Advances of Schwann cells in peripheral nerve regeneration: From mechanism to cell therapy.

Peripheral nerve injuries (PNIs) frequently occur due to various factors, including mechanical trauma such as accidents or tool-related incidents, as well as complications arising from diseases like tumor resection. These injuries frequently result in persistent numbness, impaired motor and sensory functions, neuropathic pain, or even paralysis, which can impose a significant financial burden on patients due to outcomes that often fall short of expectations. The most frequently employed clinical treatment for PNIs involves either direct sutures of the severed ends or bridging the proximal and distal stumps using autologous nerve grafts. However, autologous nerve transplantation may result in sensory and motor functional loss at the donor site, as well as neuroma formation and scarring. Transplantation of Schwann cells/Schwann cell-like cells has emerged as a promising cellular therapy to reconstruct the microenvironment and facilitate peripheral nerve regeneration. In this review, we summarize the role of Schwann cells and recent advances in Schwann cell therapy in peripheral nerve regeneration. We summarize current techniques used in cell therapy, including cell injection, 3D-printed scaffolds for cell delivery, cell encapsulation techniques, as well as the cell types employed in experiments, experimental models, and research findings. At the end of the paper, we summarize the challenges and advantages of various cells (including ESCs, iPSCs, and BMSCs) in clinical cell therapy. Our goal is to provide the theoretical and experimental basis for future treatments targeting peripheral nerves, highlighting the potential of cell therapy and tissue engineering as invaluable resources for promoting nerve regeneration.

Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain.

Surgical procedures, including nerve reconstruction and end-organ muscle reinnervation, have become more prominent in the prosthetic field over the past decade. Primarily developed to increase the functionality of prosthetic limbs, these surgical procedures have also been found to reduce postamputation neuropathic pain. Today, some of these procedures are performed more frequently for the management and prevention of postamputation pain than for prosthetic fitting, indicating a significant need for effective solutions to postamputation pain. One notable emerging procedure in this context is the Regenerative Peripheral Nerve Interface (RPNI). RPNI surgery involves an operative approach that entails splitting the nerve end longitudinally into its main fascicles and implanting these fascicles within free denervated and devascularized muscle grafts. The RPNI procedure takes a proactive stance in addressing freshly cut nerve endings, facilitating painful neuroma prevention and treatment by enabling the nerve to regenerate and innervate an end organ, i.e., the free muscle graft. Retrospective studies have shown RPNI's effectiveness in alleviating postamputation pain and preventing the formation of painful neuromas. The increasing frequency of utilization of this approach has also given rise to variations in the technique. This article aims to provide a step-by-step description of the RPNI procedure, which will serve as the standardized procedure employed in an international, randomized controlled trial (ClinicalTrials.gov, NCT05009394). In this trial, RPNI is compared to two other surgical procedures for postamputation pain management, specifically, Targeted Muscle Reinnervation (TMR) and neuroma excision coupled with intra-muscular transposition and burying.

[Progress of electrical stimulation to promote peripheral nerve regeneration].

This study reviews the latest progress on the research of electrical stimulation（ES） in peripheral nerve regeneration, summarizes the parameters in preclinical experiments and discusses the effect on nerve regeneration. A detailed description is given in the study of conditioning electrical stimulation and nerve conduit scaffolding technology combined with ES, which have been hotly researched in recent years.

Combined Targeted Muscle Reinnervation With Regenerative Peripheral Nerve Interfaces Decreases Long-Term Narcotic Use in Amputees: A Case Control Study.

PURPOSE: Combined targeted muscle reinnervation with regenerative peripheral nerve interfaces ("TMRpni") is a recently described nerve management strategy that leverages beneficial elements of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) techniques. This study aimed to evaluate the effect of TMRpni on long-term opioid consumption after amputation. We hypothesize that TMRpni decreases chronic opioid consumption in amputees. METHODS: This is a retrospective cohort study of all patients who underwent TMRpni between 2019 and 2021. These patients were age-matched at a 1:1 ratio with a control group of patients who underwent amputation without TMRpni. Statistical analysis was performed using SPSS Version 28.0. RESULTS: Thirty-one age-matched pairs of patients in the TMRpni and control groups were included. At 30 days after surgery, there was no significant difference in number of patients who required an additional refill of their opioid prescriptions (45% vs 55%, P = 0.45) or patients who continued to actively use opioids (36% vs 42%, P = 0.60). However, at 90 days after surgery, there was a significantly lower number of patients from the TMRpni group who reported continued opioid use compared with the control group (10% vs 32%, P = 0.03). CONCLUSIONS: This study demonstrates that TMRpni may translate to decreased rates of chronic opiate use. Continued study is indicated to optimize TMRpni techniques and patient selection and to determine its long-term efficacy.

Schwann Cells as Orchestrators of Nerve Repair: Implications for Tissue Regeneration and Pathologies.

Peripheral nerves exist in a stable state in adulthood providing a rapid bidirectional signaling system to control tissue structure and function. However, following injury, peripheral nerves can regenerate much more effectively than those of the central nervous system (CNS). This multicellular process is coordinated by peripheral glia, in particular Schwann cells, which have multiple roles in stimulating and nurturing the regrowth of damaged axons back to their targets. Aside from the repair of damaged nerves themselves, nerve regenerative processes have been linked to the repair of other tissues and de novo innervation appears important in establishing an environment conducive for the development and spread of tumors. In contrast, defects in these processes are linked to neuropathies, aging, and pain. In this review, we focus on the role of peripheral glia, especially Schwann cells, in multiple aspects of nerve regeneration and discuss how these findings may be relevant for pathologies associated with these processes.

Photobiomodulation and Vascularization in Conduit-Based Peripheral Nerve Repair: A Narrative Review.

Background: Peripheral nerve injuries pose a significant clinical issue for patients, especially in the most severe cases wherein complete transection (neurotmesis) results in total loss of sensory/motor function. Nerve guidance conduits (NGCs) are a common treatment option that protects and guides regenerating axons during recovery. However, treatment outcomes remain limited and often fail to achieve full reinnervation, especially in critically sized defects (>3 cm) where a lack of vascularization leads to neural necrosis. Conclusions: A multitreatment approach is, therefore, necessary to improve the efficacy of NGCs. Stimulating angiogenesis within NGCs can help alleviate oxygen deficiency through rapid inosculation with the host vasculature, whereas photobiomodulation therapy (PBMT) has demonstrated beneficial therapeutic effects on regenerating nerve cells and neovascularization. In this review, we discuss the current trends of NGCs, vascularization, and PBMT as treatments for peripheral nerve neurotmesis and highlight the need for a combinatorial approach to improve functional and clinical outcomes.

Exploration of sensations evoked during electrical stimulation of the median nerve at the wrist level.

Objective.Nerve rehabilitation following nerve injury or surgery at the wrist level is a lengthy process during which not only peripheral nerves regrow towards receptors and muscles, but also the brain undergoes plastic changes. As a result, at the time when nerves reach their targets, the brain might have already allocated some of the areas within the somatosensory cortex that originally processed hand signals to some other regions of the body. The aim of this study is to show that it is possible to evoke a variety of somatotopic sensations related to the hand while stimulating proximally to the injury, therefore, providing the brain with the relevant inputs from the hand regions affected by the nerve damage.Approach.This study included electrical stimulation of 28 able-bodied participants where an electrode that acted as a cathode was placed above the Median nerve at the wrist level. The parameters of electrical stimulation, amplitude, frequency, and pulse shape, were modulated within predefined ranges to evaluate their influence on the evoked sensations.Main results.Using this methodology, the participants reported a wide variety of somatotopic sensations from the hand regions distal to the stimulation electrode.Significance.Furthermore, to propose an accelerated stimulation tuning procedure that could be implemented in a clinical protocol and/or standalone device for providing meaningful sensations to the somatosensory cortex during nerve regeneration, we trained machine-learning techniques using the gathered data to predict the location/area, naturalness, and sensation type of the evoked sensations following different stimulation patterns.

Mimosa-Inspired Stimuli-Responsive Curling Bioadhesive Tape Promotes Peripheral Nerve Regeneration.

Trauma often results in peripheral nerve injuries (PNIs). These injuries are particularly challenging therapeutically because of variable nerve diameters, slow axonal regeneration, infection of severed ends, fragility of the nerve tissue, and the intricacy of surgical intervention. Surgical suturing is likely to cause additional damage to peripheral nerves. Therefore, an ideal nerve scaffold should possess good biocompatibility, diameter adaptability, and a stable biological interface for seamless biointegration with tissues. Inspired by the curl of Mimosa pudica, this study aimed to design and develop a diameter-adaptable, suture-free, stimulated curling bioadhesive tape (SCT) hydrogel for repairing PNI. The hydrogel is fabricated from chitosan and acrylic acid-N-hydroxysuccinimide lipid via gradient crosslinking using glutaraldehyde. It closely matches the nerves of different individuals and regions, thereby providing a bionic scaffold for axonal regeneration. In addition, this hydrogel rapidly absorbs tissue fluid from the nerve surface achieving durable wet-interface adhesion. Furthermore, the chitosan-based SCT hydrogel loaded with insulin-like growth factor-I effectively promotes peripheral nerve regeneration with excellent bioactivity. This procedure for peripheral nerve injury repair using the SCT hydrogel is simple and reduces the difficulty and duration of surgery, thereby advancing adaptive biointerfaces and reliable materials for nerve repair.

Sexually Dimorphic Pattern of Pain Mitigation Following Prophylactic Regenerative Peripheral Nerve Interface (RPNI) in a Rat Neuroma Model.

BACKGROUND: Treating neuroma pain is a clinical challenge. Identification of sex-specific nociceptive pathways allows a more individualized pain management. The Regenerative Peripheral Nerve Interface (RPNI) consists of a neurotized autologous free muscle using a severed peripheral nerve to provide physiological targets for the regenerating axons. OBJECTIVE: To evaluate prophylactic RPNI to prevent neuroma pain in male and female rats. METHODS: F344 rats of each sex were assigned to neuroma, prophylactic RPNI, or sham groups. Neuromas and RPNIs were created in both male and female rats. Weekly pain assessments including neuroma site pain and mechanical, cold, and thermal allodynia were performed for 8 weeks. Immunohistochemistry was used to evaluate macrophage infiltration and microglial expansion in the corresponding dorsal root ganglia and spinal cord segments. RESULTS: Prophylactic RPNI prevented neuroma pain in both sexes; however, female rats displayed delayed pain attenuation when compared with males. Cold allodynia and thermal allodynia were attenuated exclusively in males. Macrophage infiltration was mitigated in males, whereas females showed a reduced number of spinal cord microglia. CONCLUSION: Prophylactic RPNI can prevent neuroma site pain in both sexes. However, attenuation of both cold allodynia and thermal allodynia occurred in males exclusively, potentially because of their sexually dimorphic effect on pathological changes of the central nervous system.

Mechanism of Action of Peripheral Nerve Stimulation for Chronic Pain: A Narrative Review.

The use of stimulation of peripheral nerves to test or treat various medical disorders has been prevalent for a long time. Over the last few years, there has been growing evidence for the use of peripheral nerve stimulation (PNS) for treating a myriad of chronic pain conditions such as limb mononeuropathies, nerve entrapments, peripheral nerve injuries, phantom limb pain, complex regional pain syndrome, back pain, and even fibromyalgia. The ease of placement of a minimally invasive electrode via percutaneous approach in the close vicinity of the nerve and the ability to target various nerves have led to its widespread use and compliance. While most of the mechanism behind its role in neuromodulation is largely unknown, the gate control theory proposed by Melzack and Wall in the 1960s has been the mainstay for understanding its mechanism of action. In this review article, the authors performed a literature review to discuss the mechanism of action of PNS and discuss its safety and usefulness in treating chronic pain. The authors also discuss current PNS devices available in the market today.

Peripheral Nerve Matrix Hydrogel Promotes Recovery after Nerve Transection and Repair.

BACKGROUND: Nerve transection is the most common form of peripheral nerve injury. Treatment of peripheral nerve injury has primarily focused on stabilization and mechanical cues to guide extension of the regenerating growth cone across the site of transection. The authors investigated the effects of a peripheral nerve matrix (PNM) hydrogel on recovery after nerve transection. METHODS: The authors used rodent models to determine the effect of PNM on axon extension, electrophysiologic nerve conduction, force generation, and neuromuscular junction formation after nerve transection and repair. The authors complemented this work with in vivo and in vitro fluorescence-activated cell sorting and immunohistochemistry approaches to determine the effects of PNM on critical cell populations early after repair. RESULTS: Extension of axons from the proximal stump and overall green fluorescent protein-positive axon volume within the regenerative bridge were increased in the presence of PNM compared with an empty conduit ( P < 0.005) 21 days after repair. PNM increased electrophysiologic conduction (compound muscle action potential amplitude) across the repair site ( P < 0.05) and neuromuscular junction formation ( P = 0.04) 56 days after repair. PNM produced a shift in macrophage phenotype in vitro and in vivo ( P < 0.05) and promoted regeneration in a murine model used to characterize the early immune response to PNM ( P < 0.05). CONCLUSION: PNM, delivered by subepineural injection, promoted recovery after nerve transection with immediate repair, supporting a beneficial macrophage response, axon extension, and downstream remodeling using a range of clinically relevant outcome measures. CLINICAL RELEVANCE STATEMENT: This article describes an approach for subepineural injection at the site of nerve coaptation to modulate the response to injury and improve outcomes.

Dermal Sensory Regenerative Peripheral Nerve Interface for Reestablishing Sensory Nerve Feedback in Peripheral Afferents in the Rat.

BACKGROUND: Without meaningful, intuitive sensory feedback, even the most advanced myoelectric devices require significant cognitive demand to control. The dermal sensory regenerative peripheral nerve interface (DS-RPNI) is a biological interface designed to establish high-fidelity sensory feedback from prosthetic limbs. METHODS: DS-RPNIs were constructed in rats by securing fascicles of residual sensory peripheral nerves into autologous dermal grafts, with the objectives of confirming regeneration of sensory afferents within DS-RPNIs and establishing the reliability of afferent neural response generation with either mechanical or electrical stimulation. RESULTS: Two months after implantation, DS-RPNIs were healthy and displayed well-vascularized dermis with organized axonal collaterals throughout and no evidence of neuroma. Electrophysiologic signals were recorded proximal from DS-RPNI's sural nerve in response to both mechanical and electrical stimuli and compared with (1) full-thickness skin, (2) deepithelialized skin, and (3) transected sural nerves without DS-RPNI. Mechanical indentation of DS-RPNIs evoked compound sensory nerve action potentials (CSNAPs) that were like those evoked during indentation of full-thickness skin. CSNAP firing rates and waveform amplitudes increased in a graded fashion with increased mechanical indentation. Electrical stimuli delivered to DS-RPNIs reliably elicited CSNAPs at low current thresholds, and CSNAPs gradually increased in amplitude with increasing stimulation current. CONCLUSIONS: These findings suggest that afferent nerve fibers successfully reinnervate DS-RPNIs, and that graded stimuli applied to DS-RPNIs produce proximal sensory afferent responses similar to those evoked from normal skin. This confirmation of graded afferent signal transduction through DS-RPNI neural interfaces validate DS-RPNI's potential role of facilitating sensation in human-machine interfacing. CLINICAL RELEVANCE STATEMENT: The DS-RPNI is a novel biotic-abiotic neural interface that allows for transduction of sensory stimuli into neural signals. It is expected to advance the restoration of natural sensation and development of sensorimotor control in prosthetics.

Injectable hydrogel encapsulated with VEGF-mimetic peptide-loaded nanoliposomes promotes peripheral nerve repair in vivo.

Repair of peripheral nerve crush injury remains a major clinical challenge. Currently, oral or intravenous neurotrophic drugs are the main treatment for peripheral nerve crush injury; however, this repair process is slow, and the final effect may be uncertain. The current study aimed at developing an injectable hydrogel with vascular endothelial growth factor (VEGF)-mimetic peptide (QK)-encapsulated nanoliposomes (QK-NLs@Gel) for sustainable drug release that creates an appropriate microenvironment for nerve regeneration. The QK-encapsulated nanoliposomes (QK-NLs) could facilitate the proliferation, migration, and tube formation capacities of human umbilical vein endothelial cells through the VEGF signaling pathway. The QK-NLs@Gel hydrogel encapsulated with QK-NLs showed enhanced physical properties and appropriate biocompatibility in vitro. Thereafter, the QK-NLs@Gel hydrogel was directly injected into the site of peripheral nerve crush injury in a rat model, where it enhanced revascularization and promoted the M2-polarization of the macrophages, thus providing an optimized microenvironment for nerve regeneration. At four weeks post-surgery, the QK-NLs@Gel injected rats exhibited enhanced axon regeneration, remyelination, and better functional recovery in comparison with other groups in vivo. Overall, these findings demonstrate that the composite hydrogel could promote a multicellular pro-regenerative microenvironment at the peripheral nerve injury site, thus revealing great potential for peripheral nerve restoration. STATEMENT OF SIGNIFICANCE: Peripheral nerve injury (PNI) is a leading public health issue, and how to delivery beneficial drugs to injured sites efficiently is still a big challenge. In the current study, an injectable hydrogel with VEGF-mimetic peptide (QK)-encapsulated nanoliposomes (QK-NLs@Gel) was first developed and used to repair a rat crush injury model. Our results showed that QK-NLs promoted the proliferation, migration, and angiogenesis of HUVEC via VEGF signaling pathway in vitro. Furthermore, when injected to the crushed sites in vivo, the QK-NLs@Gel hydrogel could accelerate nerve repair through enhanced revascularization and M2-polarization of macrophages. These results collectively demonstrate that injection of QK-NLs@Gel hydrogel could create an appropriate microenvironment for peripheral nerve regeneration. This strategy is effective, economical, and convenient for clinical applications.

Loss of Gata1 decreased eosinophils, macrophages, and type 2 cytokines in regenerating nerve and delayed axon regeneration after a segmental nerve injury.

The immune system has garnered attention for its role in peripheral nerve regeneration, particularly as it pertains to regeneration across segmental injuries. Previous work demonstrated that eosinophils are recruited to regenerating nerve and express interleukin-4, amongst potential cytokines. These results suggest a direct role for eosinophils in promoting nerve regeneration. Therefore, we further considered eosinophils roles in nerve regeneration using a segmental nerve injury and Gata1 knockout (KO) mice, which are severely eosinophil deficient, compared to wild-type BALB/c mice (WT). Mice receiving a sciatic nerve gap injury demonstrated distinct cytokine expression and leukocytes within regenerating nerve. Compared to controls, Gata1 KO regenerated nerves contained decreased expression of type 2 cytokines, including Il-5 and Il-13, and decreased recruitment of eosinophils and macrophages. At this early time point during ongoing regeneration, the macrophages within Gata1 KO nerves also demonstrated significantly less M2 polarization compared to controls. Subsequently, motor and sensory axon regeneration across the gap injury was decreased in Gata1 KO compared to WT during ongoing nerve regeneration. Over longer observation to allow for more complete nerve regeneration, behavioral recovery measured by grid-walk assessment was not different comparing groups but modestly delayed in Gata1 KO compared to WT. The extent of final axon regeneration was not different amongst groups. Our data provide additional evidence suggesting eosinophils contribute to nerve regeneration across a nerve gap injury, but are not essential to regeneration in this context. Our evidence also suggests eosinophils may regulate cytokines that promote distinct macrophage phenotypes and axon regeneration.

Stem Cells and Tissue Engineering-Based Therapeutic Interventions: Promising Strategies to Improve Peripheral Nerve Regeneration.

Unlike the central nervous system, the peripheral one has the ability to regenerate itself after injury; however, this natural regeneration process is not always successful. In fact, even with some treatments, the prognosis is poor, and patients consequently suffer with the functional loss caused by injured nerves, generating several impacts on their quality of life. In the present review we aimed to address two strategies that may considerably potentiate peripheral nerve regeneration: stem cells and tissue engineering. In vitro studies have shown that pluripotent cells associated with neural scaffolds elaborated by tissue engineering can increase functional recovery, revascularization, remyelination, neurotrophin expression and reduce muscle atrophy. Although these results are very promising, it is important to note that there are some barriers to be circumvented: the host's immune response, the oncogenic properties attributed to stem cells and the duration of the pro-regenerative effects. After all, more studies are still needed to overcome the limitations of these treatments; those that address techniques for manipulating the lesion microenvironment combining different therapies seem to be the most promising and proactive ones.

Efficacy of Peripheral Nerve Field Stimulation for the Management of Chronic Low Back Pain and Persistent Spinal Pain Syndrome: A Narrative Review.

OBJECTIVES: Various approaches have been developed with a view to treating the back pain component in patients with chronic low back pain (CLBP) and persistent spinal pain syndrome (PSPS). Emerging evidence shows that peripheral nerve field stimulation (PNFS) may be an efficacious therapeutic modality against axial low back pain. Hence, the aim of the review was to evaluate the analgesic efficacy and safety of PNFS, when used alone or as an adjunct to spinal cord stimulation (SCS), for managing CLBP and PSPS. MATERIALS AND METHODS: A comprehensive search for clinical studies on PNFS and PNFS + SCS used for the management of CLBP and/or PSPS was performed using PubMed, EMBASE, MEDLINE via Proquest, and Web of Science. RESULTS: A total of 15 studies were included, of which four were randomized controlled trials (RCTs), nine were observational studies, and two were case series. For patients receiving PNFS, a significant decrease in back pain intensity and analgesic consumption, together with a significant improvement in physical functioning, was observed upon implant of the permanent system. Meanwhile, the addition of PNFS to SCS in refractory cases was associated with a significant reduction in back and leg pain, respectively. CONCLUSIONS: This review suggests that PNFS, when used alone or in combination with SCS, appears to be effective in managing back pain. However, high-quality evidence that supports the long-term analgesic efficacy and safety is still lacking. Hence, RCTs with a larger patient population and of a longer follow-up duration are warranted.

Prospects for Improving the Extent of Recovery following Peripheral Nerve Trauma: A Review.

Restoring function to damaged peripheral nerves with a gap remains challenging, with <50% of patients who undergo nerve repair surgery recovering function. Further, despite enormous efforts to improve existing techniques and develop new ones, the percentage of patients who recover function and their extent of recovery has not increased in almost 70 years. Thus, although sensory nerve grafts remain the clinical "gold standard" technique for attempting to restore function to nerves with a gap, they have significant limitations. They are effective in restoring good to excellent function only for gaps <3-5 cm, repairs performed <3-5 months post-trauma, and patients <20-25 years old. As the value of any of these variables increases, the extent of recovery decreases precipitously, and if the values of two or all three variables increase, there is little to no recovery. Therefore, novel techniques are required that increase the percentage of patients who recover function and the extent of their recovery. This review discusses the limitations of sensory nerve grafts and other techniques currently being used to repair nerves. It also discusses the use of autologous platelet-rich plasma (PRP), which appears to be the most promising technique for inducing sensory and motor recovery even when the values of all three variables are significantly greater than when sensory nerve grafts alone are not effective. Thus, there is finally the promise that patients who presently have limited to no chance of any recovery may recover good to excellent sensory and motor function.

Prophylactic Regenerative Peripheral Nerve Interfaces in Elective Lower Limb Amputations.

Regenerative peripheral nerve interface (RPNI) is a relatively new surgical technique to manage neuromas and phantom pain after limb amputation. This study evaluates prophylactic RPNI efficacy in managing post-amputation pain and neuroma formation in amputees compared with patients in which lower limb amputation was performed without this procedure. We included 28 patients who underwent above the knee amputation (AKA) or below the knee amputation (BKA) for severe soft tissue infection from July 2019 till December 2020. All patients had insulin-dependent diabetes. The patients were divided into two groups, 14 patients with primary RPNI and 14 patients without. We analyzed the demographic data, level of amputation, number of RPNIs, operative time, postoperative complications and functional outcome on the defined follow up period. The mean patient age was 68.6 years (range 49-85), 19 (67.9 %) male and 9 (32.1 %) female patients. In this study 11 (39.3 %) AKA and 17 (60.7 %) BKA were performed. Overall, 37 RPNIs were made. The mean follow-up period was 49 weeks. PROMIS T-score decreased by 15.9 points in favor for the patients with RPNI. The VAS score showed that, in the RPNI group, all 14 patients were without pain compared to the group of patients without RPNI, where the 11 (78.6 %) patients described their pain as severe. Patients with RPNI used prosthesis significantly more (p < 0.005). Data showed significant reduction in pain and high patient satisfaction after amputation with RPNIs. This technique is oriented as to prevent neuroma formation with RPNI surgery, performed at the time of amputation. RPNI surgery did not provoke complications or significant lengthening of operative time and it should be furthermore exploited as a surgical technique.

A combined experimental and computational framework to evaluate the behavior of therapeutic cells for peripheral nerve regeneration.

Recent studies have explored the potential of tissue-mimetic scaffolds in encouraging nerve regeneration. One of the major determinants of the regenerative success of cellular nerve repair constructs (NRCs) is the local microenvironment, particularly native low oxygen conditions which can affect implanted cell survival and functional performance. In vivo, cells reside in a range of environmental conditions due to the spatial gradients of nutrient concentrations that are established. Here we evaluate in vitro the differences in cellular behavior that such conditions induce, including key biological features such as oxygen metabolism, glucose consumption, cell death, and vascular endothelial growth factor secretion. Experimental measurements are used to devise and parameterize a mathematical model that describes the behavior of the cells. The proposed model effectively describes the interactions between cells and their microenvironment and could in the future be extended, allowing researchers to compare the behavior of different therapeutic cells. Such a combinatorial approach could be used to accelerate the clinical translation of NRCs by identifying which critical design features should be optimized when fabricating engineered nerve repair conduits.