Complex regional pain syndrome patient treated with a below knee amputation, implanting nerves directly into muscle: A case report.

Persistent, disabling lower extremity pain, outside the distribution of a single nerve, is termed chronic regional pain syndrome (CRPS), but, in reality, this chronic pain is often due to multiple peripheral nerve injuries. It is the purpose of this report to describe the first application of the "traditional," nerve implantation into muscle, usually used in the treatment of a painful neuroma, as a pre-emptive surgical technique in doing a below knee amputation (BKA). In 2011, a 51-year-old woman developed severe, disabling CRPS, after a series of operations to treat an enchondroma of the left fifth metatarsal. When appropriate peripheral nerve surgeries failed to relieve distal pain, a BKA was elected. The approach to the BKA included implantation of each transected peripheral nerve directly into an adjacent muscle. At 5.0 years after the patient's BKA, the woman reported full use of this extremity, using the prosthesis, and was free of phantom limb and residual limb pain. This anecdotal experience gives insight that long-term relief of lower extremity CRPS can be achieved by a traditional BKA utilizing the approach of implanting each transected nerve into an adjacent muscle.

What Is the Impact of Postoperative Antibiotic Prophylaxis on Tissue Expander Infection Rates in Pediatric Patients?

BACKGROUND: Tissue expansion in the pediatric population can be complicated by high rates of infection and extrusion. The aim of this study was to examine the impact of postoperative antibiotic prophylaxis on infectious complications. METHODS: A retrospective study of all pediatric patients who underwent tissue expander insertion at a children's hospital over a 12-year period was performed. Predictor variables included age, sex, race, indication, anatomical location, number of expanders inserted, serial expansion, history of infection or extrusion, and postoperative antibiotics. Outcome variables included infection and extrusion. Bivariate and multivariate analyses were performed to identify factors associated with infection and/or extrusion. RESULTS: A total of 180 patients who underwent 317 operations for tissue expander insertion were included in this study. Postoperative infection and/or extrusion occurred after 73 operations (23 percent). Postoperative prophylactic antibiotics were prescribed after 232 operations (75 percent), and only perioperative (≤24 hours) antibiotics were administered in 85 cases (25 percent). There were no significant differences in the rate of infection (12.1 percent versus 8.9 percent; p = 0.46), extrusion (16.8 percent versus 17.7 percent; p = 0.88), or infection and/or extrusion (23.7 percent versus 24.1 percent; p = 0.95) between these two groups. Multivariate analysis revealed that postoperative antibiotics did not have a significant association with infection and/or extrusion (OR, 0.84; 95 percent CI, 0.44 to 1.63; p = 0.61). CONCLUSIONS: The rates of infection/extrusion were similar between pediatric patients who received only perioperative antibiotics (≤24 hours) and those who were prescribed a course of postoperative antibiotics. Based on these results, a course of postoperative prophylactic antibiotics may be unnecessary after insertion of tissue expanders in pediatric patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Pediatric Tissue Expansion: Predictors of Premature Expander Removal in a Single Surgeon's Experience with 472 Expanders.

BACKGROUND: Tissue expansion is used for soft-tissue reconstruction in pediatric patients. The expansion process can be complicated by infection and extrusion, leading to premature expander removal. The aim of this study was to identify risk factors associated with premature expander removal caused by infection or extrusion in pediatric patients. METHODS: A retrospective study of pediatric patients who underwent tissue expansion performed by the senior author (R.J.R.) over a 12-year period was performed. Predictor variables included age, sex, race, indication, anatomical location, number of expanders, serial expansion, and expander size. Bivariate and multivariate analyses were performed to identify risk factors for premature expander removal. RESULTS: A total of 139 patients with 472 expanders were included in this study. Complications occurred with 78 expanders (16.5 percent). Premature expander removal caused by infection or exposure occurred with 51 expanders (10.8 percent). In terms of location, the highest rates of premature removal occurred in the lower extremity (20.0 percent) and scalp (16.3 percent). Multivariate analysis identified younger age (0 to 6 years compared with 13 to 17 years; OR, 3.98; 95 percent CI, 1.13 to 14.08; p = 0.03), greater number of expanders (OR, 1.45; 95 percent CI, 1.03 to 2.03; p = 0.03), and lower extremity location (OR, 4.27; 95 percent CI, 1.45 to 12.53; p = 0.008) were associated with an increased odds of premature expander removal. CONCLUSIONS: Expander removal occurred in approximately 10 percent of tissue expanders. Odds of premature removal is increased with younger age, greater number of expanders, and lower extremity location. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Poly(ε-Caprolactone) Nanofiber Wrap Improves Nerve Regeneration and Functional Outcomes after Delayed Nerve Repair.

BACKGROUND: The purpose of this study was to assess the efficacy of biodegradable, electrospun poly(ε-caprolactone) nanofiber nerve conduits in improving nerve regeneration. METHODS: The authors used a rat forelimb chronic denervation model to assess the effects of poly(ε-caprolactone) conduits on improving nerve regeneration and upper extremity function. Three groups of rats were examined: (1) negative-control animals (n = 5), which underwent 8 weeks of median nerve chronic denervation injury followed by repair with no conduit; (2) experimental animals (n = 5), which underwent 8 weeks of median nerve chronic denervation followed by repair and poly(ε-caprolactone) nerve conduit wrapping of the nerve coaptation site; and (3) positive-control animals (n = 5), which were naive controls. All animals underwent compound muscle action potential and functional testing. At 14 weeks after repair, the median nerve and flexor muscles were harvested for histologic analysis. RESULTS: Histomorphometric analysis of regenerating median nerves demonstrated augmented axonal regeneration in experimental versus negative control animals (total axon count, 1769 ± 672 versus 1072 ± 123.80; p = 0.0468). With regard to functional recovery, experimental and negative-control animals (1.67 ± 0.04 versus 0.97 ± 0.39; p = 0.036) had regained 34.9 percent and 25.4 percent, respectively, of baseline hand grip strength at 14 weeks after repair. Lastly, less collagen deposition at the nerve coaptation site of experimental animals was found when compared to control animals (p < 0.05). CONCLUSION: Biodegradable, poly(ε-caprolactone) nanofiber nerve conduits can improve nerve regeneration and subsequent physiologic extremity function in the setting of delayed nerve repair by decreasing the scar burden at nerve coaptation sites.

Glial Cell Line-Derived Neurotrophic Factor and Chondroitinase Promote Axonal Regeneration in a Chronic Denervation Animal Model.

Functional recovery following nerve injury declines when target re-innervation is delayed. Currently, no intervention exists to improve outcomes after prolonged denervation. We explored the neuroregenerative effects of glial cell line-derived neurotrophic factor (GDNF) and chondroitinase (CDN) in a chronic denervation animal model. A fibrin-based sustained delivery method for growth factors was optimized in vitro and in vivo, and then tested in our animal model. GDNF, CDN, and GDNF+CDN were injected into the denervated stump at the time of nerve repair. Histomorphometry and retrograde labeling were used to assess axonal regeneration. The mechanisms promoting such regeneration were explored with immunofluorescence. Five weeks after repair, the GDNF+CDN group had the highest number and maturity of axons. GDNF was noted to preferentially promote axonal maturity, whereas CDN predominantly increased the number of axons. GDNF favored motor neuron regeneration, and upregulated Ki67 in Schwann cells. CDN did not favor motor versus sensory regeneration and was noted to cleave inhibitory endoneurial proteoglycans. Early measures of nerve regeneration after delayed repair are improved by activating Schwann cells and breaking down the inhibitory proteoglycans in the distal nerve segment, suggesting a role for GDNF+CDN to be translated for human nerve repairs.

Macroporous nanofiber wraps promote axonal regeneration and functional recovery in nerve repair by limiting fibrosis.

Functional outcomes following nerve repair remain suboptimal. Scarring at the repair site is a major impediment to regeneration. A biomaterial scaffold applied around the coaptation site that decreases inflammation holds great potential in reducing scarring, enhancing axonal growth, and improving functional recovery. In this study, we evaluated the effect of a macroporous nanofiber wrap, comprised of nonwoven electrospun poly-ε-caprolactone (PCL), in improving axonal regeneration in a rat sciatic nerve cut and direct repair model. Controls consisted of conventional epineurial repair. We also evaluated our wrap against the commercially available AxoGuard wrap. At five weeks following repair, the nanofiber wrap group showed a significantly decreased intraneural macrophage invasion and collagen deposition at the repair site. This was associated with increased expression of the anti-inflammatory cytokine (IL-10), decreased expression of the pro-inflammatory cytokine (TNF-α), and a decrease in the M1:M2 macrophage phenotype ratio. These findings suggest that this nanofiber wrap, with its unique macroporosity, is modulating the inflammatory response at the repair site by polarizing macrophages towards a pro-regenerative M2 phenotype. Concomitantly, a higher number of regenerated axons was noted. At sixteen weeks, the nanofiber wrap resulted in enhanced functional recovery as demonstrated by electrophysiology, neuromuscular re-innervation, and muscle histology. When compared to the AxoGuard wrap, the nanofiber wrap showed similar inflammation at the repair site and similar nerve morphometric findings, but there was a trend towards a lower overall number of macrophages invading the wrap wall. These results demonstrate favorable outcomes of the macroporous nanofiber wrap in promoting neuroregeneration and functional recovery following nerve repair. STATEMENT OF SIGNIFICANCE: Electrospun nanofiber scaffolds, with specific fiber and pore sizes, were shown to modulate the immune response and create a regenerative environment. In this paper, we present a macroporous nanofiber wrap, made of poly-ε-caprolactone, to be applied at the coaptation site in primary nerve repair. We show that it regulates the inflammatory response at the repair site and decreases scarring/fibrosis. This results in enhanced axonal regeneration, allowing a higher number of axons to cross the suture line and reach the target muscle in a timely fashion. Functional outcomes are thus improved.

Mesenchymal Stem Cells Enhance Nerve Regeneration in a Rat Sciatic Nerve Repair and Hindlimb Transplant Model.

This study investigates the efficacy of local and intravenous mesenchymal stem cell (MSC) administration to augment neuroregeneration in both a sciatic nerve cut-and-repair and rat hindlimb transplant model. Bone marrow-derived MSCs were harvested and purified from Brown-Norway (BN) rats. Sciatic nerve transections and repairs were performed in three groups of Lewis (LEW) rats: negative controls (n = 4), local MSCs (epineural) injection (n = 4), and systemic MSCs (intravenous) injection (n = 4). Syngeneic (LEW-LEW) (n = 4) and allogeneic (BN-LEW) (n = 4) hindlimb transplants were performed and assessed for neuroregeneration after local or systemic MSC treatment. Rats undergoing sciatic nerve cut-and-repair and treated with either local or systemic injection of MSCs had significant improvement in the speed of recovery of compound muscle action potential amplitudes and axon counts when compared with negative controls. Similarly, rats undergoing allogeneic hindlimb transplants treated with local injection of MSCs exhibited significantly increased axon counts. Similarly, systemic MSC treatment resulted in improved nerve regeneration following allogeneic hindlimb transplants. Systemic administration had a more pronounced effect on electromotor recovery while local injection was more effective at increasing fiber counts, suggesting different targets of action. Local and systemic MSC injections significantly improve the pace and degree of nerve regeneration after nerve injury and hindlimb transplantation.

Changing paradigms in lower extremity reconstruction in war-related injuries.

BACKGROUND: Ballistic high-energy trauma has substantially increased the severity of non-fatal extremity injuries incurred in modern warfare. Expedient medical care, refinement in surgical techniques, and soft tissue coverage have brought about a paradigm shift in the management of lower extremity wounds during the last decade with an increased emphasis on limb salvage. METHODS: A literature-based study was conducted to analyze reconstructive modalities based on the location, depth, and severity of wounds, as well as mechanism of injury, concomitant vascular injuries and open fractures, choice of flap, timing of definitive reconstruction, and complications. RESULTS: Extremity injuries account for over 60 % of injuries in the recent conflicts in Iraq and Afghanistan, with the majority secondary to explosive devices. The severity of these injuries is profound compared with civilian registries, and conventional injury scoring systems have failed to accurately predict outcomes in combat trauma. The mainstay of treatment is serial debridement, negative pressure therapy, fracture stabilization, and treatment of concomitant injuries by the forward medical teams with subsequent definitive reconstruction after transport to an advanced military treatment facility. Autologous reconstruction with free tissue transfer and pedicled flaps remains the primary modality for soft tissue coverage in limb salvage. Adjunct innovative modalities, such as external tissue expansion, dermal substitutes, and regenerative matrices, have also been successfully utilized for limb salvage. CONCLUSION: Lower extremity injuries account for the vast majority of injuries in modern warzones. Explosive devices represent the most common mechanism of injury, with blast impact leading to extensive soft tissue injuries necessitating complex reconstructive strategies. Serial debridement, negative pressure therapy, and autologous reconstruction with free tissue transfer and pedicled flaps remain the mainstay of treatment in recent conflicts.

Algorithmic Approach to Overcome Scalp Deficiency in the Setting of Secondary Cranial Reconstruction.

BACKGROUND: Multidisciplinary approaches have shown improved outcomes in secondary cranial reconstruction, however, scalp deficiency remains a common obstacle for tension-free scalp closure during cranioplasty. Therefore, our objective was to create an algorithmic approach using a novel concept of "component separation" to help minimize potential complications. METHODS: The authors tested the hypothesis of achieving greater scalp mobility by way of "component separation" in a half-scalp, bilateral cadaver study, and describe within 2 clinical examples. Pterional-sized (N = 2) and hemicraniectomy-sized (N = 2) scalp flaps were dissected on 2 cadaveric heads using an internal control for each scenario. All flaps (N = 4) were created with (experimental group) and without (control group) "retaining ligament release." Total amounts of scalp mobility were measured bilaterally and compared accordingly. RESULTS: Scalp flap mobility was calculated from the sagittal midline using identical arcs of rotation. With zero tension, we observed an increased distance of movement equaling 1 cm for the "experimental" pterional flap, compared with the contralateral "control." Similarly, we found an increase of additional 2 cm in scalp mobility for the "experimental" hemicraniectomy-sized flap. CONCLUSIONS: Tension free scalp closure is most critical for achieving improved outcomes in secondary cranial reconstruction. In this study, we show that a range of 1 to 2 additional centimeters may be gained through a component separation, which is of critical value during scalp closure following cranioplasty. Therefore, based on our high volume cranioplasty experience and cadaver study presented, we offer some new insight on methods to overcome scalp deficiency accompanying secondary cranial reconstruction.

Evaluation of microvascular anastomosis using real-time, ultra-high-resolution, Fourier domain Doppler optical coherence tomography.

BACKGROUND: Evolution in microsurgical techniques and tools has paved the way for supermicrosurgical anastomoses, with vessel diameters often approaching below 0.8 mm in the clinical realm and even smaller (0.2 to 0.3 mm) in murine models. Several imaging and monitoring devices have been introduced for postoperative monitoring, but intraoperative guidance, assessment, and predictability have remained limited to binocular optical microscopy and the surgeon's experience. The authors present a high-resolution, real-time, three-dimensional imaging modality for intraoperative evaluation of luminal narrowing, thrombus formation, and flow alterations. METHODS: An imaging modality that provides immediate, in-depth, high-resolution, three-dimensional structure view and flow information of the anastomosed site, called phase-resolved Doppler optical coherence tomography, was developed. Twenty-two mouse femoral artery anastomoses and 17 mouse venous anastomoses were performed and evaluated. Flow status, vessel inner lumen three-dimensional structure, and early thrombus detection were analyzed based on imaging results. Predictions formed correlated with actual long-term surgical outcomes. Eventually, four cases of mouse orthotopic limb transplantation were carried out, and predicted long-term patency based on imaging results was confirmed by actual results. RESULTS: The assessments based on high-resolution three-dimensional visualization of the vessel flow status and inner lumen provided by phase-resolved Doppler optical coherence tomography show 92 percent sensitivity and 90 percent specificity for arterial anastomoses and 90 percent sensitivity and 86 percent specificity for venous anastomoses. CONCLUSIONS: Phase-resolved Doppler optical coherence tomography is an effective evaluation tool for microvascular anastomosis. It can predict the long-term vessel patency with high sensitivity and specificity.

Stem cell-based approaches to improve nerve regeneration: potential implications for reconstructive transplantation?

Reconstructive transplantation has become a viable option to restore form and function after devastating tissue loss. Functional recovery is a key determinant of overall success and critically depends on the quality and pace of nerve regeneration. Several molecular and cell-based therapies have been postulated and tested in pre-clinical animal models to enhance nerve regeneration. Schwann cells remain the mainstay of research focus providing neurotrophic support and signaling cues for regenerating axons. Alternative cell sources such as mesenchymal stem cells and adipose-derived stromal cells have also been tested in pre-clinical animal models and in clinical trials due to their relative ease of harvest, rapid expansion in vitro, minimal immunogenicity, and capacity to integrate and survive within host tissues, thereby overcoming many of the challenges faced by culturing of human Schwann cells and nerve allografting. Induced pluripotent stem cell-derived Schwann cells are of particular interest since they can provide abundant, patient-specific autologous Schwann cells. The majority of experimental evidence on cell-based therapies, however, has been generated using stem cell-seeded nerve guides that were developed to enhance nerve regeneration across "gaps" in neural repair. Although primary end-to-end repair is the preferred method of neurorrhaphy in reconstructive transplantation, mechanistic studies elucidating the principles of cell-based therapies from nerve guidance conduits will form the foundation of further research employing stem cells in end-to-end repair of donor and recipient nerves. This review presents key components of nerve regeneration in reconstructive transplantation and highlights the pre-clinical studies that utilize stem cells to enhance nerve regeneration.

Injectable bioadhesive hydrogels with innate antibacterial properties.

Surgical site infections cause significant postoperative morbidity and increased healthcare costs. Bioadhesives used to fill surgical voids and support wound healing are typically devoid of antibacterial activity. Here we report novel syringe-injectable bioadhesive hydrogels with inherent antibacterial properties prepared from mixing polydextran aldehyde and branched polyethylenimine. These adhesives kill both Gram-negative and Gram-positive bacteria, while sparing human erythrocytes. An optimal composition of 2.5 wt% oxidized dextran and 6.9 wt% polyethylenimine sets within seconds forming a mechanically rigid (~1,700 Pa) gel offering a maximum adhesive stress of ~2.8 kPa. A murine infection model showed that the adhesive is capable of killing Streptococcus pyogenes introduced subcutaneously at the bioadhesive's surface, with minimal inflammatory response. The adhesive was also effective in a cecal ligation and puncture model, preventing sepsis and significantly improving survival. These bioadhesives represent novel, inherently antibacterial materials for wound-filling applications.

Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges.

Refinements in microsurgical techniques coupled with advances in immunosuppressive and immunomodulatory protocols have enabled broader clinical application of vascularized composite allotransplantation (VCA) with encouraging immunological, functional, and esthetic results. However, skin rejection remains a significant obstacle and a serious complication for VCA recipients. Clinical and histopathological features of rejection in VCA have been described in a number of studies, which led to the development of an international consensus on the classification guidelines of rejection in the context of VCA. Nevertheless, currently available diagnostic modalities still have several limitations and shortcomings that can pose a significant diagnostic challenge, particularly when signs of rejection are found to be equivocal. In this review, we provide a critical analysis of these advances and challenges in diagnosing skin rejection. Specifically, we highlight the gaps in understanding of rejection mechanisms, the shortfalls in correlating cellular, molecular, and clinicopathologic markers with rejection grades, deficiencies in defining chronic rejection, and antibody-mediated rejection after VCA, as well as providing an outlook on novel concepts, such as the utilization of advanced computational analyses and cross-disciplinary diagnostic approaches.

A critical analysis of rejection in vascularized composite allotransplantation: clinical, cellular and molecular aspects, current challenges, and novel concepts.

Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures.

Cutaneous collateral axonal sprouting re-innervates the skin component and restores sensation of denervated Swine osteomyocutaneous alloflaps.

Reconstructive transplantation such as extremity and face transplantation is a viable treatment option for select patients with devastating tissue loss. Sensorimotor recovery is a critical determinant of overall success of such transplants. Although motor function recovery has been extensively studied, mechanisms of sensory re-innervation are not well established. Recent clinical reports of face transplants confirm progressive sensory improvement even in cases where optimal repair of sensory nerves was not achieved. Two forms of sensory nerve regeneration are known. In regenerative sprouting, axonal outgrowth occurs from the transected nerve stump while in collateral sprouting, reinnervation of denervated tissue occurs through growth of uninjured axons into the denervated tissue. The latter mechanism may be more important in settings where transected sensory nerves cannot be re-apposed. In this study, denervated osteomyocutaneous alloflaps (hind- limb transplants) from Major Histocompatibility Complex (MHC)-defined MGH miniature swine were performed to specifically evaluate collateral axonal sprouting for cutaneous sensory re-innervation. The skin component of the flap was externalized and serial skin sections extending from native skin to the grafted flap were biopsied. In order to visualize regenerating axonal structures in the dermis and epidermis, 50 um frozen sections were immunostained against axonal and Schwann cell markers. In all alloflaps, collateral axonal sprouts from adjacent recipient skin extended into the denervated skin component along the dermal-epidermal junction from the periphery towards the center. On day 100 post-transplant, regenerating sprouts reached 0.5 cm into the flap centripetally. Eight months following transplant, epidermal fibers were visualized 1.5 cm from the margin (rate of regeneration 0.06 mm per day). All animals had pinprick sensation in the periphery of the transplanted skin within 3 months post-transplant. Restoration of sensory input through collateral axonal sprouting can revive interaction with the environment; restore defense mechanisms and aid in cortical re-integration of vascularized composite allografts.