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Browsing by Author "Borschel, Gregory H."
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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 MedicinePeripheral 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.Item Combined local delivery of tacrolimus and stem cells in hydrogel for enhancing peripheral nerve regeneration(Wiley, 2021-07) Saffari, Tiam M.; Chan, Katelyn; Saffari, Sara; Zuo, Kevin J.; McGovern, Renee M.; Reid, Joel M.; Borschel, Gregory H.; Shin, Alexander Y.; Medicine, School of MedicineThe application of scaffold-based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration-approved immunosuppressant) has been explored. In this study, a fibrin gel-based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose-derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic-co-glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug-released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.Item Corneal Neurotization: Preoperative Patient Workup and Surgical Decision-making(Wolters Kluwer, 2023-10-11) Daeschler, Simeon C.; Woo, Jyh Haur; Hussein, Isra; Ali, Asim; Borschel, Gregory H.; Surgery, School of MedicineBackground: The use of sensory nerve transfers to the anesthetic cornea has transformed the treatment of neurotrophic keratopathy by restoring ocular surface sensation and activating dysfunctional epithelial repair mechanisms. However, despite numerous reports on surgical techniques, there is a scarcity of information on the interdisciplinary management, preoperative assessment, and surgical decision-making, which are equally critical to treatment success. Methods: This Special Topic presents a standardized, interdisciplinary preoperative workup based on our 10-year experience with corneal neurotization in 32 eyes of patients with neurotrophic keratopathy. Results: Our assessment includes a medical history review, ophthalmic evaluation, and systematic facial sensory donor nerve mapping for light touch and pain modalities. This approach enables evidence-based patient selection, optimal surgery timing, and suitable donor nerve identification, including backup options. Conclusions: Based on a decade-long experience, this special topic highlights the importance of interdisciplinary collaboration and provides a practical roadmap for optimizing patient selection and surgical decision-making in patients undergoing corneal neurotization.Item Dynamic Reconstruction of Facial Paralysis in Craniofacial Microsomia(Wolters Kluwer, 2022-04) Zuo, Kevin J.; Heinelt, Martina; Ho, Emily S.; Forrest, Christopher R.; Zuker, Ronald M.; Borschel, Gregory H.; Medicine, School of MedicineBACKGROUND: Craniofacial microsomia is associated with maxillomandibular hypoplasia, microtia, soft-tissue deficiency, and variable severity of cranial nerve dysfunction, most often of the facial nerve. This study evaluated the incidence of facial paralysis in patients with craniofacial microsomia and outcomes after free functioning muscle transfer for dynamic smile reconstruction. METHODS: A single-center, retrospective, cross-sectional study was performed from 1985 to 2018 to identify pediatric patients with craniofacial microsomia and severe facial nerve dysfunction who underwent dynamic smile reconstruction with free functioning muscle transfer. Preoperative and postoperative facial symmetry and oral commissure excursion during maximal smile were measured using photogrammetric facial analysis software. RESULTS: This study included 186 patients with craniofacial microsomia; 41 patients (21 male patients, 20 female patients) had documented facial nerve dysfunction (22 percent) affecting all branches (51 percent) or the mandibular branch only (24 percent). Patients with severe facial paralysis (n = 8) underwent smile reconstruction with a free functioning muscle transfer neurotized either with a cross-face nerve graft (n = 7) or with the ipsilateral motor nerve to masseter (n =1). All patients achieved volitional muscle contraction with improvement in lip symmetry and oral commissure excursion (median, 8 mm; interquartile range, 3 to 10 mm). The timing of orthognathic surgery and facial paralysis reconstruction was an important consideration in optimizing patient outcomes. CONCLUSIONS: The authors' institution's incidence of facial nerve dysfunction in children with craniofacial microsomia is 22 percent. Free functioning muscle transfer is a reliable option for smile reconstruction in children with craniofacial microsomia. To optimize outcomes, a novel treatment algorithm is proposed for craniofacial microsomia patients likely to require both orthognathic surgery and facial paralysis reconstruction.Item Foretinib mitigates cutaneous nerve fiber loss in experimental diabetic neuropathy(Springer Nature, 2022-05-19) Daeschler, Simeon C.; Zhang, Jennifer; Gordon, Tessa; Borschel, Gregory H.; Feinberg, Konstantin; Surgery, School of MedicineDiabetes is by far, the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.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 MedicineBackground: 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.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 MedicineMorphological 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.Item Outcomes after Anterior Interosseous Nerve to Ulnar Motor Nerve Transfer(Thieme, 2023-01-11) Gross, Jeffrey N.; Dawson, Steven E.; Wu, Gerald J.; Loewenstein, Scott; Borschel, Gregory H.; Adkinson, Joshua M.; Surgery, School of MedicineBackground: Ulnar nerve lesions proximal to the elbow can result in loss of intrinsic muscle function of the hand. The anterior interosseous nerve (AIN) to deep motor branch of the ulnar nerve (DBUN) transfer has been demonstrated to provide intrinsic muscle reinnervation, thereby preventing clawing and improving pinch and grip strength. The purpose of this study was to evaluate the efficacy of the AIN to DBUN transfer in restoring intrinsic muscle function for patients with traumatic ulnar nerve lesions. Methods: We performed a prospective, multi-institutional study of outcomes following AIN to DBUN transfer for high ulnar nerve injuries. Twelve patients were identified, nine of which were enrolled in the study. The mean time from injury to surgery was 15 weeks. Results: At final follow-up (mean postoperative follow-up 18 months + 15.5), clawing was observed in all nine patients with metacarpophalangeal joint hyperextension of the ring finger averaging 8.9 degrees (+ 10.8) and small finger averaging 14.6 degrees (+ 12.5). Grip strength of the affected hand was 27% of the unaffected extremity. Pinch strength of the affected hand was 29% of the unaffected extremity. None of our patients experienced claw prevention after either end-to-end ( n = 4) or end-to-side ( n = 5) AIN to DBUN transfer. Conclusion: We conclude that, in traumatic high ulnar nerve injuries, the AIN to DBUN transfer does not provide adequate intrinsic muscle reinnervation to prevent clawing and normalize grip and pinch strength.Item Schwann Cells Are Key Regulators of Corneal Epithelial Renewal(Association for Research in Vision and Ophthalmology (ARVO), 2023) Mirmoeini, Kaveh; Tajdaran, Kiana; Zhang, Jennifer; Gordon, Tessa; Ali, Asim; Kaplan, David R.; Feinberg, Konstantin; Borschel, Gregory H.; Surgery, School of MedicinePurpose: Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue-innervating axon terminals mediate tissue regeneration. This study defines the critical role of the corneal axon-ensheathing SCs in homeostatic and regenerative corneal epithelial cell renewal. Methods: SC localization in the cornea was determined by in situ hybridization and immunohistochemistry with SC markers. In vivo SC visualization and/or ablation were performed in mice with inducible corneal SC-specific expression of tdTomato and/or Diphtheria toxin, respectively. The relative locations of SCs and LSCs were observed with immunohistochemical analysis of harvested genetically SC-prelabeled mouse corneas with LSC-specific antibodies. The correlation between cornea-innervating axons and the appearance of SCs was ascertained using corneal denervation in rats. To determine the limbal niche cellular composition and gene expression changes associated with innervation-dependent epithelial renewal, single-cell RNA sequencing (scRNA-seq) of dissociated healthy, de-epithelized, and denervated cornea limbi was performed. Results: We observed limbal enrichment of corneal axon-associated myelinating and non-myelinating SCs. Induced local genetic ablation of SCs, although leaving corneal sensory innervation intact, markedly inhibited corneal epithelial renewal. scRNA-seq analysis (1) highlighted the transcriptional heterogenicity of cells populating the limbal niche, and (2) identified transcriptional changes associated with corneal innervation and during wound healing that model potential regulatory paracrine interactions between SCs and LSCs. Conclusions: Limbal SCs are required for innervation-dependent corneal epithelial renewal.Item Supraclavicular Approach to the Brachial Plexus(Wolters Kluwer, 2023-01-23) Dawson, Steven E.; Gross, Jeffrey N.; Berns, Jessica M.; Weinzerl, Thomas; Adkinson, Joshua M.; Borschel, Gregory H.; Surgery, School of MedicineBackground: The brachial plexus consists of an intricate array of nerves originating from the C5–T1 ventral rami of the spinal cord. Their course is complex and can be substantially distorted after injury. Thus, dissection of the brachial plexus can be difficult. Here, we present a practical approach to the supraclavicular dissection of the brachial plexus, with emphasis on relevant anatomy and surgical landmarks. Methods: This anatomical review was prepared using intraoperative surgical imaging. In addition, illustrations are used to display the images in schematic form. We present a stepwise surgical approach to the supraclavicular dissection of the brachial plexus. We highlight the differences between pre- and postganglionic nerve root injuries, and also relevant anatomical variants of the brachial plexus. Results: Eleven steps are recommended to facilitate the supraclavicular approach to the brachial plexus. Conclusion: The supraclavicular dissection of the brachial plexus is reliable with consistent landmarks and can be carried out in a stepwise fashion.