellulite). To innovate also requires a detailed exploration of the technical limitations of existing devices and the economic and reimbursement environment that may stimulate or impede innovation in this area. What is required is an ongoing dialogue between plastic surgeons (who understand the clinical problem) and technology developers (who understand what is technically possible). This will undoubtedly lead to the development of more effective technologies that more fully address the needs of patients and physicians to improve the delivery of medical care. The innovation and commercialization processes are well understood, and plastic surgeons must be familiar with each step of the journey. The critical beginning for developing new technology is an idea based on a human problem. The moment of invention can occur anywhere: in the operating room, in the office, or while reading the literature. Plastic surgeons, on a daily or weekly basis, think of ways to improve the outcomes for their patients. Unfortunately, these ideas are not routinely translated into products that can change clinical practice and benefit thousands of patients. Once a plastic surgeon thinks of a novel technology, the first step is to look through the literature and the U.S. Patent and Trademark Office database to see whether it already exists. This can be done online in a few hours and will help the practitioner know what alternative technologies may already exist. If the idea is novel, intellectual property should be developed through filing of provisional patents, which can be done for less than $100 by the surgeon-inventor himself of herself. From the Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, and the Department of Plastic Surgery, University of Texas Southwestern School of Medicine. Received for publication July 17, 2009; accepted July 21, 2009. Copyright ©2009 by the American Society of Plastic Surgeons

Topical and Transdermal Delivery of HIF-1 Modulators to Prevent and Treat Chronic Wounds

Abstract: Compositions and methods are provided for the prevention and treatment of chronic wounds, including, without limitation, pressure ulcers and diabetic ulcers, by transdermal delivery of an agent that increases activity of HIF-1α in the wound.

Intracranial microvascular free flaps.

Abstract: Large acquired intracranial defects can result from trauma or surgery. When reoperation is required because of infection or tumor recurrence, management of the intracranial dead space can be challenging. By providing well-vascularized bulky tissue, intracranial microvascular free flaps offer potential solutions to these life-threatening complications. A multi-institutional retrospective chart and radiographic review was performed of all patients who underwent microvascular free-flap surgery for salvage treatment of postoperative intracranial infections between 1998 and 2006. A total of six patients were identified with large intracranial defects and postoperative intracranial infections. Four patients had parenchymal resections for tumor or seizure and two patients had posttraumatic encephalomalacia. All patients underwent operative debridement and intracranial free-flap reconstruction using the latissimus dorsi muscle ( N = 2), rectus abdominis muscle ( N = 2), or omentum ( N = 2). All patients had titanium ( N = 4) or Medpor ( N = 2) cranioplasties. We concluded that surgery or trauma can result in significant intracranial dead space. Treatment of postoperative intracranial infection can be challenging. Vascularized free tissue transfer not only fills the void, but also provides a delivery system for immune cells, antibodies, and systemically administered antibiotics. The early use of this technique when intracranial dead space and infection coexist is beneficial.

Treatment or prevention of scars and/or keloids

Abstract: Devices, bandages, kits and methods are described that can control or regulate the mechanical environment of a wound to ameliorate scar and/or keloid formation. The mechanical environment of a wound includes stress, strain, and any combination of stress and strain. The control of a wound's mechanical environment can be active, passive, dynamic, or static. The devices are configured to be removably secured to a skin surface in proximity to the wound site and shield the wound from endogenous and/or exogenous stress.

Tissue Engineering Applications in Plastic Surgery

Abstract: Plastic surgery, a derivative of the Greek word plastikos, is in essence a specialty of “forming or molding” to repair defects that may arise from traumatic mechanisms, extirpation of malignancies, or congenital malformations [20]. As one of the broadest surgical specialties, plastic surgeons are confronted with defects in all regions of the body including the integument, craniomaxillofacial region, extremities, breast, and trunk. When addressing large defects which are unlikely to heal on their own, surgeons have a wide array of tools for reconstruction, including the use of autogenous grafts, allogeneic substitutes, and synthetic materials. Each of these reconstructive options has a corresponding clinical situation that it addresses best. However, these resources are also accompanied by their inherent disadvantages. When wounds are assessed to be unlikely to heal in a timely fashion because of size or inadequate blood supply, plastic surgeons have over the years devised a plethora of local flaps, and with the advent of microsurgical technology, a host of microvascular free tissue transfers. Autogenous grafts are considered ideal because of their lack of immunogenicity. However, the use of autogenous grafts is tempered by consideration for donor site morbidity and relatively limited quantities. Allogeneic substitutes offer an alternative, but the risks of disease transmission, immunologic rejection, and graft-versus-host disease are not negligible. Finally, synthetic materials are frequently used but are associated with concerns for infection, tissue incorporation, and structural integrity.

Methods for the treatment or prevention or scars and/or keloids

Abstract: Devices, bandages, kits and methods are described that can control or regulate the mechanical environment of a wound to ameliorate scar and/or keloid formation. The mechanical environment of a wound includes stress, strain, and any combination of stress and strain. The control of a wound's mechanical environment can be active, passive, dynamic, or static. The devices are configured to be removably secured to a skin surface in proximity to the wound site and shield the wound from endogenous and/or exogenous stress.

ヒアルロン酸および／またはその誘導体の糸、その作製方法、ならびにその使用

Abstract: 【課題】組織抵抗に関係なく、特定の位置に均一に投与することができる新たな物理的形態のヒアルロン酸または架橋ヒアルロン酸の提供。 【解決手段】ブタンジオールジグリシジルエーテル（ＢＤＤＥ）を用いて架橋された架橋ヒアルロン酸またはその塩からなり、外科手術用途、眼科手術、創傷閉鎖、薬物送達、または関節内注射において使用するための乾燥した糸。糸は、非架橋ヒアルロン酸またはその塩をさらに含み、ヒアルロン酸またはその塩と架橋剤との架橋度は０．０１％〜２０％である糸。乾燥した糸が２．５４〜５０８μｍの直径を有し、０．４４５〜２２．２Ｎの糸の軸方向の引張強さを有する糸。 【選択図】図４Ｅ