Translational bioengineering strategies for peripheral nerve regeneration: opportunities, challenges, and novel concepts.

Peripheral nerve injuries remain a challenging problem in need of better treatment strategies. Despite best efforts at surgical reconstruction and postoperative rehabilitation, patients are often left with persistent, debilitating motor and sensory deficits. There are currently no therapeutic strategies proven to enhance the regenerative process in humans. A clinical need exists for the development of technologies to promote nerve regeneration and improve functional outcomes. Recent advances in the fields of tissue engineering and nanotechnology have enabled biomaterial scaffolds to modulate the host response to tissue repair through tailored mechanical, chemical, and conductive cues. New bioengineered approaches have enabled targeted, sustained delivery of protein therapeutics with the capacity to unlock the clinical potential of a myriad of neurotrophic growth factors that have demonstrated promise in enhancing regenerative outcomes. As such, further exploration of combinatory strategies leveraging these technological advances may offer a pathway towards clinically translatable solutions to advance the care of patients with peripheral nerve injuries. This review first presents the various emerging bioengineering strategies that can be applied for the management of nerve gap injuries. We cover the rationale and limitations for their use as an alternative to autografts, focusing on the approaches to increase the number of regenerating axons crossing the repair site, and facilitating their growth towards the distal stump. We also discuss the emerging growth factor-based therapeutic strategies designed to improve functional outcomes in a multimodal fashion, by accelerating axonal growth, improving the distal regenerative environment, and preventing end-organs atrophy.

Sustained IGF-1 delivery ameliorates effects of chronic denervation and improves functional recovery after peripheral nerve injury and repair.

Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge. We hypothesized that a novel nanoparticle (NP) delivery system can provide controlled release of bioactive IGF-1 targeted to denervated muscle and nerve tissue to achieve improved motor recovery through amelioration of denervation-induced muscle atrophy and SC senescence and enhanced axonal regeneration. Biodegradable NPs with encapsulated IGF-1/dextran sulfate polyelectrolyte complexes were formulated using a flash nanoprecipitation method to preserve IGF-1 bioactivity and maximize encapsulation efficiencies. Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.

Insulin-Like Growth Factor-1: A Promising Therapeutic Target for Peripheral Nerve Injury.

Patients who sustain peripheral nerve injuries (PNIs) are often left with debilitating sensory and motor loss. Presently, there is a lack of clinically available therapeutics that can be given as an adjunct to surgical repair to enhance the regenerative process. Insulin-like growth factor-1 (IGF-1) represents a promising therapeutic target to meet this need, given its well-described trophic and anti-apoptotic effects on neurons, Schwann cells (SCs), and myocytes. Here, we review the literature regarding the therapeutic potential of IGF-1 in PNI. We appraised the literature for the various approaches of IGF-1 administration with the aim of identifying which are the most promising in offering a pathway toward clinical application. We also sought to determine the optimal reported dosage ranges for the various delivery approaches that have been investigated.

Defining the relative impact of muscle versus Schwann cell denervation on functional recovery after delayed nerve repair.

Functional recovery following peripheral nerve injury worsens with increasing durations of delay prior to repair. From the time of injury until re-innervation occurs, denervated muscle undergoes progressive atrophy that limits the extent to which motor function can be restored. Similarly, Schwann cells (SC) in the distal nerve lacking axonal interaction progressively lose their capacity to proliferate and support regenerating axons. The relative contributions of these processes to diminished functional recovery is unclear. We developed a novel rat model to isolate the effects of SC vs. muscle denervation on functional recovery. Four different groups underwent the following interventions for 12 weeks prior to nerve transfer: 1) muscle denervation; 2) SC denervation; 3) muscle + SC denervation (negative control); 4) no denervation (positive control). Functional recovery was measured weekly using the stimulated grip strength testing (SGST). Animals were sacrificed 13 weeks post nerve transfer. Retrograde labeling was used to assess the number of motor neurons that regenerated their axons. Immunofluorescence was performed to evaluate target muscle re-innervation and atrophy, and to assess the phenotype of the SC within the distal nerve segment. Functional recovery in the muscle denervation and SC denervation groups mirrored that of the negative and positive control groups, respectively. The SC denervation group achieved better functional recovery, with a greater number of reinnervated motor endplates and less muscle atrophy, than the muscle denervation group. Retrograde labeling suggested a higher number of neurons contributing to muscle reinnervation in the muscle denervation group as compared to SC denervation (p > 0.05). The distal nerve segment in the muscle denervation group had a greater proportion of SCs expressing the proliferation marker Ki67 as compared to the SC denervation group (p < 0.05). Conversely, the SC denervation group had a higher percentage of senescent SCs expressing p16 as compared to the muscle denervation group (p < 0.05). The deleterious effects of muscle denervation are more consequential than the effects of SC denervation on functional recovery. The effects of 12 weeks of SC denervation on functional outcome were negligible. Future studies are needed to determine whether longer periods of SC denervation negatively impact functional recovery.

Mechanisms and outcomes of the supercharged end-to-side nerve transfer: a review of preclinical and clinical studies.

Proximal peripheral nerve injuries often result in poor functional outcomes, chiefly because of the long time period between injury and the reinnervation of distal targets, which leads to muscle and Schwann cell atrophy. The supercharged end-to-side (SETS) nerve transfer is a recent technical innovation that introduces donor axons distally into the side of an injured nerve to rapidly innervate and support end organs while allowing for additional reinnervation after a proximal repair at the injury site. However, the mechanisms by which donor axons grow within the recipient nerve, contribute to muscle function, and impact the regeneration of native recipient axons are poorly understood. This uncertainty has slowed the transfer's clinical adoption. The primary objective of this article is to comprehensively review the mechanisms underpinning axonal regeneration and functional recovery after a SETS nerve transfer. A secondary objective is to report current clinical applications in the upper limb and their functional outcomes. The authors also propose directions for future research with the aim of maximizing the clinical utility of the SETS transfer for peripheral nerve surgeons and their patients.

Stimulated grip strength measurement: Validation of a novel method for functional assessment.

BACKGROUND: Reliable measurement of functional recovery is critical in translational peripheral nerve regeneration research. Behavioral functional assessments such as volitional grip strength testing (vGST) are limited by inherent behavioral variability. Isometric tetanic force testing (ITFT) is highly reliable but precludes serial measurements. Combining elements of vGST and ITFT, stimulated grip strength testing (sGST) involves percutaneous median nerve stimulation to elicit maximal tetanic contraction of digital flexors, thereby allowing for consistent measurement of maximal grip strength. METHODS: We measured side-to-side equivalence of force using sGST, vGST, and ITFT to determine relative reliability and repeatability. We also performed weekly force measurements following median nerve repair. RESULTS: sGST demonstrated greater reliability and inter-trial repeatability than vGST and similar reliability to ITFT, with the added benefit of serial measurements. CONCLUSIONS: sGST is a valid method for assessing functional recovery that addresses the limitations of the currently available modalities used in translational peripheral nerve regeneration research.

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.

New Frontiers in Robotic-Assisted Microsurgical Reconstruction.

Robotic surgery has revolutionized minimally invasive surgery. Owing to its unique features and key advantages, robotic surgery is being used for complex cases across surgical specialties. It has been introduced into reconstructive surgery, and is being applied in microsurgery. Robotic surgery combines properties of conventional microsurgery, endoscopic surgery, and telesurgery. It holds great promise in expanding the boundaries of reconstructive microsurgery. However, there are constraints that limit its widespread use. We present the different clinical applications of robotic microsurgery, highlighting its advantages over conventional microsurgery, and outlining the main limitations that might prevent its widespread use.

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.

Prevalence of leprous neuropathy determined by neurosensory testing in an endemic zone in Ecuador: Development of an algorithm to identify patients benefiting from early neurolysis.

The success of a microneurosurgical intervention in leprous neuropathy (LN) depends on the diagnosis of chronic compression before irreversible paralysis and digital loss occurs. In order to determine the effectiveness of a different approach for early identification of LN, neurosensory testing with the Pressure-Specified Sensory Device™ (PSSD), a validated and sensitive test, was performed in an endemic zone for leprosy. A cross-sectional study was conducted to analyze a patient sample meeting the World Health Organization (WHO) criteria for Hansen's disease. The prevalence of LN was based on the presence of ≥1 abnormal PSSD pressure threshold for a two-point static touch. A total of 312 upper and lower extremity nerves were evaluated in 39 patients. The PSSD found a 97.4% prevalence of LN. Tinel's sign was identified in 60% of these patients. An algorithm for early identification of patients with LN was proposed using PSSD testing based on the unilateral screening of the ulnar and deep peroneal nerves.

Growth Hormone Therapy Accelerates Axonal Regeneration, Promotes Motor Reinnervation, and Reduces Muscle Atrophy following Peripheral Nerve Injury.

BACKGROUND: Therapies to improve outcomes following peripheral nerve injury are lacking. Prolonged denervation of muscle and Schwann cells contributes to poor outcomes. In this study, the authors assess the effects of growth hormone therapy on axonal regeneration, Schwann cell and muscle maintenance, and end-organ reinnervation in rats. METHODS: Male Sprague-Dawley rats underwent sciatic nerve transection and repair and femoral nerve transection without repair and received either daily subcutaneous growth hormone (0.4 mg/day) or no treatment (n = 8 per group). At 5 weeks, the authors assessed axonal regeneration within the sciatic nerve, muscle atrophy within the gastrocnemius muscle, motor endplate reinnervation within the soleus muscle, and Schwann cell proliferation within the denervated distal femoral nerve. RESULTS: Growth hormone-treated animals demonstrated greater percentage increase in body mass (12.2 ± 1.8 versus 8.5 ± 1.5; p = 0.0044), greater number of regenerating myelinated axons (13,876 ± 2036 versus 8645 ± 3279; p = 0.0018) and g-ratio (0.64 ± 0.11 versus 0.51 ± 0.06; p = 0.01), greater percentage reinnervation of motor endplates (75.8 ± 8.7 versus 38.2 ± 22.6; p = 0.0008), and greater muscle myofibril cross-sectional area (731.8 ± 157 µm versus 545.2 ± 144.3 µm; p = 0.027). CONCLUSIONS: In male rats, growth hormone therapy accelerates axonal regeneration, reduces muscle atrophy, and promotes muscle reinnervation. Growth hormone therapy may also maintain proliferating Schwann cells in the setting of prolonged denervation. These findings suggest potential for improved outcomes with growth hormone therapy after peripheral nerve injuries.

Pyoderma Gangrenosum After Breast Surgery: Diagnostic Pearls and Treatment Recommendations Based on a Systematic Literature Review.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare cutaneous disorder that poses a diagnostic challenge in the postoperative period. A systematic literature review was performed to determine distinguishing characteristics of PG in the setting of breast surgery that can facilitate timely diagnosis and appropriate treatment. METHODS: PubMed, EMBASE, Scopus, and Web of Science databases were systematically searched for articles with cases of PG occurring after breast surgery. Forty-three relevant articles, including 49 case reports, were identified. RESULTS: PG manifested bilaterally in 30 of 34 cases (88%) in which bilateral surgery was performed. Abdominal wounds were present in 6 of 7 cases in which an abdominal donor site was used for breast reconstruction. Nipples were spared from wound involvement in 33 of 37 cases (89%) in which nipples were present after surgery. Presence of fever was noted in 27 cases (55%) and leukocytosis in 21 cases (43%). A total of 33 patients (67%) underwent wound debridement. Successful medical treatment most commonly involved steroids (41 cases, 84%) and cyclosporine (10 cases, 20%). CONCLUSIONS: Pertinent clinical features were identified that may aid in timely diagnosis and treatment of PG after breast surgery. Appearance of discrete wounds involving multiple surgical sites that surround but spare the nipples should raise suspicion for PG rather than infection or ischemia, even with concomitant fever and leukocytosis. Wound debridement should be minimized and skin grafting considered only after medical therapy is initiated. Cognizance of these features may enable prompt therapeutic intervention that minimizes morbidity and improves outcomes.

Reconstruction of Large Abdominal Wall Defects Using Neurotized Vascular Composite Allografts.

BACKGROUND: Abdominal wall vascularized composite allotransplantation is the second most common form of vascularized composite allotransplantation. Sensory and functional recovery are expected in other forms but have never been demonstrated in abdominal wall vascularized composite allotransplantation. The authors hypothesize that coaptation of two thoracolumbar nerves will result in reinnervation of the alloflap and maintenance of the muscle component. METHODS: Adult, male, 10-week-old Brown Norway and Lewis rats were used for experiments. The rat donor's common iliac vessels were anastomosed to the recipient's femoral vessels. Intercostal nerves T10/L1 were coapted. Four groups (n = 5 per group) were included for study: group 1, Lewis, intercostal nerves cut, not repaired; group 2, Lewis intercostal nerves cut, T10/L1 repaired; group 3, allogeneic Brown Norway-to-Lewis abdominal wall vascularized composite allotransplantation, T10/L1 repaired; and group 4, syngeneic Lewis-to-Lewis abdominal wall vascularized composite allotransplantation, T10/L1 repaired. Animals were killed on postoperative day 60. Nerve regeneration was assessed using muscle weight analysis, myofibril cross-sectional area, nerve histomorphometry, and neuromuscular junction percentage reinnervation. RESULTS: Groups 2, 3, and 4 maintained a significantly greater percentage of postharvest weight compared with group 1 (p < 0.05). Group 1 had significantly decreased myofibril cross-sectional area compared with controls (p < 0.05). There was no significant difference in myofibril cross-sectional area in groups 2 through 4 compared with controls (p > 0.05). Group 1 had significantly decreased percentage reinnervation of the alloflap compared with controls (p < 0.05). There was no significant difference when comparing group 2 through 4 with internal, contralateral controls (p > 0.05). CONCLUSION: In a murine model for abdominal wall vascularized composite allotransplantation, coaptation of T10/L1 will allow for reinnervation of the alloflap and maintenance of the muscle component.

The emerging role of tissue plasminogen activator in the management of severe frostbite.

This article presents a small case series demonstrating clinical success with thrombolytic agents for severe frostbite injury to the lower extremities. The authors report three patients with severe frostbite injuries to their distal lower extremities who were managed with urgent interventional radiology and intra-arterial tissue plasminogen activator infusion according to a prespecified protocol. Limbs and digits were successfully salvaged and patients returned to normal activity within 2 weeks. Although further studies are needed, results of this study support a new approach in the management of frostbite: from conservative management and observation to urgent interventional radiology and possible tissue plasminogen activator infusion. A protocol for the management of such injuries is presented.

Discrepancy in Initial Pediatric Burn Estimates and Its Impact on Fluid Resuscitation.

One of the fundamental aspects of initial burn care is the ability to accurately measure the TBSA of injured tissue. Discrepancies between initial estimates of burn size and actual TBSA (determined at the burn unit) have long been reported. These inconsistencies have the potential for unnecessary patient transfer and inappropriate fluid administration which may result in morbidity. In an effort to study these inconsistencies and their impact on initial care, we evaluated the differences between initial TBSA estimates and its impact on fluid resuscitation at an American Burn Association-verified pediatric burn center. A prospective observational study of 50 consecutive burn patients admitted to Shriner's Hospital for Children in Boston, Massachusetts, between October 2011 and April 2012 was performed. Data collected included age, mechanism of burn injury, type of referral center, referring hospital TBSA, and volume of fluid administration as well as admission TBSA and volume of fluid administration. Determination of over or under resuscitation was based on comparing the amount of fluids received at the referral center to that received at the pediatric burn center. A total of 50 patients were admitted during the 7-month study period. The average age was 4.1 years old (25 days-16 years) and the average TBSA was 2.5% (0.25-55%). There were significant differences in the TBSA calculations between referring centers and the pediatric burn center. Overestimation of scald and contact burn size (P < .05) was noted with no difference in flame burn size estimation. Community referrals were more likely than tertiary centers to overestimate TBSA (P < .05 vs P = .29). Overall, 59% of study patients were administered more fluid at the referring hospital than would have been expected by the burn size calculated at our facility. Inconsistencies with the estimation of TBSA burn between referring hospitals and tertiary referral centers remains a problem in pediatric patients and may lead to inappropriate resuscitation. This study highlights the continued need for educational outreach programs and for the provision of novel resources to initial burn providers. Additional support through online resources (eg, Lund-Browder diagram) and remotely assisting providers during their TBSA measurements are potential options which may help to improve the initial care of burn patients.

Functional abdominal wall reconstruction using an innervated abdominal wall vascularized composite tissue allograft: a cadaveric study and review of the literature.

BACKGROUND: Large, composite abdominal wall defects represent complex problems requiring a multidisciplinary approach for reconstruction. Abdominal wall vascularized composite allotransplantation (AW-VCA) has been successfully performed in 21 patients, already receiving solid organ transplants, to provide immediate abdominal closure. The current study aims to establish a novel anatomic model for AW-VCA that retains motor and sensory function in an effort to preserve form and function while preventing complications. METHODS: Three fresh cadaver torsos were obtained. Dissection was started in the midaxillary line bilaterally through the skin and subcutaneous fascia until the external oblique was encountered. The thoracolumbar nerves were identified and measurements were obtained. A peritoneal dissection from the costal margin to pubic symphysis was performed and the vascular pedicle was identified for subsequent microsurgical anastomosis. RESULTS: The mean size of the abdominal wall graft harvested was 615 ± 120 cm(2). The mean time of abdominal wall procurement was ∼150 ± 12 minutes. The mean number of thoracolumbar nerves identified was 5 ± 1.4 on each side. The mean length of the skeletonized thoracolumbar nerves was 7.8 ± 1.7 cm. The cross-sectional diameter of all nerves as they entered the rectus abdominis was greater than 2 mm. CONCLUSIONS: Motor function and sensory recovery is expected in other forms of vascularized composite allotransplantation, such as the hand or face; however, this has never been tested in AW-VCA. This study demonstrates feasibility for the transplantation of large, composite abdominal wall constructs that potentially retains movement, strength, and sensation through neurotization of both sensory and motor nerves.

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.

Neoadjuvant chemotherapy and short-term morbidity in patients undergoing mastectomy with and without breast reconstruction.

IMPORTANCE: Neoadjuvant chemotherapy (NC) is increasingly being used in patients with breast cancer, and evidence-based reports related to its independent effects on morbidity after mastectomy with immediate breast reconstruction are limited. OBJECTIVE: To determine the effect of NC on 30-day postoperative morbidity in women undergoing mastectomy with or without immediate breast reconstruction. DESIGN, SETTING, AND PARTICIPANTS: All women undergoing mastectomy with or without immediate breast reconstruction from January 1, 2005, through December 31, 2011, at university and private hospitals internationally were analyzed using the American College of Surgeons National Surgical Quality Improvement Program 2005-2011 databases. Patients who received NC were compared with those without a history of NC to estimate the relative odds of 30-day postoperative overall, systemic, and surgical site morbidity using model-wise multivariable logistic regression. EXPOSURE: Neoadjuvant chemotherapy. MAIN OUTCOMES AND MEASURES: Thirty-day postoperative morbidity (overall, systemic, and surgical site). RESULTS: Of 85,851 women, 66,593 (77.6%) underwent mastectomy without breast reconstruction, with 2876 (4.3%) receiving NC; 7893 patients were excluded because of missing exposure data. The immediate breast reconstruction population included 19,258 patients (22.4%), with 820 (4.3%) receiving NC. After univariable analysis, NC was associated with a 20% lower odds of overall morbidity in the group undergoing mastectomy without breast reconstruction (odds ratio [OR], 0.80; 95% CI, 0.71-0.91) but had no significant effect in the immediate breast reconstruction group (OR, 0.98; 95% CI, 0.79-1.23). After adjustment for confounding, NC was independently associated with lower overall morbidity in the group undergoing mastectomy without breast reconstruction (OR, 0.61; 95% CI, 0.51-0.73) and the immediate tissue expander reconstruction subgroup (OR, 0.49; 95% CI, 0.30-0.84). Neoadjuvant chemotherapy was associated with decreased odds of systemic morbidity in 4 different populations: complete sample (OR, 0.59; 95% CI, 0.49-0.71), mastectomy without breast reconstruction (OR, 0.59; 95% CI, 0.48-0.72), any immediate breast reconstruction (OR, 0.57; 95% CI, 0.37-0.88), and the tissue expander subgroup (OR, 0.41; 95% CI, 0.23-0.72). CONCLUSIONS AND RELEVANCE: Our study supports the safety of NC in women undergoing mastectomy with or without immediate breast reconstruction. Neoadjuvant chemotherapy is associated with lower overall morbidity in the patients undergoing mastectomy without breast reconstruction and in those undergoing tissue expander breast reconstruction. In addition, the odds of systemic morbidity were decreased in patients undergoing mastectomy with and without immediate breast reconstruction. The mechanisms behind the protective association of NC remain unknown and warrant further investigation.