Browsing by Subject "Nerve regeneration"

Now showing 1 - 7 of 7
  • Thumbnail Image
    Item
    A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair
    (Wolters Kluwer, 2024) Daeschler, Simeon C.; So, Katelyn J. W.; Feinberg, Konstantin; Manoraj, Marina; Cheung, Jenny; Zhang, Jennifer; Mirmoeini, Kaveh; Santerre, J. Paul; Gordon, Tessa; Borschel, Gregory H.; Surgery, School of Medicine
    Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.
  • Thumbnail Image
    Item
    Advancing Nerve Regeneration: Translational Perspectives of Tacrolimus (FK506)
    (MDPI, 2023-08-14) Daeschler, Simeon C.; Feinberg, Konstantin; Harhaus, Leila; Kneser, Ulrich; Gordon, Tessa; Borschel, Gregory H.; Ophthalmology, School of Medicine
    Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.
  • Thumbnail Image
    Item
    Biohacking Nerve Repair: Novel Biomaterials, Local Drug Delivery, Electrical Stimulation, and Allografts to Aid Surgical Repair
    (MDPI, 2024-07-31) Crabtree, Jordan R.; Mulenga, Chilando M.; Tran, Khoa; Feinberg, Konstantin; Santerre, J. Paul; Borschel, Gregory H.; Surgery, School of Medicine
    The regenerative capacity of the peripheral nervous system is limited, and peripheral nerve injuries often result in incomplete healing and poor outcomes even after repair. Transection injuries that induce a nerve gap necessitate microsurgical intervention; however, even the current gold standard of repair, autologous nerve graft, frequently results in poor functional recovery. Several interventions have been developed to augment the surgical repair of peripheral nerves, and the application of functional biomaterials, local delivery of bioactive substances, electrical stimulation, and allografts are among the most promising approaches to enhance innate healing across a nerve gap. Biocompatible polymers with optimized degradation rates, topographic features, and other functions provided by their composition have been incorporated into novel nerve conduits (NCs). Many of these allow for the delivery of drugs, neurotrophic factors, and whole cells locally to nerve repair sites, mitigating adverse effects that limit their systemic use. The electrical stimulation of repaired nerves in the perioperative period has shown benefits to healing and recovery in human trials, and novel biomaterials to enhance these effects show promise in preclinical models. The use of acellular nerve allografts (ANAs) circumvents the morbidity of donor nerve harvest necessitated by the use of autografts, and improvements in tissue-processing techniques may allow for more readily available and cost-effective options. Each of these interventions aid in neural regeneration after repair when applied independently, and their differing forms, benefits, and methods of application present ample opportunity for synergistic effects when applied in combination.
  • Thumbnail Image
    Item
    Mesenchymal stem cells and local tacrolimus delivery synergistically enhance neurite extension
    (Wiley, 2021) Saffari, Sara; Saffari, Tiam M.; Chan, Katelyn; Borschel, Gregory H.; Shin, Alexander Y.; Surgery, School of Medicine
    Background: The aim of this study was to investigate the combined effect of mesenchymal stem cells (MSC) and local delivery of tacrolimus (FK506) on nerve regeneration when applied to nerve autografts and decellularized allografts. Methods: A three-dimensional in vitro compartmented cell culture system consisting of a neonatal dorsal root ganglion adjacent to a nerve graft was used to evaluate the regenerating neurites into the peripheral nerve scaffold. Nerve autografts and allografts were treated with (i) undifferentiated MSCs, (ii) FK506 (100 ng/mL) or (iii) both (N = 9/group). After 48 hours, neurite extension was measured to quantify nerve regeneration and stem cell viability was evaluated. Results: Stem cell viability was confirmed in all MSC-treated grafts. Neurite extension was superior in autografts treated with FK506, and MSCs and FK506 combined (p < 0.001 and p = 0.0001, respectively), and autografts treated with MSCs (p = 0.12) were comparable to untreated autografts. In allografts, FK506 treatment and combined treatment were superior to controls (p < 0.001 and p = 0.0001, respectively), and treatment with MSCs (p = 0.09) was comparable to controls. All autograft groups were superior compared to their respective allograft treatment group (p < 0.05) in neurite extension. Conclusions: Alone, either MSC or FK506 treatment improved neurite outgrowth, and combined they further enhanced neurite extension in both autografts and allografts.
  • Thumbnail Image
    Item
    Optical tissue clearing enables rapid, precise and comprehensive assessment of three-dimensional morphology in experimental nerve regeneration research
    (Wolters Kluwer, 2022) Daeschler, Simeon C.; Zhang, Jennifer; Gordon, Tessa; Borschel, Gregory H.; Surgery, School of Medicine
    Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children's Laboratory Animal Services Committee (49871/9) on November 9, 2019.
  • Thumbnail Image
    Item
    Risk Factors for a False-Negative Examination in Complete Upper Extremity Nerve Lacerations
    (Sage, 2021) Loewenstein, Scott N.; Wulbrecht, Reed; Leonhard, Vanessa; Sasor, Sarah; Cook, Julia; Timsina, Lava; Adkinson, Joshua; Surgery, School of Medicine
    Background: Many patients with complete nerve lacerations after upper extremity trauma have a documented normal peripheral nerve examination at the time of initial evaluation. The purpose of this study was to determine whether physician-, patient-, and injury-related factors increase the risk of false-negative nerve examinations. Methods: A statewide health information exchange was used to identify complete upper extremity nerve lacerations subsequently confirmed by surgical exploration at 1 pediatric and 2 adult level I trauma centers in a single city from January 2013 to January 2017. Charts were manually reviewed to build a database that included Glasgow Coma Scale score, urine drug screen results, blood alcohol level, presence of concomitant trauma, type of injury, level of injury, laterality, initial provider examination, and initial specialist examination. Bivariate and multivariable analyses were performed to evaluate risk factors for a false-negative examination. Results: Two hundred eighty-eight patients met inclusion criteria. The overall false-negative examination rate was 32.5% at initial encounter, which was higher among emergency medicine physicians compared with extremity subspecialists (P < .001) and among trauma surgeons compared with surgical subspecialists (P = .002). The false-negative rate decreased to 8% at subsequent encounter (P < .001). Risk factors for a false-negative nerve examination included physician specialty, a gunshot wound mechanism of injury, injury at the elbow, and age greater than 71 years. Conclusion: There is a high false-negative rate among upper extremity neurotmesis injuries. Patients with an injury pattern that may lead to nerve injury warrant prompt referral to an upper extremity specialist in an effort to optimize outcomes.
  • Thumbnail Image
    Item
    VP1: Combined Local Delivery of Tacrolimus and Stem Cells in Fibrin Gel is a Viable Potential Treatment for Enhancing Peripheral Nerve Regeneration
    (Wolters Kluwer, 2022) Saffari, Tiam M.; Chan, K.; Saffari, S.; Zuo, K. J.; Borschel, G. H.; Shin, A. Y.; Surgery, School of Medicine
    INTRODUCTION: The immunosuppressive and neuroregenerative potential of tacrolimus (FK506) may overcome the rejection of stem cells to enhance nerve regeneration. The aim of this study was to determine the feasibility and effectiveness of combining local, sustained delivery of tacrolimus (FK506) with stem cells. MATERIALS AND METHODS: The drug release profile of local FK506 over the course of 35 days was evaluated in phosphate-buffered saline (PBS). FK506 was incorporated into fibrin gel in poly(lactic-co-glycolic) acid (PLGA) microspheres in concentrations of 0.01 ng/mL and 100 ng/mL and incubated in phosphate-buffered saline (PBS) at physiological temperature. Microspheres were prepared and characterized according to validated protocols by Tajdaran et al. (2015). Adipose derived mesenchymal stem cells (MSCs) were cultured in collected PBS to mimic systemic exposure representing released concentrations at day 7, 15 and 28 from 0.01 ng/mL and 100 ng/mL microspheres. MSCs were cultured in the following groups: (i) hydrogel only, (ii) PLGA empty microspheres in hydrogel, (iii) Hydrogel Infused with Stem cells and Tacrolimus (HIST) 0.01 ng/mL, and (iv) HIST 100 ng/mL. Staining against CD90 was conducted to confirm stem cell characterization. MSC viability was evaluated at 24h, 48h, 72h, and seven days using Live/Dead staining and MTS assays. RESULTS: Microspheres containing 0.01 ng/mL showed depletion of FK506 by 13 days. FK506 microspheres containing 100 ng/mL revealed a sustained release up to 35 days. An inflation point was observed at day 15 due to erosion of gel, resulting in an increase of FK506 release. CD90 staining confirmed stem cell characterization. MSCs were viable up to seven days and no significant differences in viability were found between groups. CONCLUSION: Encapsulation of 100 ng/mL FK506 microspheres and MSCs in hydrogel is feasible and has strong potential to enhance survival of transplanted cells, which may ultimately lead to improved nerve regeneration.