Reconstruction of digit planer injuries using component transfer of double second toes: A case report.

The purpose of this report is to show that customized component second-toe transfers may improve functional and aesthetic outcomes following bone, soft tissue, and joint destruction of traumatically injured digits. A 22-year-old male sustained a planer injury resulting in loss of the distal volar soft tissues of the middle, ring, and small fingers, along with variable destruction of middle phalanges and distal interphalangeal joints. Simultaneous vascularized second-toe transfers were performed with customized joint and pulp reconstruction of middle and small fingers. The ring finger was salvaged using non-vascularized autologous bone graft and acellular dermal matrix. The patient had an uncomplicated postoperative course. Five-year strength, sensory and patient reported outcomes represent overall satisfactory results. Strength testing revealed the injured hand to perform within 90% strength of the uninjured side. Sensory outcomes showed present but diminished sensory perception in each of the injured digits. The patient's upper extremity function, physical health, quality of life, and foot health were overall acceptable, and he returned to using his hand for typing, writing, weight-lifting, and woodworking.

Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds.

In diabetes, stromal cell-derived factor-1 (SDF-1) expression and progenitor cell recruitment are reduced. Dipeptidyl peptidase-4 (DPP-4) inhibits SDF-1 expression and progenitor cell recruitment. Here we examined the impact of the DPP-4 inhibitor, MK0626, on progenitor cell kinetics in the context of wound healing. Wildtype (WT) murine fibroblasts cultured under high-glucose to reproduce a diabetic microenvironment were exposed to MK0626, glipizide, or no treatment, and SDF-1 expression was measured with ELISA. Diabetic mice received MK0626, glipizide, or no treatment for 6 weeks and then were wounded. Immunohistochemistry was used to quantify neovascularization and SDF-1 expression. Gene expression was measured at the RNA and protein level using quantitative polymerase chain reaction and ELISA, respectively. Flow cytometry was used to characterize bone marrow-derived mesenchymal progenitor cell (BM-MPC) population recruitment to wounds. BM-MPC gene expression was assayed using microfluidic single cell analysis. WT murine fibroblasts exposed to MK0626 demonstrated increased SDF-1 expression. MK0626 treatment significantly accelerated wound healing and increased wound vascularity, SDF-1 expression, and dermal thickness in diabetic wounds. MK0626 treatment increased the number of BM-MPCs present in bone marrow and in diabetic wounds. MK0626 had no effect on BM-MPC population dynamics. BM-MPCs harvested from MK0626-treated mice exhibited increased chemotaxis in response to SDF-1 when compared to diabetic controls. Treatment with a DPP-4 inhibitor significantly improved wound healing, angiogenesis, and endogenous progenitor cell recruitment in the setting of diabetes.

PHD-2 Suppression in Mesenchymal Stromal Cells Enhances Wound Healing.

BACKGROUND: Cell therapy with mesenchymal stromal cells is a promising strategy for tissue repair. Restoration of blood flow to ischemic tissues is a key step in wound repair, and mesenchymal stromal cells have been shown to be proangiogenic. Angiogenesis is critically regulated by the hypoxia-inducible factor (HIF) superfamily, consisting of transcription factors targeted for degradation by prolyl hydroxylase domain (PHD)-2. The aim of this study was to enhance the proangiogenic capability of mesenchymal stromal cells and to use these modified cells to promote wound healing. METHODS: Mesenchymal stromal cells harvested from mouse bone marrow were transduced with short hairpin RNA (shRNA) against PHD-2; control cells were transduced with scrambled shRNA (shScramble) construct. Gene expression quantification, human umbilical vein endothelial cell tube formation assays, and wound healing assays were used to assess the effect of PHD knockdown mesenchymal stromal cells on wound healing dynamics. RESULTS: PHD-2 knockdown mesenchymal stromal cells overexpressed HIF-1α and multiple angiogenic factors compared to control (p < 0.05). Human umbilical vein endothelial cells treated with conditioned medium from PHD-2 knockdown mesenchymal stromal cells exhibited increased formation of capillary-like structures and enhanced migration compared with human umbilical vein endothelial cells treated with conditioned medium from shScramble-transduced mesenchymal stromal cells (p < 0.05). Wounds treated with PHD-2 knockdown mesenchymal stromal cells healed at a significantly accelerated rate compared with wounds treated with shScramble mesenchymal stromal cells (p < 0.05). Histologic studies revealed increased blood vessel density and increased cellularity in the wounds treated with PHD-2 knockdown mesenchymal stromal cells (p < 0.05). CONCLUSIONS: Silencing PHD-2 in mesenchymal stromal cells augments their proangiogenic potential in wound healing therapy. This effect appears to be mediated by overexpression of HIF family transcription factors and up-regulation of multiple downstream angiogenic factors.

The Role of Focal Adhesion Kinase in Keratinocyte Fibrogenic Gene Expression.

Abnormal skin scarring causes functional impairment, psychological stress, and high socioeconomic cost. Evidence shows that altered mechanotransduction pathways have been linked to both inflammation and fibrosis, and that focal adhesion kinase (FAK) is a key mediator of these processes. We investigated the importance of keratinocyte FAK at the single cell level in key fibrogenic pathways critical for scar formation. Keratinocytes were isolated from wildtype and keratinocyte-specific FAK-deleted mice, cultured, and sorted into single cells. Keratinocytes were evaluated using a microfluidic-based platform for high-resolution transcriptional analysis. Partitive clustering, gene enrichment analysis, and network modeling were applied to characterize the significance of FAK on regulating keratinocyte subpopulations and fibrogenic pathways important for scar formation. Considerable transcriptional heterogeneity was observed within the keratinocyte populations. FAK-deleted keratinocytes demonstrated increased expression of genes integral to mechanotransduction and extracellular matrix production, including Igtbl, Mmpla, and Col4a1. Transcriptional activities upon FAK deletion were not identical across all single keratinocytes, resulting in higher frequency of a minor subpopulation characterized by a matrix-remodeling profile compared to wildtype keratinocyte population. The importance of keratinocyte FAK signaling gene expression was revealed. A minor subpopulation of keratinocytes characterized by a matrix-modulating profile may be a keratinocyte subset important for mechanotransduction and scar formation.

Injured Anterior Superior Alveolar Nerve Endoscopically Resected within Maxillary Sinus.

Posttraumatic facial pain is due to an injured nerve, most often a branch of the trigeminal nerve. While surgical approaches to injuries of the supraorbital, supratrochlear, infraorbital, and inferior alveolar nerves have been reported, an injury to the anterior superior alveolar nerve (ASAN) has not been reported. An algorithm is proposed for the diagnosis of injury to the ASAN versus the infraorbital nerve itself. A case is reported in which pain relief was achieved by dividing the ASAN within the maxillary sinus, leaving the proximal end exposed within the sinus at the level of the orbital floor.

Evidence-Based Medicine: Management of Metacarpal Fractures.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand metacarpal anatomy and its role in fracture pathology. 2. Determine when surgical intervention is needed for metacarpal fractures. 3. Understand the various treatment options for surgical fixation of metacarpal fractures. 4. Describe the role for external fixation in managing difficult metacarpal fractures. BACKGROUND: Metacarpal fractures are common injuries that plastic surgeons should be able to evaluate and treat. The goal of this review is to highlight current evidence for managing metacarpal fractures. This Continuing Medical Education article consists of a literature review, illustrations, videos, and an online Continuing Medical Education examination. METHODS: The authors reviewed the scientific literature from 2000 to 2015 regarding treatment of metacarpal fractures. Cadaver models were used for instructional videography demonstrating common surgical techniques. Multiple-choice questions were created to review pertinent topics. A discussion and references are provided. RESULTS: Numerous treatment options have been described for metacarpal fractures, including splinting, percutaneous fixation, open reduction with internal fixation, and external fixation. All modalities are acceptable strategies for treating metacarpal fractures. The ultimate goal is to maximize hand function with minimal morbidity. CONCLUSIONS: A thorough understanding of treatment modalities is helpful in evaluating and managing metacarpal fractures. Although the current literature supports a wide array of treatment strategies, high-level evidence to guide fracture management remains lacking.

Proximalization of the Vascularized Toe Joint in Finger Proximal Interphalangeal Joint Reconstruction: A Technique to Derive Optimal Flexion From a Joint With Expected Limited Motion.

When used to reconstruct a finger proximal interphalangeal joint, a free toe interphalangeal joint, without modification, cannot meet the motion demands of the finger to allow palm touchdown. This limitation is the direct result of the toe interphalangeal joint having an intrinsic arc of motion that delivers less flexion than that of a normal functioning finger proximal interphalangeal joint. By modifying the inset of the transferred joint to an extra-anatomical more proximal position, this limitation can be overcome. With a mathematical justification highlighted by a clinical illustration, we demonstrate the feasibility and utility of this "proximalization" technique.

Medial Femoral Condyle Flap.

Supplemental Digital Content is available in the text.

Nonoperative Management of Acute Upper Limb Ischemia.

BACKGROUND: Acute upper limb ischemia (AULI) is an uncommon emergency warranting immediate evaluation and treatment. The role of nonsurgical therapies including endovascular techniques, thrombolytics, and anticoagulation remains undefined. The authors systematically reviewed the current literature on the nonsurgical treatment of acute ischemia of the upper extremity. METHODS: A PubMed and Embase search was conducted, and articles were screened using predetermined criteria. Data collected included patient demographics, cause of upper limb ischemia, type of nonsurgical treatment used, treatment outcomes, and complications. Patients were divided into 4 treatment groups: catheter embolectomy, catheter-directed thrombolysis, endovascular stenting, and anticoagulation/medical therapy alone. RESULTS: Twenty-three retrospective studies met the search criteria. Of 1326 reported occlusions, 92% (1221) were attributed to thromboembolic disease. The second most common cause was iatrogenic (1.5%). Overall limb salvage rates were excellent with catheter embolectomy (862 of 882 cases, 97.7%) and catheter-directed thrombolysis (110 of 114 cases, 96.5%). Limb salvage rates were also high with anticoagulation/medical therapy (158 of 165 cases, 95.8%), but poor functional outcomes were more often reported. CONCLUSIONS: High-quality evidence to guide the nonsurgical treatment of AULI is lacking. Retrospective studies support the utility of catheter-based embolectomy and thrombolysis for distal ischemia. Whether a surgical or nonsurgical approach is taken, anticoagulation therapy remains a mainstay of both treatment and prevention of AULI. Because AULI patients often have underlying cardiac and/or systemic disease, a multidisciplinary approach is essential to minimize complications and prevent future occurrences.

Distally Based Iliotibial Band Flap: Anatomic Study with Surgical Considerations.

Background Reconstruction of high-risk fascia, tendon, or ligament defects may benefit from vascularized tissue. The iliotibial band (ITB), a thick fibrous tract of connective tissue, serves as a potential donor site for free tissue transfer but its blood supply has not been thoroughly investigated. The aim of this anatomical study was to investigate the vascular supply to the distal ITB and its role as a free fascial flap. Methods We dissected 16 fresh-frozen cadaveric legs and injected latex into the superolateral geniculate artery (SLGA). A distal ITB fascial flap was designed and measurements were taken for flap dimensions, pedicle length and size, and SLGA perfusion territory. Results The SLGA perfused 11.5 ± 2.3 cm of distal ITB (proximal to the lateral femoral epicondyle) and provided 6.4 ± 0.7cm of pedicle length to the ITB flap. Conclusions Chimeric options to include bone (from the lateral femoral condyle), cartilage (from the lateral femoral trochlea), muscle (from vastus lateralis or biceps femoris), and skin are possible. Surgical harvest techniques are proposed, including preservation of ITB insertions to minimize lateral knee instability. Clinical validation is needed to determine the role of the distal ITB free fascial flap in reconstructive microsurgery.

Multiple Subsets of Brain Tumor Initiating Cells Coexist in Glioblastoma.

Brain tumor-initiating cells (BTICs) are self-renewing multipotent cells critical for tumor maintenance and growth. Using single-cell microfluidic profiling, we identified multiple subpopulations of BTICs coexisting in human glioblastoma, characterized by distinct surface marker expression and single-cell molecular profiles relating to divergent bulk tissue molecular subtypes. These data suggest BTIC subpopulation heterogeneity as an underlying source of intra-tumoral bulk tissue molecular heterogeneity, and will support future studies into BTIC subpopulation-specific therapies. Stem Cells 2016;34:1702-1707.

Knee Donor Site Morbidity Following Harvest of Medial Femoral Trochlea Osteochondral Flaps for Carpal Reconstruction.

PURPOSE: This study examines donor site morbidity associated with the medial femoral trochlea (MFT) when used as a donor site for vascularized osteochondral flaps for reconstruction of challenging carpal defects such as proximal pole scaphoid nonunion and advanced Kienböck disease. METHODS: The retrospective study population included all patients who had undergone MFT flap harvest for scaphoid or lunate reconstruction. Chart review, patient questionnaires, and validated knee function assessment tools were used: International Knee Documentation Committee Subjective Knee Form scores ranged from 0 (maximal disability) to 100 (no disability). Western Ontario and McMaster Universities osteoarthritis index scores ranged from 0% (no disability) to 100% (maximal disability). Magnetic resonance imaging and radiographs were obtained on the donor knee on the majority of patients. RESULTS: Questionnaire response rate was 79% (45 of 57 patients). Average patient age was 35 ± 11 years (range, 19-70 years). Average postoperative follow-up was 27 ± 17 months (range, 9-108 months). The indication for MFT flap reconstruction was scaphoid nonunion in 30 patients and Kienböck disease in 15 patients. All 45 patients had a stable knee on examination. Magnetic resonance and radiographic imaging obtained on 35 patients exhibited no pathological changes. Average duration of postoperative pain was 56 ± 59 days (range, 0-360 days); average duration until patients reported the knee returning to normal was 90 ± 60 days (range, 14-360 days). Forty-three of 44 patients would have the same surgery again if needed; overall satisfaction with the surgery was rated as 5 ± 1 (range, 2-5) on a scale from 0 (no satisfaction) to 5 (maximal satisfaction). Average International Knee Documentation Committee score was 96 ± 9 (range, 56.3-100) and the average Western Ontario and McMaster Universities score was 6% ± 16% (range, 0%-68%). CONCLUSIONS: Medial femoral trochlea osteochondral flap harvest results in minimal donor site morbidity in the majority of patients. Symptoms are time limited. Intermediate-term follow-up demonstrates excellent results in subjective outcome measures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Challenges and Opportunities in Drug Delivery for Wound Healing.

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.

Trauma-induced heterotopic bone formation and the role of the immune system: A review.

Extremity trauma, spinal cord injuries, head injuries, and burn injuries place patients at high risk of pathologic extraskeletal bone formation. This heterotopic bone causes severe pain, deformities, and joint contractures. The immune system has been increasingly implicated in this debilitating condition. This review summarizes the various roles immune cells and inflammation play in the formation of ectopic bone and highlights potential areas of future investigation and treatment. Cell types in both the innate and adaptive immune system such as neutrophils, macrophages, mast cells, B cells, and T cells have all been implicated as having a role in ectopic bone formation through various mechanisms. Many of these cell types are promising areas of therapeutic investigation for potential treatment. The immune system has also been known to also influence osteoclastogenesis, which is heavily involved in ectopic bone formation. Chronic inflammation is also known to have an inhibitory role in the formation of ectopic bone, whereas acute inflammation is necessary for ectopic bone formation.

Stem Cells in Wound Healing: The Future of Regenerative Medicine? A Mini-Review.

The increased risk of disease and decreased capacity to respond to tissue insult in the setting of aging results from complex changes in homeostatic mechanisms, including the regulation of oxidative stress and cellular heterogeneity. In aged skin, the healing capacity is markedly diminished resulting in a high risk for chronic wounds. Stem cell-based therapies have the potential to enhance cutaneous regeneration, largely through trophic and paracrine activity. Candidate cell populations for therapeutic application include adult mesenchymal stem cells, embryonic stem cells and induced pluripotent stem cells. Autologous cell-based approaches are ideal to minimize immune rejection but may be limited by the declining cellular function associated with aging. One strategy to overcome age-related impairments in various stem cell populations is to identify and enrich with functionally superior stem cell subsets via single cell transcriptomics. Another approach is to optimize cell delivery to the harsh environment of aged wounds via scaffold-based cell applications to enhance engraftment and paracrine activity of therapeutic stem cells. In this review, we shed light on challenges and recent advances surrounding stem cell therapies for wound healing and discuss limitations for their clinical adoption.

Heterotopic Ossification following Tissue Transfer for Combat-Casualty Complex Periarticular Injuries.

BACKGROUND: Although mechanisms underlying heterotopic ossification remain unknown, certain risk factors can influence heterotopic bone formation. The purpose of this study was to determine whether flaps used in periarticular reconstruction had any effect on heterotopic ossification formation. METHODS: A retrospective review of periarticular injuries requiring flap coverage from 2003 through 2014 was performed. Flap types, Injury Severity Scores, functional outcomes, and complications were reviewed. Radiology findings were assessed to determine heterotopic ossification rates and grades. RESULTS: Three hundred eighty-nine flaps were performed for traumatic extremity coverage over the 13-year study period. Sixty-nine of these flaps were used for periarticular coverage. The rate of periarticular heterotopic ossification was 47 percent for fasciocutaneous versus 54 percent for muscle-based flap coverage (p = 0.88). There were no significant differences in Injury Severity Score (p = 0.44) or overall heterotopic ossification formation (p = 0.97) between groups; however, the grade of heterotopic ossification within muscle-based flap cohort was significantly higher (1.70 for muscle versus 1.06 for the fasciocutaneous cohort; p = 0.002). CONCLUSIONS: Combat-related trauma is associated with high rates of heterotopic ossification, with an overall formation rate exceeding 85 percent for our patients requiring periarticular flap coverage. Although no difference in the rate of heterotopic ossification formation was found between fasciocutaneous and muscle flap coverages, a significantly increased severity of heterotopic ossification was seen in periarticular muscle-based flaps. These findings suggest that flap composition might not affect the rate of heterotopic ossification formation but may have an effect on ectopic bone formation severity.

Filamin A Mediates Wound Closure by Promoting Elastic Deformation and Maintenance of Tension in the Collagen Matrix.

Fibroblasts have a central role in wound healing via matrix production, remodeling, and contraction. Their role as mechanoresponsive cells during tissue repair is evident, but the molecular mechanisms of this process remain uncertain. Filamin A, an intracellular protein that stabilizes the actin cytoskeleton regulates fibroblast-matrix interactions. Fibroblast defects in cytoskeletal dynamics may underlie key aspects of chronic wound pathophysiology.

Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing.

BACKGROUND: Diabetes and aging are known risk factors for impaired neovascularization in response to ischemic insult, resulting in chronic wounds, and poor outcomes following myocardial infarction and cerebrovascular injury. Hypoxia-inducible factor (HIF)-1α, has been identified as a critical regulator of the response to ischemic injury and is dysfunctional in diabetic and elderly patients. To better understand the role of this master hypoxia regulator within cutaneous tissue, the authors generated and evaluated a fibroblast-specific HIF-1α knockout mouse model. METHODS: The authors generated floxed HIF-1 mice (HIF-1) by introducing loxP sites around exon 1 of the HIF-1 allele in C57BL/6J mice. Fibroblast-restricted HIF-1α knockout (FbKO) mice were generated by breeding our HIF-1 with tamoxifen-inducible Col1a2-Cre mice (Col1a2-CreER). HIF-1α knockout was evaluated on a DNA, RNA, and protein level. Knockout and wild-type mice were subjected to ischemic flap and wound healing models, and CD31 immunohistochemistry was performed to assess vascularity of healed wounds. RESULTS: Quantitative real-time polymerase chain reaction of FbKO skin demonstrated significantly reduced Hif1 and Vegfa expression compared with wild-type. This finding was confirmed at the protein level (p < 0.05). HIF-1α knockout mice showed significantly impaired revascularization of ischemic tissue and wound closure and vascularity (p < 0.05). CONCLUSIONS: Loss of HIF-1α from fibroblasts results in delayed wound healing, reduced wound vascularity, and significant impairment in the ischemic neovascular response. These findings provide new insight into the importance of cell-specific responses to hypoxia during cutaneous neovascularization.

Load-Dependent Emission Factors and Chemical Characteristics of IVOCs from a Medium-Duty Diesel Engine.

A detailed understanding of the climate and air quality impacts of mobile-source emissions requires the characterization of intermediate-volatility organic compounds (IVOCs), relatively-low-vapor-pressure gas-phase species that may generate secondary organic aerosol with high yields. Due to challenges associated with IVOC detection and quantification, IVOC emissions remain poorly understood at present. Here, we describe measurements of the magnitude and composition of IVOC emissions from a medium-duty diesel engine. Measurements are made on an engine dynamometer and utilize a new mass-spectrometric instrument to characterize the load dependence of the emissions in near-real-time. Results from steady-state engine operation indicate that IVOC emissions are highly dependent on engine power, with highest emissions at engine idle and low-load operation (≤25% maximum rated power) with a chemical composition dominated by saturated hydrocarbon species. Results suggest that unburned fuel components are the dominant IVOCs emitted at low loads. As engine load increases, IVOC emissions decline rapidly and become increasingly characterized by unsaturated hydrocarbons and oxygenated organics, newly formed from incomplete combustion processes at elevated engine temperatures and pressures. Engine transients, including a cold-start ignition and engine acceleration, show IVOC emission profiles that are different in amount or composition compared to steady-state combustion, underscoring the utility of characterizing IVOC emissions with high time resolution across realistic engine operating conditions. We find possible evidence for IVOC losses on unheated dilution and sampling surfaces, which need to be carefully accounted for in IVOC emission studies.