Justin Burrell - Academia.edu (original) (raw)

Papers by Justin Burrell

Bioactive Materials, 2022

Nerve injury requiring surgical repair often results in poor functional recovery due to the inabi... more Nerve injury requiring surgical repair often results in poor functional recovery due to the inability of host axons to re-grow long distances and reform meaningful connections with the target muscle. While surgeons can re-route local axon fascicles to the target muscle, there are no technologies to provide an exogenous source of axons without sacrificing healthy nerves. Accordingly, we have developed tissue engineered neuromuscular interfaces (TE-NMIs) as the first injectable microtissue containing motor and sensory neurons in an anatomically-inspired architecture. TE-NMIs provide axon tracts that are intended to integrate with denervated distal structures and preserve regenerative capacity during prolonged periods without host innervation. Following implant, we found that TE-NMI axons promoted Schwann cell maintenance, integrated with distal muscle, and preserved an evoked muscle response out to 20-weeks post nerve transection in absence of innervation from host axons. By repopulating the distal sheath with exogenous axons, TE-NMIs also enabled putative delayed fusion with proximal host axons, a phenomenon previously not achievable in delayed repair scenarios due to distal axon degeneration. Here, we found immediate electrophysiological recovery after fusion with proximal host axons and improved axon maturation and muscle reinnervation at 24-weeks post-transection (4-weeks following delayed nerve fusion). These findings show that TE-NMIs provide the potential to improve functional recovery following delayed nerve repair.

Frontiers in Surgery, 2022

Facial nerve trauma often leads to disfiguring facial muscle paralysis. Despite several promising... more Facial nerve trauma often leads to disfiguring facial muscle paralysis. Despite several promising advancements, facial nerve repair procedures often do not lead to complete functional recovery. Development of novel repair strategies requires testing in relevant preclinical models that replicate key clinical features. Several studies have reported that fusogens, such as polyethylene glycol (PEG), can improve functional recovery by enabling immediate reconnection of injured axons; however, these findings have yet to be demonstrated in a large animal model. We first describe a porcine model of facial nerve injury and repair, including the relevant anatomy, surgical approach, and naive nerve morphometry. Next, we report positive findings from a proof-of-concept experiment testing whether a neurorrhaphy performed in conjunction with a PEG solution maintained electrophysiological nerve conduction at an acute time point in a large animal model. The buccal branch of the facial nerve was tra...

Microsurgery, 2022

Dear Editor, Severe nerve injury often leads to devastating sensorimotor functional deficits due ... more Dear Editor, Severe nerve injury often leads to devastating sensorimotor functional deficits due to the slow rates of axon regeneration that leads to prolonged periods of denervation, diminishing the likelihood for successful reinnervation. Meaningful functional recovery is largely dependent on the injury severity, that is, crush injury may result in spontaneous functionality whereas more severe injury resulting in transection requires surgical intervention. Several surgical strategies are available for peripheral nerve repair, including autologous nerve grafts (autografts), nerve conduits, acellular nerve allografts, and nerve transfers. For proximal nerve injury and/or segmental nerve injury resulting in a defect greater than 3 cm, autologous nerve grafts (autografts) are the clinical gold standard that enable rapid axon regeneration by providing access to pro-regenerative Schwann cells and anisotropic support from the donor native nerve architecture (Pfister et al., 2011). Despite being considered the clinical gold standard for segmental defect reconstruction, the orientation of the donor nerve autograft remains widely debated. The article “Comparison between normal and reverse orientation of graft in functional and histomorphological outcomes after autologous nerve grafting: An experimental study in the mouse model” details an extensive investigation of the effect of autograft orientation on peripheral nerve repair in mice (Lee et al., 2021). Histological and behavioral outcome measures are provided that suggest normal oriented autografts enable greater regeneration and diminished muscle atrophy compared to reverse autografts, and there is no benefit to motor function dependent on autograft orientation. While we applaud the authors for pursuing this critical research, clinical inference is often complicated based on small animal models for several reasons, including the lack of a multi-fascicular architecture of a human nerve (Pelot et al., 2020) and also the superior nerve regenerative capacity (Gordon & Borschel, 2017). Lee et al compared the effect of autograft orientation on nerve regeneration in mice by repairing a 3 mm defect was repaired using a 5 mm autograft either in normal or reversed orientation (Lee et al., 2021). Mice are commonly utilized model for high-throughput preclinical testing of novel therapeutics and/or studying mechanism of action(s) following nerve injury. However, small animal models are inherently limited due to the relatively small regenerative distance compared to clinical scenarios. Although the authors note some of these limitations, we kindly remind readers that the clinical justification for reversing nerve graft orientation is that it may mitigate the potential mis-routing effects of arborization (de Ruiter et al., 2008); thus the regenerative distance and number of graft branches may have a direct impact on nerve regeneration and functional recovery. In clinical practice, the sural nerve, a multifascicular sensory nerve with many branching points, is commonly selected as the autograft donor nerve (Mackinnon & Dellon, 1988). In the present article, histological images of the mouse sciatic nerve clearly demonstrate a polyfascicular distal segment and monofascicular proximal stump, which may be insufficient to adequately model a human repair. Therefore, we caution against drawing conclusions regarding autograft orientation based on findings in small animal models across a short 5 mm defect. Another important consideration for clinical implementation for donor nerve selection is diameter mismatch. Sural nerve grafts often have a smaller diameter compared to the injured nerves that can often be overcome with cabling (Matos Cruz & De Jesus, 2021). Lee et al. selected the mouse sciatic nerve as the donor nerve, which would perfectly match the injured nerve in the proximodistally oriented autografts and potentially improve outcome metrics. To the best of our knowledge, it is not possible replicate these important clinical considerations that significantly impact the likelihood for meaningful recovery in a small animal model. We suggest further research is necessary in a large animal model testing the effect of nerve autograft orientation would be better suited due to the presence of branching points, similar to human nerve grafts (Burrell et al., 2020). This again makes it difficult to extrapolate the study findings to the clinical condition. Overall, we caution against extrapolating these histological and behavioral findings in a small animal model to human clinical practice. With over 50,000 peripheral nerve repair procedures performed annually in the United States alone the question of autograft polarity is a critical clinical question (Evans, 2001). In conclusion, we praise the authors efforts, yet our intention with this letter is to highlight the need for additional research in a clinically relevant large animal model or through randomized controlled trials to more…

Handbook of Tissue Engineering Scaffolds: Volume Two, 2019

Abstract Peripheral nerve injury (PNI) is a common affliction for which there are few effective t... more Abstract Peripheral nerve injury (PNI) is a common affliction for which there are few effective treatment options. PNI, including root avulsions, occurs in 2%–5% of all trauma cases in the United States, including assaults and motor vehicle accidents, and a significant proportion of warfighter injuries involve peripheral nerves (Wang et al., 2017; Robinson, 2000; Pfister et al., 2011). PNIs that do not result in damage to overall nerve structure, such as crush or stretch injuries, generally result in a wait-and-see approach to determine if function returns spontaneously (Ali et al., 2014, 2015; Zager, 2014). However, PNI resulting from a nerve transection requires a surgical procedure to reconnect the proximal and distal nerve stumps directly (if possible) or by inserting a biological or synthetic bridging graft between them (Pfister et al., 2011). Overall, in cases requiring surgical intervention, outcomes of surgical repair for traumatic PNI are generally unsatisfactory as only 50% of patients achieve good to normal restoration of function, irrespective of repair strategy or injury location (Ruijs et al., 2005).

npj Regenerative Medicine, 2021

Achieving a satisfactory functional recovery after severe peripheral nerve injuries (PNI) remains... more Achieving a satisfactory functional recovery after severe peripheral nerve injuries (PNI) remains one of the major clinical challenges despite advances in microsurgical techniques. Nerve autografting is currently the gold standard for the treatment of PNI, but there exist several major limitations. Accumulating evidence has shown that various types of nerve guidance conduits (NGCs) combined with post-natal stem cells as the supportive cells may represent a promising alternative to nerve autografts. In this study, gingiva-derived mesenchymal stem cells (GMSCs) under 3D-culture in soft collagen hydrogel showed significantly increased expression of a panel of genes related to development/differentiation of neural crest stem-like cells (NCSC) and/or Schwann cell precursor-like (SCP) cells and associated with NOTCH3 signaling pathway activation as compared to their 2D-cultured counterparts. The upregulation of NCSC-related genes induced by 3D-collagen hydrogel was abrogated by the presen...

Progress in Neurobiology, 2021

Peripheral nerve injuries result in disrupted cellular communication between the central nervous ... more Peripheral nerve injuries result in disrupted cellular communication between the central nervous system and somatic distal end targets. The peripheral nervous system is capable of independent and extensive regeneration; however, meaningful target muscle reinnervation and functional recovery remain limited and may result in chronic neuropathic pain and diminished quality of life. Macrophages, the primary innate immune cells of the body, are critical contributors to regeneration of the injured peripheral nervous system. However, in some clinical scenarios, macrophages may fail to provide adequate support with optimal timing, duration, and location. Here, we review the history of immunosuppressive and immunomodulatory strategies to treat nerve injuries. Thereafter, we enumerate the ways in which macrophages contribute to successful nerve regeneration. We argue that implementing macrophage-based immunomodulatory therapies is a promising treatment strategy for nerve injuries across a wide range of clinical presentations.

Tissue Engineering Part A, 2021

Existing strategies for repair of major peripheral nerve injury (PNI) are inefficient at promotin... more Existing strategies for repair of major peripheral nerve injury (PNI) are inefficient at promoting axon regeneration and functional recovery, and are generally ineffective for nerve lesions >5 cm. To address this need, we have previously developed tissue engineered nerve grafts (TENGs) through the process of axon stretch-growth. TENGs consist of living, centimeter-scale, aligned axon tracts that accelerate axon regeneration at rates equivalent to the gold standard autograft in small and large animal models of PNI, by providing a newfound mechanism-of-action referred to as axon facilitated axon regeneration (AFAR). To enable clinical-grade biomanufacturing of TENGs, a suitable cell source that is hypoimmunogenic, exhibits low batch-to-batch variability, and able to tolerate axon stretch-growth must be utilized. To fulfill these requirements, a genetically engineered xenogeneic cell source, GalSafe® neurons, produced by Revivicor, Inc. have been selected to advance TENG biofabrication for eventual clinical use. To this end, sensory and motor neurons were harvested from genetically engineered GalSafe® day 40 swine embryos, cultured in custom mechanobioreactors, and axon tracts were successfully stretch-grown to 5 cm within 20 days. Importantly, both sensory and motor GalSafe® neurons were observed to tolerate established axon stretch-growth regimes of ≥1 mm/day to produce continuous, healthy axon tracts spanning 1, 3, or 5 cm. Once stretch-grown, 1 cm GalSafe® TENGs were transplanted into a 1 cm lesion in the sciatic nerve of athymic rats. Regeneration was assessed through histological measures at the terminal time point of 2 and 8 weeks. Neurons from GalSafe® TENGs survived and elicited AFAR as observed when using wild-type TENGs. At 8 weeks post-repair, myelinated regenerated axons were observed in the nerve section distal to the injury site, confirming axon regeneration across the lesion. These experiments are the first to demonstrate successful harvest and axon stretch-growth of GalSafe® neurons for use as starting biomass for bioengineered nerve grafts as well as initial safety and efficacy in an established preclinical model - important steps for the advancement of clinical-grade TENGs for future regulatory testing and eventual clinical trials.

Frontiers in Bioengineering and Biotechnology, 2020

Following peripheral nerve injury comprising a segmental defect, the extent of axon regeneration ... more Following peripheral nerve injury comprising a segmental defect, the extent of axon regeneration decreases precipitously with increasing gap length. Schwann cells play a key role in driving axon re-growth by forming aligned tubular guidance structures called bands of Büngner, which readily occurs in distal nerve segments as well as within autografts – currently the most reliable clinically-available bridging strategy. However, host Schwann cells generally fail to infiltrate large-gap acellular scaffolds, resulting in markedly inferior outcomes and motivating the development of next-generation bridging strategies capable of fully exploiting the inherent pro-regenerative capability of Schwann cells. We sought to create preformed, implantable Schwann cell-laden microtissue that emulates the anisotropic structure and function of naturally-occurring bands of Büngner. Accordingly, we developed a biofabrication scheme leveraging biomaterial-induced self-assembly of dissociated rat primary ...

npj Parkinson's Disease, 2020

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecti... more Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1–2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway—a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD...

Neurosurgery, 2020

BACKGROUND Millions of Americans experience residual deficits from traumatic peripheral nerve inj... more BACKGROUND Millions of Americans experience residual deficits from traumatic peripheral nerve injury (PNI). Despite advancements in surgical technique, repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with slow rates of axonal regeneration. Novel surgical solutions require valid preclinical models that adequately replicate the key challenges of clinical PNI. OBJECTIVE To develop a preclinical model of PNI in swine that addresses 2 challenging, clinically relevant PNI scenarios: long segmental defects (≥5 cm) and ultra-long regenerative distances (20-27 cm). Thus, we aim to demonstrate that a porcine model of major PNI is suitable as a potential framework to evaluate novel regenerative strategies prior to clinical deployment. METHODS A 5-cm-long common peroneal nerve or deep peroneal nerve injury was repaired using a saphenous nerve or sural nerve autograft, respectively. Histological and e...

Peripheral nerve injury (PNI) impacts millions annually, often leaving debilitated patients with ... more Peripheral nerve injury (PNI) impacts millions annually, often leaving debilitated patients with minimal repair options to improve functional recovery. Our group has previously developed tissue engineered nerve grafts (TENGs) featuring long, aligned axonal tracts from dorsal root ganglia (DRG) neurons that are fabricated in custom bioreactors using the process of axon “stretch-growth”. We have shown that TENGs effectively serve as “living scaffolds” to promote regeneration across segmental nerve defects by exploiting the newfound mechanism of axon-facilitated axon regeneration, or “AFAR”, by simultaneously providing haptic and neurotrophic support. To extend this work, the current study investigated the efficacy of living versus non-living regenerative scaffolds in preserving host sensory and motor neuronal health following nerve repair. Rats were assigned across five groups: naïve, or repair using autograft, nerve guidance tube (NGT) with collagen, NGT + non-aligned DRG populations...

Advanced Science, 2019

Conductive biomaterials are important to mimic electrophysiological characteristics of tissues, s... more Conductive biomaterials are important to mimic electrophysiological characteristics of tissues, such as neural, skeletal muscle, and cardiovascular tissues, toward applications in tissue repair [1] and as biosensors, [2] bioelectrodes, [3] flexible/ wearable electronics, [4] and electrically controlled drug delivery systems. [5] There are numerous well-known conductive polymers, such as polypyrroles, [6] polyanilines, [7] polythiophenes, [8] and poly(3,4-ethylene dioxythiophenes), [9] which have been explored as electroresponsive materials and to alter cellular behaviors such as cell differentiation and proliferation. [7,8a,9b] Metal nanoparticles (e.g., gold and silver nanoparticles) and Conductive Hydrogels

Approximately 20 million Americans currently experience residual deficits from traumatic peripher... more Approximately 20 million Americans currently experience residual deficits from traumatic peripheral nerve injury. Despite recent advancements in surgical technique, peripheral nerve repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with relatively slow rates of axonal regeneration. Development of novel surgical solutions requires valid preclinical models that adequately replicate the key challenges of clinical peripheral nerve injury. Our team has developed a porcine model using Yucatan minipigs that provides an opportunity to investigate peripheral nerve regeneration using different nerves tailored for a specific mechanism of interest, such as (1) nerve modality: motor, sensory, and mixed-modality; (2) injury length: short versus long gap; and (3) total regenerative distance: proximal versus distal injury. Here, we describe a comprehensive porcine model of two challenging clinically releva...

SSRN Electronic Journal, 2018

Achievements in intracortical brain-machine interfaces are compromised by limitations in long-ter... more Achievements in intracortical brain-machine interfaces are compromised by limitations in long-term performance and information transfer rate. A biological intermediary between devices and the brain based on synaptic integration may offer a specificity and permanence that has eluded neural interfaces to date. Accordingly, we have developed the first "living electrodes" comprised of implantable axonal tracts protected within soft hydrogel cylinders to enable biologically-mediated monitoring and modulation of brain activity. Here we demonstrate the controlled fabrication, rapid axonal outgrowth, reproducible cytoarchitecture, and axonal conduction of these engineered constructs in vitro. We also present simultaneous optical stimulation and recording of neuronal activity in vitro, transplantation in rat cortex, and their survival, integration, and activity over time in vivo as a proof-of-concept for this neural interface paradigm. The creation and functional validation of living electrodes is a critical step towards developing a new class of neural interfaces using targeted, synaptic-based integration with native circuitry.

Scientific reports, Jan 26, 2018

Despite the promising neuro-regenerative capacities of stem cells, there is currently no licensed... more Despite the promising neuro-regenerative capacities of stem cells, there is currently no licensed stem cell-based product in the repair and regeneration of peripheral nerve injuries. Here, we explored the potential use of human gingiva-derived mesenchymal stem cells (GMSCs) as the only cellular component in 3D bio-printed scaffold-free neural constructs that were transplantable to bridge facial nerve defects in rats. We showed that GMSCs have the propensity to aggregate into compact 3D-spheroids that could produce their own matrix. When cultured under either 2D- or 3D-collagen scaffolds, GMSC spheroids were found to be more capable of differentiating into both neuronal and Schwann-like cells than their adherent counterparts. Using a scaffold-free 3D bio-printer system, nerve constructs were printed from GMSC spheroids in the absence of exogenous scaffolds and allowed to mature in a bioreactor. In vivo transplantation of the GMSC-laden nerve constructs promoted regeneration and funct...

Advanced Functional Materials, 2017

Brain-computer interface and neuromodulation strategies relying on penetrating non-organic electr... more Brain-computer interface and neuromodulation strategies relying on penetrating non-organic electrodes/optrodes are limited by an inflammatory foreign body response that ultimately diminishes performance. A novel "biohybrid" strategy is advanced, whereby living neurons, biomaterials, and microelectrode/optical technology are used together to provide a biologicallybased vehicle to probe and modulate nervous-system activity. Microtissue engineering techniques are employed to create axon-based "living electrodes", which are columnar microstructures comprised of neuronal population(s) projecting long axonal tracts within the lumen of a hydrogel designed to chaperone delivery into the brain. Upon microinjection, the axonal segment penetrates to prescribed depth for synaptic integration with local host neurons, with the perikaryal segment remaining externalized below conforming electrical-optical arrays. In this paradigm, only the biological component ultimately remains in the brain, potentially attenuating a chronic foreignbody response. Axon-based living electrodes are constructed using multiple neuronal subtypes, each with differential capacity to stimulate, inhibit, and/or modulate neural circuitry based on specificity uniquely afforded by synaptic integration, yet ultimately computer controlled by optical/electrical components on the brain surface. Current efforts are assessing the efficacy of this biohybrid interface for targeted, synaptic-based neuromodulation, and the specificity, spatial density and long-term fidelity versus conventional microelectronic or optical substrates alone. Serruya et al.

Journal of visualized experiments : JoVE, May 31, 2017

Functional recovery rarely occurs following injury or disease-induced degeneration within the cen... more Functional recovery rarely occurs following injury or disease-induced degeneration within the central nervous system (CNS) due to the inhibitory environment and the limited capacity for neurogenesis. We are developing a strategy to simultaneously address neuronal and axonal pathway loss within the damaged CNS. This manuscript presents the fabrication protocol for micro-tissue engineered neural networks (micro-TENNs), implantable constructs consisting of neurons and aligned axonal tracts spanning the extracellular matrix (ECM) lumen of a preformed hydrogel cylinder hundreds of microns in diameter that may extend centimeters in length. Neuronal aggregates are delimited to the extremes of the three-dimensional encasement and are spanned by axonal projections. Micro-TENNs are uniquely poised as a strategy for CNS reconstruction, emulating aspects of brain connectome cytoarchitecture and potentially providing means for network replacement. The neuronal aggregates may synapse with host ti...

Critical Reviews in Biomedical Engineering, 2016

The ideal neuroprosthetic interface permits high-quality neural recording and stimulation of the ... more The ideal neuroprosthetic interface permits high-quality neural recording and stimulation of the nervous system while reliably providing clinical benefits over chronic periods. Although current technologies have made notable strides in this direction, significant improvements must be made to better achieve these design goals and satisfy clinical needs. This article provides an overview of the state of neuroprosthetic interfaces, starting with the design and placement of these interfaces before exploring the stimulation and recording platforms yielded from contemporary research. Finally, we outline emerging research trends in an effort to explore the potential next generation of neuroprosthetic interfaces.