Surgical Feasibility Study on Cadaver for Vascularized Wrist Joint Transplantation.

PURPOSE: Despite modern advancements in the treatment of late stages of wrist joint degeneration, few reliable options exist for patients requiring motion-preserving reconstruction of their radiocarpal and midcarpal joints. Vascularized composite allotransplantation (VCA) could be considered an option for wrist reconstruction in the future. The goal of this study was to describe the relevant anatomy and design a potential surgical technique for wrist VCA. METHODS: Anatomic studies were performed on 17 human upper extremities. The arterial system of each cadaver was injected with latex dye or radiographic contrast. After injecting a contrast medium visible on a computerized tomography (CT) scan, the initial three specimens were examined using microCT. This confirmed joint vascular patency and allowed for the dissection of the other specimens that were injected with latex for the study of joint vascularization and the design of the wrist VCA. We then outlined a donor and recipient surgical technique for transplant based on recipient CT scans. Customized cutting guides were designed for the transplant procedure. After the procedure, we performed angiography of the VCA to determine the vascularity of the transplant. RESULTS: Using a combined volar and dorsal approach, we were able to perform a complete wrist VCA procedure. After the completed transplant procedure, angiographic imaging of the specimens demonstrated that the flap dissection and transplantation preserved the nutrient endosteal supply to the distal end of the radius and ulna, as well as to the carpal bones and the metacarpal bases. CONCLUSIONS: The dissection of the donor, recipient, and the entire vascularized joint transplant procedure served to illustrate the anatomical feasibility of the cadaveric surgical technique. This establishes an anatomic basis for the possibility of future human clinical applications. CLINICAL RELEVANCE: This study helps investigate the anatomical feasibility of a wrist VCA.

Fasciocutaneous Free Tissue Transfer in Limb Salvage: Prior Flap as a Split-thickness Skin Graft Donor Site.

Free flap surgery for limb salvage has become the surgical standard for reconstruction of bone and soft tissue with success rates and flap survivals of 94%-95%. The soft tissue defect dictates the technique of coverage. In many cases, multiple techniques of soft tissue coverage are necessary, ranging from myocutaneous and fasciocutaneous free flaps to split-thickness skin grafts (STSGs). It has been shown that fasciocutaneous free flaps are not inferior to muscle flaps in treatment of lower leg limb salvage. Although a complete flap loss is rare, it is not uncommon to have partial flap necrosis, wound dehiscence, or secondary soft tissue defects, necessitating further minor reconstruction, which we call "touch up" skin grafts. In many of these secondary procedures, split thickness skin grafts are sufficient. We have been using the skin portion of the fasciocutaneous free flap as a donor site for harvesting STSGs for quite some time without disadvantages. We believe that minimizing additional donor site morbidity is of great importance. The free tissue transfer is insensate and readily available at the site of injury, making prepping and draping simple as well as cosmetically acceptable, as the transferred free tissue, unfortunately, is rarely a perfect fit. The associated pain, discomfort, and scar of an additional donor site can be avoided. In our case series, we did not experience any flap loss, infections, or complications. Thus, harvesting an STSG from a fasciocutaneous free flap seems to be a feasible option to be considered in limb salvage.

Surgical Treatment of Symptomatic End-Neuroma With a New Bioresorbable Copolyester Nerve Capping Device: A Multicenter Prospective Cohort Study.

BACKGROUND: Neuroma-induced neuropathic pain is associated with loss of function and reduced quality of life. No consistently effective standard-of-care treatment has been defined. Neurocap, a bioresorbable nerve capping device, has been designed to isolate the nerve stump from surrounding tissues to reduce development of symptomatic end-neuromas. METHODS: Patients with peripheral symptomatic end-neuromas were included in a prospective, multicenter, single-arm design. Data were collected presurgery up till 24 months postsurgery. Eligible patients with neuromas were identified based on blocks using anesthetic. Intervention included surgical excision and capping of the transected proximal nerve end with the Neurocap. Main outcome measures were pain, function, recurrence of symptomatic neuroma, use of analgesics, and adverse events. RESULTS: In total, 73 patients with 50 upper-extremity and 23 lower-extremity end-neuromas were enrolled. End-neuromas were predominately located in the digits and lower leg. Statistical power of the study outcomes was preserved by 46 of 73 patients completing 24-month follow-up. The mean VAS-Pain score at baseline was 70.2 ± 17.8 (scale 0-100) and decreased significantly to 31 ± 32.5 (P < 0.001). Function significantly improved over time. The recurrence rate of confirmed symptomatic neuroma was low (2 of 98 capped nerves). Adverse event rate was low and included pain and infection; there were no unexpected device-related adverse events. Most patients reported lower use of nonsteroidal anti-inflammatory drugs, opioids, and antineuropathic medications at last follow-up compared with baseline. CONCLUSIONS: End-neuroma treatment with excision and capping resulted in long-term significant reduction in reported pain, disability, and analgesic medication use. Adverse event rate was low.

Targeting cartilage EGFR pathway for osteoarthritis treatment.

Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor-α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.

Loss of Elbow Flexion in Congenital Arthrogryposis Treated with a Bipolar Latissimus Transfer: A Case Report.

CASE: A 20-year-old man with congenital arthrogryposis presented for evaluation of biceps dysfunction. Although his left elbow was supple with 0° to 110° passive range of motion (ROM), he had no active ROM and was unable to perform basic activities of daily living such as bringing his hand to his mouth to feed himself. A bipolar latissimus transfer was performed to achieve functional active ROM. CONCLUSION: Bipolar latissimus transfer is a challenging, robust flap able to restore active elbow flexion in select groups of patients with biceps dysfunction, supple elbow, and functional latissimus dorsi.

Robustness Testing of Mesenchymal Stem Cell Monotherapy Following Vascularized Composite Allotransplantation.

BACKGROUND: Immunosuppression risks are a major concern with vascularized composite allotransplantation (VCA). As an emerging strategy, the antirejection role played by mesenchymal stem cells (MSCs) is receiving attention. However, the current literature reports are inconclusive regarding the robustness of the MSC monotherapy. Using a rat forelimb VCA model, this study tested the robustness of the immunomodulation efficacy of gingival-derived MSCs (GMSCs) and bone marrow-derived MSCs (BMMSCs). METHODS: Forelimbs were transplanted on pairs of major histocompatibility complex-incompatible rats (Wistar-Kyoto donor, Lewis [LEW] recipient). Twenty-four LEW rats were randomly divided into four groups, including control (no treatment) and three treatment groups: rapamycin (2 mg/kg/day for 28 days, postoperatively), BMMSC and GMSC, both of which received donor-derived stem cells administered intravenously on postoperative days (PODs) 0, 3, 7, and 14. Rejection was considered as 80% skin necrosis of the allograft. Microcomputed tomography (µCT) was performed to evaluate healing at osteosynthesis site. On POD 14, limbs from each group underwent histological analysis and rejection grading using the Banff system. RESULTS: Both BMMSC (15.0 days) and GMSC (14.7 days) treatment failed to prolong VCA survival in comparison with the control group (13.8 days; p > 0.050), while the rapamycin significantly delayed acute VCA rejection (24.5 days; p = 0.003). Micro-CT imaging revealed no gross visual difference across all groups. Histology revealed that the control group was most severely affected (grades III and IV) followed by MSC (grade II) and rapamycin (grade I). CONCLUSION: MSC monotherapy, both BMMSC and GMSC, did not inhibit rejection in our VCA model. Skin immunogenicity is an important issue in promoting rejection, and a concomitant immunosuppression regimen should be considered to prolong allograft survival.

Pediatric vascularized composite allotransplantation: What is the landscape for obtaining appropriate donors in the United States?

Listing the world's first pediatric bilateral hand transplant patient for a donor posed many challenges including matching the appropriate donor age, bone size, skin tone, and growth potential in an already limited donor population. This study describes the prevalence and distribution of potential pediatric VCA donors in the United States. We assessed the UNOS database from 2008 to 2015 to identify the prevalence of potential pediatric VCA donors. Standard VCA inclusion and exclusion criteria were applied to the dataset for all pediatric solid organ donors. Frequency analyses were performed of characteristics important for VCA matching. The dataset began with 57 300 brain-dead donors and after applying the inclusion and exclusion criteria including age <18, decreased to 4663 (8.1%). The number of pediatric potential VCA donors per UNOS region ranged from 11 to 112/year. The majority of pediatric potential VCA donors were blood type O Whites, with the least common profile being blood type AB of "other" ethnicity. The present study confirmed that pediatric VCA donors are rare and may require longer travel times for procurement and listing at multiple centers in order to find a suitable donor. This will be a limiting factor for the expansion of pediatric VCA.

Variability in the Analgesic Response to Ibuprofen Is Associated With Cyclooxygenase Activation in Inflammatory Pain.

The mechanisms underlying interindividual variability in analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) are not well understood. Therefore, we performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars and were treated with ibuprofen (400 mg; N = 19) or placebo (N = 10). Analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, or the degree of cyclooxygenase inhibition by ibuprofen. Compared with partial responders to ibuprofen (N = 9, required rescue medication within the dosing interval), complete responders (N = 10, no rescue medication) exhibited greater induction of urinary prostaglandin metabolites and serum tumor necrosis factor-α and interleukin 8. Differentially expressed genes in peripheral blood mononuclear cells were enriched for inflammation-related pathways. These findings suggest that a less pronounced activation of the inflammatory prostanoid system is associated with insufficient pain relief on ibuprofen alone and the need for additional therapeutic intervention.

Prevention of Opioid-Induced Nausea and Vomiting During Treatment of Moderate to Severe Acute Pain: A Randomized Placebo-Controlled Trial Comparing CL-108 (Hydrocodone 7.5 mg/Acetaminophen 325 mg/Rapid-Release, Low-Dose Promethazine 12.5 mg) with Conventional Hydrocodone 7.5 mg/Acetaminophen 325 mg.

OBJECTIVES: To evaluate the prevention of opioid-induced nausea and vomiting (OINV) and the relief of moderate to severe acute pain by CL-108, a novel drug combining a low-dose antiemetic (rapid-release promethazine 12.5 mg) with hydrocodone 7.5 mg/acetaminophen 325 mg (HC/APAP) was used. METHODS: This was a multicenter, randomized, double-blind, placebo- and active-controlled multidose study. After surgical extraction of two or more impacted third molar teeth (including at least one mandibular impaction), 466 patients with moderate to severe pain (measured on a categorical pain intensity scale [PI-CAT]) were randomized to CL-108, HC/APAP, or placebo. Over the next 24 hours, patients used the PI-CAT to assess pain at regular intervals whereas nausea, vomiting, and other opioid-related side effects were also assessed prospectively. Study medications were taken every four to six hours as needed; supplemental rescue analgesic and antiemetic medications were permitted. Co-primary end points were the incidence of OINV and the time-weighted sum of pain intensity differences over 24 hours (SPID24). RESULTS: Relative to HC/APAP treatment alone, CL-108 treatment reduced OINV by 64% (P < 0.001). Treatment with CL-108 significantly reduced pain intensity compared with placebo (SPID24 = 16.2 vs 3.5, P < 0.001). There were no unexpected or serious adverse events. CONCLUSIONS: CL-108 is a safe and effective combination analgesic/antiemetic for the prevention of OINV during treatment of moderate to severe acute pain.

Vascularized composite allotransplantation in the United States: A descriptive analysis of the Organ Procurement and Transplantation Network Data.

On July 3, 2014, the Organ Procurement and Transplantation Network/United Network for Organ Sharing was charged with the oversight of vascularized composite allograft (VCA) procurement and transplantation in the United States. As of December 31, 2017, 61 VCA programs at 27 centers were approved in the United States. Fifty candidates have been added to the waiting list at 15 centers. Twenty-eight VCA transplants have been performed at 14 programs (10 upper limb, 10 uterus, 5 craniofacial, 1 scalp, 1 abdominal wall, and 1 penile). Twenty-two VCAs were procured from 21 deceased donors, resulting in 109 non-VCA organs transplanted (15 hearts, 3 intestine, 40 kidney, 20 livers, 24 lungs, and 7 pancreata). Six uterus transplants were performed from living donors. Fourteen candidates were still waiting at 9 centers on December 31, 2017. Two of the 10 uterus recipients had live births and 3 still had viable grafts. Seventeen of 18 nonuterus recipients had functioning grafts. At present, VCA is an emerging field with a small number of patients transplanted. Data on posttransplant survival and functional outcomes continue to be collected to further the understanding of this complex and evolving field. Further systematic data are important for policy refinement and assurance of patient safety.

Preparation is the Only Shortcut You Need in Surgery: A Guide to Surgical Rehearsals for Hand and Upper Extremity Transplantation.

As upper extremity transplantation is becoming more accepted worldwide, the demand for a fresh tissue cadaveric training model for this procedure is increasing and necessary to assure surgical success. Surgical rehearsals can decrease operative time, improve technique, and reduce errors made on the actual day of surgery. The purpose of this article is to describe a method for surgical rehearsal of upper extremity transplantation using cadaveric specimens based on the clinical experience of an academic institution with an active transplantation program. The logistics of rehearsal setup, equipment, and modified version of procedural checklists are described.

Meeting Report of the 13th Congress of the International Society of Vascularized Composite Allotransplantation.

The International Society of Vascularized Composite Allotransplantation held its 13th congress "Defining Success" in October 2017 in Salzburg, Austria. A total of 122 delegates from 22 countries representing 5 continents attended the conference. The theme strived to provide pathways to accomplish best possible outcomes in this unique and multifaceted field of transplantation. "Ignite talks," a new feature introduced for the first time at the Salzburg meeting served as key elements for productive discussions on both congress days. The "ignitors" had been selected as experts from Europe, the Americas and Asia in vascularized composite allotransplantation and neighboring disciplines and provided a global perspective of their topic. Posttransplant treatment regimens, including the most burdensome side effects of immunosuppressants in addition to novel and future therapeutic options were discussed in depth. An additional ethics symposium summarized and advanced topics that had been discussed during the first international workshop on bioethical challenges in reconstructive transplantation held earlier in 2017.

Versatility of the Medial Femoral Condyle Flap for Extremity Reconstruction and Identification of Risk Factors for Nonunion, Delayed Time to Union, and Complications.

BACKGROUND: The medial femoral condyle (MFC) flap has become a popular choice for treatment of small bony defects. We aim to describe outcomes after MFC flap treatment of upper and lower extremity osseous defects and test the null hypothesis that no factors influence risks for nonunion, increased time to union, and complications. METHODS: A retrospective chart review was performed on all patients undergoing MFC free vascularized bone flaps by the senior author between May 2010 and March 2016. Preoperative, intraoperative, and postoperative data were collected. RESULTS: We identified 29 patients for inclusion (22 upper and 7 lower extremity reconstructions) treated with the MFC flap for diagnoses including long bone nonunion, avascular necrosis (AVN), or AVN with nonunion. Mean postoperative follow-up was 56 weeks. The average patient was 38 years old (range = 17-61 years) and had undergone 1.5 previous failed surgeries. Union was achieved in 86% of patients at a mean of 15.8 weeks (83% at 17.9 weeks for the scaphoid). No patient with lunate AVN progressed. There were no intraoperative flap complications or bone flap loss, but 28% underwent additional unplanned surgical procedures. We identified previous surgery as a risk factor for delayed union but did not observe significant risk factors predictive of nonunion or complications requiring unplanned reoperation. CONCLUSIONS: Extremity reconstruction using the MFC corticocancellous flap results in a high rate of union yet minimal donor morbidity for a challenging patient cohort. Previous surgery was a risk factor for increased time to union.

Massive cortical reorganization is reversible following bilateral transplants of the hands: evidence from the first successful bilateral pediatric hand transplant patient.

In this repeated measures case study, we show that sensory deafferentation after limb amputation leads to changes in cortical somatotopic maps which are reversible after restoration of sensory input. Using magnetoencephalography (MEG), we observed in a child with bilateral hand transplants large-scale shifts in somatosensory lip cortical representation from anatomic hand area to anatomic face region. After recovery of tactile sensation in the digits, responses to finger stimulation were localized to orthotopic sensory cortex, but with atypical electrophysiologic features (amplitude and frequencies).

Does the use of arteriovenous loops increase complications rates in posttraumatic microsurgical lower extremity reconstruction?-A matched-pair analysis.

INTRODUCTION: The use of arteriovenous (AV) loops in microsurgical lower extremity reconstruction is a controversial topic. The objective of the present study was to assess the impact of AV loops on complication rates following microsurgical reconstruction of posttraumatic lower extremity defects. PATIENTS AND METHODS: Patients who underwent free flap coverage of posttraumatic defects in combination with an AV loop (Group 1) were identified and matched for age, body mass index (BMI), tobacco use, defect location, and flap type with patients who underwent reconstruction without vein grafts (Group 2). Outcomes of interest included complication rate and flap loss rate. RESULTS: Groups 1 and 2 consisted of 10 patients each with a mean age of 51 years (range, 21-79 years) and 47.3 years (range, 22-69 years), respectively (P = 0.596). No differences were noted regarding flap loss (P = 1.0), intraoperative (P = 0.474) or postoperative complication rate [surgical site infection (P = 1.0), bleeding (P = 1.0), delayed wound healing (P = 0.23), dehiscence (P = 0.58), and osseous non-union (P = 1.0)]. Only one flap loss was noted in Group 1. The only differences were increased operative time (P = 0.03) and increased length of stay (P = 0.009) in Group 1. CONCLUSION: Our results suggest that utilization of vein grafts with creation of AV loops followed by single-stage division and free flap transfer for reconstruction of posttraumatic lower extremity defects achieve reconstructive outcomes similar to those obtained in patients in whom no vein grafts are necessary.

Variable Operative Experience in Hand Surgery for Plastic Surgery Residents.

BACKGROUND: Efforts to standardize hand surgery training during plastic surgery residency remain challenging. We analyze the variability of operative hand experience at U.S. plastic surgery residency programs. METHODS: Operative case logs of chief residents in accredited U.S. plastic surgery residency programs were analyzed (2011-2015). Trends in fold differences of hand surgery case volume between the 10th and 90th percentiles of residents were assessed graphically. Percentile data were used to calculate the number of residents achieving case minimums in hand surgery for 2015. RESULTS: Case logs from 818 plastic surgery residents were analyzed of which a minority were from integrated (35.7%) versus independent/combined (64.3%) residents. Trend analysis of fold differences in case volume demonstrated decreasing variability among procedure categories over time. By 2015, fold differences for hand reconstruction, tendon cases, nerve cases, arthroplasty/arthrodesis, amputation, arterial repair, Dupuytren release, and neoplasm cases were below 10-fold. Congenital deformity cases among independent/combined residents was the sole category that exceeded 10-fold by 2015. Percentile data suggested that approximately 10% of independent/combined residents did not meet case minimums for arterial repair and congenital deformity in 2015. CONCLUSIONS: Variable operative experience during plastic surgery residency may limit adequate exposure to hand surgery for certain residents. Future studies should establish empiric case minimums for plastic surgery residents to ensure hand surgery competency upon graduation.