Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

Gliding Resistance After Epitendinous-First Repair of Flexor Digitorum Profundus in Zone II.

PURPOSE: The importance of flexor tendon repair with both core and epitendinous suture placement has been well established. The objective of this study was to determine whether suture placement order affects gliding resistance and bunching in flexor digitorum profundus tendons in a human ex vivo model. METHODS: The flexor digitorum profundus tendons of the index, middle, ring, and little fingers of paired cadaver forearms were tested intact for excursion and mean gliding resistance in flexion and extension across the A2 pulley. Tendons were subsequently transected and repaired with either an epitendinous-first (n = 12) or a control (n = 12) repair. Gliding resistance of pair-matched tendons were analyzed at cycle 1 and during the steady state of tendon motion. The tendon repair breaking strength was also measured. RESULTS: The mean steady state gliding resistance was less for the epitendinous-first repair than for the control repair in flexion (0.61 N vs 0.72 N) and significantly less in extension (0.68 N vs 0.85 N). Similar results were seen for cycle 1. None of the repairs demonstrated gap formation; however, control repairs exhibited increased bunching. Load to failure was similar for both groups. CONCLUSIONS: The order of suture placement for flexor tendon repair is important. Epitendinous-first repair significantly decreased mean gliding resistance, allowed for easier placement of core sutures, and resulted in decreased bunching. CLINICAL RELEVANCE: Epitendinous-first flexor tendon repairs may contribute to improved clinical outcomes compared with control repairs by decreasing gliding resistance and bunching.

Flow-through omental flap to free anterolateral thigh flap for complex chest wall reconstruction: Case report and review of the literature.

Despite the options currently available for chest wall reconstruction, patients with complex composite defects may still pose a significant challenge for the reconstructive surgeon when only using conventional methods. In particular, prior radiotherapy and/or large en bloc resection may leave inadequate regional flaps and recipient vessels for free tissue transfer. Here, we describe a case in which we reconstruct a 14 cm × 18 cm complex chest wall defect, secondary to tumor resection and infected sternum debridement, with a pedicled flow-through omental flap to a 14 cm × 22 cm free anterolateral thigh flap using the omental gastroepiploic vessels as recipient vessels. Reconstruction was successful with excellent flap viability, and no complications at recipient or donor sites. We review the literature on complex chest wall reconstruction and introduce this valuable option of utilizing a pedicled omental flap as a flow-through flap to a free flap for patients without viable recipient vessels or local flaps.

A novel mouse model for frostbite injury.

BACKGROUND: Frostbite injury occurs when exposure to cold results in frozen tissue. To screen drugs and other field therapies that might improve the outcome for a frostbite victim, it would be helpful to have a reliable and cost-effective preclinical in vivo model. OBJECTIVE: We sought to create a novel mouse skin model of induced frostbite injury. This model would allow quantification of the surface area of involved skin, histology of the wound, rate of wound healing, and skin loss in a standardized fashion after the frostbite injury. METHODS: Thirty-six mice were studied. Standardized 2.9-cm diameter circles were tattooed on the mouse dorsum. Magnets frozen in dry ice (-78.5°C) were used to create a frostbite injury on skin within the circle, either as a continuous 5-minute freeze or as 3 repeated freeze (1-minute) and thaw (3-minute) cycles. Appearance, healing rate, skin surface area loss, and histology were recorded until the wounds were healed. RESULTS: The amount of skin surface area loss was approximately 50% for both freeze methods. Although the time to surface skin healing was similar for both freeze methods, the initial healing rate was significantly (P = .001) slower in mice exposed to the freeze-thaw cycles compared with the continuous freeze model. Histopathology reflected inflammatory changes, cell death, and necrosis. CONCLUSIONS: This novel in vivo mouse model for frostbite allows quantification of affected skin surface area, histology, healing rate, and skin loss and has the potential of being utilized to screen future treatment modalities.

The Underrepresented Minority in Hand Surgery: Challenges and Strategy for Success.

Hand surgery is a subspecialty that requires additional fellowship training after a primary residency; a long and competitive journey to achieve success. An underrepresented in medicine (UIM) student's journey to becoming a hand surgeon in the United States adds another level of challenge given several defined obstacles. Despite the lack of representation, the chances of becoming a hand surgeon are difficult but not impossible. A comprehensive strategy for an UIM student to become a hand surgeon is outlined in detail.

Relapse of Pediatric Coccidioidomycosis Tenosynovitis.

Disseminated coccidioidomycosis is a rare cause of flexor tendon tenosynovitis, particularly in the pediatric population. We present the case of a 2-month-old male infant with disseminated coccidioidomycosis of the right index finger, which was initially treated with debridement and long-term antifungal therapy. Six months after discontinuing antifungal medications and at the age of 2 years, the patient presented with relapse of coccidioidomycosis of his right index finger. Serial debridement and long-term antifungal therapy resulted in disease quiescence. The relapse of pediatric coccidioidomycosis tenosynovitis using surgical management with accompanying magnetic resonance imaging, histopathology, and intraoperative findings is described herein. Coccidioidomycosis should be considered for the differential diagnosis of pediatric patients who have traveled to or live in endemic areas and present with indolent hand infections.

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

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-1alpha (HIF-1alpha), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1alpha functional activity was specifically caused by impaired HIF-1alpha 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-1alpha/p300 interaction and transactivation by HIF-1alpha. 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.

Vascularized Ulnar Transposition and Radioulnoscapholunate Fusion With Volar Locking Plate in a Dorsal Position Following Resection of Giant Cell Tumor of the Distal Radius.

Giant cell tumor of the distal radius is a rare, locally destructive, and frequently recurrent tumor. We present a case of Campanacci Grade III giant cell tumor of the distal radius with pathologic fracture and cortical destruction which was treated with neoadjuvant denosumab. This facilitated en-bloc resection of the entire distal radius, including the articular surface, while minimizing tumor contamination. Reconstruction was accomplished using a vascularized ulnar transposition flap to facilitate radioulnoscapholunate fusion, which was fixated using a long-stem contralateral variable angle locking volar distal radius plate in a dorsal position. This case illustrates multidisciplinary management of a challenging reconstructive problem and demonstrates a novel strategy for fixation which repurposes familiar and readily available hardware to provide optimal osteosynthesis.

Murine cathepsin F deficiency causes neuronal lipofuscinosis and late-onset neurological disease.

Cathepsin F (cat F) is a widely expressed lysosomal cysteine protease whose in vivo role is unknown. To address this issue, mice deficient in cat F were generated via homologous recombination. Although cat F-/- mice appeared healthy and reproduced normally, they developed progressive hind leg weakness and decline in motor coordination at 12 to 16 months of age, followed by significant weight loss and death within 6 months. cat F was found to be expressed throughout the central nervous system (CNS). cat F-/- neurons accumulated eosinophilic granules that had features typical of lysosomal lipofuscin by electron microscopy. Large amounts of autofluorescent lipofuscin, characteristic of the neurodegenerative disease neuronal ceroid lipofuscinosis (NCL), accumulated throughout the CNS but not in visceral organs, beginning as early as 6 weeks of age. Pronounced gliosis, an indicator of neuronal stress and neurodegeneration, was also apparent in older cat F-/- mice. cat F is the only cysteine cathepsin whose inactivation alone causes a lysosomal storage defect and progressive neurological features in mice. The late onset suggests that this gene may be a candidate for adult-onset NCL.

ß-Catenin-Dependent Wnt Signaling: A Pathway in Acute Cutaneous Wounding.

BACKGROUND: Acute wound healing is a dynamic process that results in the formation of scar tissue. The mechanisms of this process are not well understood; numerous signaling pathways are thought to play a major role. Here, the authors have identified ß-catenin-dependent Wnt signaling as an early acute-phase reactant in acute wound healing and scar formation. METHODS: The authors created 6-mm full-thickness excisional cutaneous wounds on adult ß-catenin-dependent Wnt signal (BAT-gal) reporter mice. The expression of canonical Wnt after wounding was analyzed using X-gal staining and quantitative real-time polymerase chain reaction. Next, recombinant mouse Wnt3a (rmWnt3a) was injected subcutaneously to the wound edge, daily. The mice were killed at stratified time points, up to 15 days after injury. Histologic analysis, quantitative real-time polymerase chain reaction, and Western blot were performed. RESULTS: Numerous individual Wnt ligands increased in expression after wounding, including Wnt3a, Wnt4, Wnt10a, and Wnt11. A specific pattern of Wnt activity was observed, localized to the hair follicle and epidermis. Mice injected with rmWnt3a exhibited faster wound closure, increased scar size, and greater expression of fibroblast growth factor receptor-2 and type I collagen. CONCLUSIONS: The authors' data suggest that ß-catenin-dependent Wnt signaling expression increases shortly after cutaneous wounding, and exogenous rmWnt3a accelerates reepithelialization, wound matrix maturation, and scar formation. Future experiments will focus on the intersection of Wnt signaling and other known profibrotic cytokines.

Intratendinous Injection of Hydrogel for Reseeding Decellularized Human Flexor Tendons.

BACKGROUND: Decellularized cadaveric tendons are a potential source for reconstruction. Reseeding to enhance healing is ideal; however, cells placed on the tendon surface result in inadequate delivery. The authors used an injection technique to evaluate intratendinous cell delivery. METHODS: Decellularized tendons were reseeded with adipose-derived stem cells in culture, and injected with fetal bovine serum or hydrogel. PKH26-stained cells in cross-section were quantified. To evaluate cell viability, the authors delivered luciferase-labeled cells and performed bioluminescent imaging. To evaluate synthetic ability, the authors performed immunohistochemistry of procollagen. Adipose-derived stem cells' ability to attract tenocytes was assessed using transwell inserts. Cell-to-cell interaction was assessed by co-culturing, measuring proliferation and collagen production, and quantifying synergy. Finally, tensile strength was tested. RESULTS: Both fetal bovine serum (p < 0.001) and hydrogel (p < 0.001) injection led to more cells inside the tendon compared with culturing. Hydrogel injection initially demonstrated greater bioluminescence than culturing (p < 0.005) and fetal bovine serum injection (p < 0.05). Injection groups demonstrated intratendinous procollagen staining correlating with the cells' location. Co-culture led to greater tenocyte migration (p < 0.05). Interaction index of proliferation and collagen production assays were greater than 1 for all co-culture ratios, demonstrating synergistic proliferation and collagen production compared with controls (p < 0.05). There were no differences in tensile strength. CONCLUSIONS: Hydrogel injection demonstrated the greatest intratendinous seeding efficiency and consistency, without compromising tensile strength. Intratendinous cells demonstrated synthetic capabilities and can potentially attract tenocytes inside the tendon, where synergy would promote intrinsic tendon healing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Intracranial dermoid cyst mimicking hemorrhage. Case report and review of the literature.

Intracranial dermoid cysts are rare congenital lesions that result from abnormal sequestration of ectodermal cells during neural tube formation. Dermoid cysts are typically hypodense on computed tomography, but when hyperdense may mimic a hemorrhage. The authors report the case of a 16-year-old boy who presented with a history of chronic progressive headaches. Findings on a CT scan were indicative of hemorrhage. Magnetic resonance imaging revealed the lesion to be a dermoid cyst with unusual characteristics. Upon gross resection, the lesion appeared to be a dermoid cyst without hemorrhage, but histological evaluation revealed evidence of hemorrhage. The authors describe their experience and review the literature, emphasizing that a dermoid cyst may have unusual radiographic characteristics indicative of hemorrhage and may contain areas of hemorrhage on histological examination.

An Inexpensive Bismuth-Petrolatum Dressing for Treatment of Burns.

BACKGROUND: Xeroform remains the current standard for treating superficial partial-thickness burns but can be prohibitively expensive in developing countries with prevalent burn injuries. This study (1) describes the production of an alternative low-cost dressing and (2) compares the alternative dressing and Xeroform using the metrics of cost-effectiveness, antimicrobial activity, and biocompatibility in vitro, and wound healing in vivo. METHODS: To produce the alternative dressing, 3% bismuth tribromophenate powder was combined with petroleum jelly by hand and applied to Kerlix gauze. To assess cost-effectiveness, the unit costs of Xeroform and components of the alternative dressing were compared. To assess antimicrobial properties, the dressings were placed on agar plated with Escherichia coli and the Kirby-Bauer assay performed. To assess biocompatibility, the dressings were incubated with human dermal fibroblasts and cells stained with methylene blue. To assess in vivo wound healing, dressings were applied to excisional wounds on rats and the rate of re-epithelialization calculated. RESULTS: The alternative dressing costs 34% of the least expensive brand of Xeroform. Antimicrobial assays showed that both dressings had similar bacteriostatic effects. Biocompatibility assays showed that there was no statistical difference (P < 0.05) in the cytotoxicity of Xeroform, alternative dressing, and Kerlix gauze. Finally, the in vivo healing model showed no statistical difference (P < 0.05) in mean re-epithelialization time between Xeroform (13.0 ± 1.6 days) and alternative dressing (13.5 ± 1.0 days). CONCLUSIONS: Xeroform is biocompatible, reduces infection, and enhances healing of burn wounds by preventing desiccation and mechanical trauma. Handmade petrolatum gauze may be a low-cost replacement for Xeroform. Future studies will focus on clinical trials in burn units.

Tendon Regeneration with Tendon Hydrogel-Based Cell Delivery: A Comparison of Fibroblasts and Adipose-Derived Stem Cells.

BACKGROUND: Tendon hydrogel is a promising biomaterial for improving repair strength after tendon injury. This study compares the capacity of fibroblasts and adipose-derived stem cells to proliferate, survive, and acquire tenogenic properties when seeded into tendon hydrogel in vitro and in vivo. METHODS: The effect of cell density on hydrogel contraction was measured macroscopically. To assess tenogenic properties, RNA was isolated from cells seeded in vitro in hydrogel, and tenocyte markers were quantified. To assess in vitro proliferation and survival, MTS and live-dead assays were performed. Finally, to assess the in vivo survival of cells in hydrogel, subcutaneous injections were performed on rats and in vivo imaging was performed. RESULTS: At 0.5 million cells/ml, both the fibroblasts and adipose-derived stem cells induced minimal hydrogel contraction compared with higher cellular concentrations. Fibroblasts and adipose-derived stem cells seeded at 0.5 million cells/ml in tendon hydrogel up-regulated several tenocyte markers after 1 week. On MTS assay, fibroblasts and adipose-derived stem cells proliferated in hydrogel at similar rates. On live-dead assay, fibroblasts survived longer than adipose-derived stem cells. With use of the in vivo imaging system and histologic evaluation, fibroblasts survived longer than adipose-derived stem cells in hydrogel in vivo. CONCLUSIONS: Tendon healing is mediated by the proliferation, survival, and tenogenic differentiation of cells at the site of injury. Tendon hydrogel delivering dermal fibroblasts may improve and stimulate this process compared with adipose-derived stem cells. Future studies will be needed to evaluate the effects of this hydrogel-based cell delivery on chronic tendon injuries.

Cloud-Based Applications for Organizing and Reviewing Plastic Surgery Content.

Cloud-based applications including Box, Dropbox, Google Drive, Evernote, Notability, and Zotero are available for smartphones, tablets, and laptops and have revolutionized the manner in which medical students and surgeons read and utilize plastic surgery literature. Here we provide an overview of the use of Cloud computing in practice and propose an algorithm for organizing the vast amount of plastic surgery literature. Given the incredible amount of data being produced in plastic surgery and other surgical subspecialties, it is prudent for plastic surgeons to lead the process of providing solutions for the efficient organization and effective integration of the ever-increasing data into clinical practice.

Ten-year retrospective analysis of incisional herniorrhaphy following renal transplantation.

HYPOTHESIS: Repair of incisional hernias in renal transplant recipients is compromised because of immunosuppressive therapy. DESIGN: Retrospective review. SETTING: University tertiary care institution. PATIENTS: Forty-two recipients of renal transplants or combined renal-pancreas transplants who underwent incisional herniorrhaphy were included in our study. INTERVENTION: Incisional herniorrhaphy. MAIN OUTCOME MEASURES: Postoperative complications and recurrence of incisional hernia. RESULTS: Forty-two patients (mean age, 49.6 years) underwent incisional herniorrhaphy (mean area, 99.9 cm(2)) following renal transplantation (26 cadaveric donor renal, 12 combined renal-pancreas, and 4 living related donor renal) from January 1, 1995, to December 31, 2005. Using various techniques, hernia repairs were performed on average 36.4 months following transplantation. Diabetes mellitus was a frequent cause of end-stage renal disease (16 patients), followed by polycystic kidney disease (6 patients), focal segmental glomerular sclerosis (3 patients), hypertension (2 patients), Alport syndrome (2 patients), and IgA nephropathy (2 patients), with 11 patients having lupus or glomerulonephritis. Four patients developed cellulitis, 2 patients required mesh removal, and 1 patient was admitted for abscess drainage and intravenous antibiotics. Fourteen patients had recurrence of incisional hernias, with 3 patients experiencing 2 recurrences and 1 patient experiencing 4 recurrences. CONCLUSIONS: To our knowledge, this is the largest series of incisional herniorrhaphies performed among patients following renal transplantation. Although smoking history, the presence of diabetes, and immunosuppressive therapy were not associated with the initial development of an incisional hernia, they were associated with complications. Component separation performed by transplant and plastic and reconstructive surgeons should be considered in the setting of recurrent hernias and large defects.

Engineered pullulan-collagen composite dermal hydrogels improve early cutaneous wound healing.

New strategies for skin regeneration are needed to address the significant medical burden caused by cutaneous wounds and disease. In this study, pullulan-collagen composite hydrogel matrices were fabricated using a salt-induced phase inversion technique, resulting in a structured yet soft scaffold for skin engineering. Salt crystallization induced interconnected pore formation, and modification of collagen concentration permitted regulation of scaffold pore size. Hydrogel architecture recapitulated the reticular distribution of human dermal matrix while maintaining flexible properties essential for skin applications. In vitro, collagen hydrogel scaffolds retained their open porous architecture and viably sustained human fibroblasts and murine mesenchymal stem cells and endothelial cells. In vivo, hydrogel-treated murine excisional wounds demonstrated improved wound closure, which was associated with increased recruitment of stromal cells and formation of vascularized granulation tissue. In conclusion, salt-induced phase inversion techniques can be used to create modifiable pullulan-collagen composite dermal scaffolds that augment early wound healing. These novel biomatrices can potentially serve as a structured delivery template for cells and biomolecules in regenerative skin applications.