The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration

Pan, Deng; Hunter, Daniel A.; Schellhardt, Lauren; Jo, Sally; Santosa, Katherine B.; Larson, Ellen L.; Fuchs, Anja; Snyder‐Warwick, Alison K.; Mackinnon, Susan E.; Wood, Matthew D.

doi:10.1016/j.expneurol.2019.05.009

Cited by 43 publications

(49 citation statements)

References 40 publications

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“…Animal studies have yet to demonstrate that nerve graft alternatives can reliably facilitate axon regeneration across longer defects (>30 mm), despite their robust abilities to promote regeneration across shorter defects . A review of this specific topic is available: see Kornfeld et al However, there is limited understanding as to why few axons regenerate across these long graft alternatives despite cues to promote axon growth and regeneration that succeed at shorter lengths.…”

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

“…While the cause of limited axon regeneration across long nerve graft alternatives is still controversial, a series of recent studies has illuminated some novel and insightful findings. Using ANAs as a model nerve graft alterative, these studies compared the regenerative processes within short (noncritical length) vs long (critical length) ANAs revealing that cell repopulation of ANAs due to length was the primary reason for limited axon regeneration (Figure ). In these studies, to establish whether the environment that develops in long nerve graft alternatives, not the ability of neurons to regenerate their axons over long distances, is responsible for axon growth arrest, experiments were performed whereby long alternatives were shortened <30 mm in length.…”

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

“…Long nerve graft alternatives develop an environment limiting axon regeneration. Using ANAs as a model, studies have compared the regenerative processes within short (noncritical length) vs long (critical length) ANAs to discover factors contributing to successful or failed nerve regeneration across ANAs . A, Short ANAs are repopulated with cells similar to previously described in Figure .…”

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

“…A, Short ANAs are repopulated with cells similar to previously described in Figure . Conversely, (B) long ANAs are repopulated with an environmental imbalance consisting of altered populations of immune cells, cells expressing markers of senescence, and delayed angiogenesis compared with their shorter counterparts . These cumulative changes to long ANAs limit axon regeneration and represent a “barrier” to axon regeneration [Color figure can be viewed at wileyonlinelibrary.com]…”

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

“…Furthermore, a direct causal relationship between T cells and nerve regeneration across ANAs was demonstrated. Nerve regeneration across short (20 mm) ANAs, which normally support robust axon regeneration across the gap, was decreased by ~50% in T cell deficient rats . Overall, research regarding the role of the immune system represents an important area that needs further examination in this context (Figure ).…”

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

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Advances in the repair of segmental nerve injuries and trends in reconstruction

2020

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Despite advances in surgery, the reconstruction of segmental nerve injuries continues to pose challenges. In this review, current neurobiology regarding regeneration across a nerve defect is discussed in detail. Recent findings include the complex roles of nonneuronal cells in nerve defect regeneration, such as the role of the innate immune system in angiogenesis and how Schwann cells migrate within the defect. Clinically, the repair of nerve defects is still best served by using nerve autografts with the exception of small, noncritical sensory nerve defects, which can be repaired using autograft alternatives, such as processed or acellular nerve allografts. Given current clinical limits for when alternatives can be used, advanced solutions to repair nerve defects demonstrated in animals are highlighted. These highlights include alternatives designed with novel topology and materials, delivery of drugs specifically known to accelerate axon growth, and greater attention to the role of the immune system. K E Y W O R D S acellular nerve allograft, autograft, nerve gap, nerve guidance conduit, peripheral nerve 2 | BIOLOGY OF NERVE REGENERATION ACROSS A DEFECT Peripheral nerve is capable of robust regeneration following injury. The molecular and cellular mechanisms have primarily been studied in rodent models. Following injury, neurons and their axons and the nonneuronal cellular environment distal to the injury undergo immediate morphological and molecular changes. Within the axon, there is a rapid influx of ions, principally calcium, as well as a disruption of transport proteins signaling a disruption to homeostasis with its end-organ. This multifactorial injury response from axon damage is rapidly transported to the neuron cell Abbreviations: ANA, acellular nerve allograft; ECM, extracellular matrix; FDA, Food and Drug Administration; FK506, tacrolimus; GDNF, glial cell line-derived neurotrophic factor; GFRα1, glial cell line-derived neurotrophic factor family receptor alpha-1; MRC, Medical Research

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Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

Section: Future Research Needed To Improve Alternative Designsmentioning

confidence: 99%

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Advances in the repair of segmental nerve injuries and trends in reconstruction

2020

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Preparation and assessment of an optimized multichannel acellular nerve allograft for peripheral nerve regeneration

et al. 2022

Bioengineering & Transla Med

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Peripheral nerve regeneration after injury is still a clinical problem. The application of autologous nerve grafting, the gold standard treatment, is greatly restricted. Acellular nerve allografts (ANAs) are considered promising alternatives, but they are difficult to achieve satisfactory therapeutic outcomes, which may be attributed to their compact inherent ultrastructure and substantial loss of extracellular matrix (ECM) components. Regarding these deficiencies, this study developed an optimized multichannel ANA by a modified decellularization method. These innovative ANAs were demonstrated to retain more ECM bioactive molecules and regenerative factors, with effective elimination of cellular antigens. The presence of microchannels with larger pore size allowed ANAs to gain higher porosity and better swelling performance, which improves their internal ultrastructure. Their mechanical properties were more similar to those of native nerves. Moreover, the optimized ANAs exhibited good biocompatibility and possessed significant advantages in supporting the proliferation and migration of Schwann cells in vitro. The in vivo results further confirmed their superior capacity to promote axon regrowth and myelination as well as restore innervation of target muscles, leading to better functional recovery than the conventional ANAs. Overall, this study demonstrates that the optimized multichannel ANAs have great potential for clinical application and offer new insight into the further improvement of ANAs.

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A feasibility study transplanting macrophages to a segmental nerve injury

Pan,

Schofield,

Schellhardt

et al. 2023

Muscle and Nerve

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Introduction/AimsPromoting regeneration after segmental nerve injury repair is a challenge, but improving angiogenesis could be beneficial. Macrophages facilitate regeneration after injury by promoting angiogenesis. Our aim in this study was to evaluate the feasibility and effects of transplanting exogenous macrophages to a segmental nerve injury.MethodsBone marrow–derived cells were harvested from donor mice and differentiated to macrophages (BMDM), then suspended within fibrin hydrogels to facilitate BMDM transplantation. BMDM survival was characterized in vitro. The effect of this BMDM fibrin hydrogel construct at a nerve injury site was assessed using a mouse sciatic nerve gap injury. Mice were equally distributed to “fibrin+Mφ” (fibrin hydrogels containing culture medium and BMDM) or “fibrin” hydrogel control (fibrin hydrogels containing culture medium alone) groups. Flow cytometry (n = 3/group/endpoint) and immunohistochemical analysis (n = 5/group/endpoint) of the nerve gap region were performed at days 3, 5, and 7 after repair.ResultsIncorporating macrophage colony‐stimulating factor (M‐CSF) improved BMDM survival and expansion. Transplanted BMDM survived for at least 7 days in a nerve gap (~40% retained at day 3 and ~15% retained at day 7). From transplantation, macrophage quantities within the nerve gap were elevated when comparing fibrin+Mφ with fibrin control (~25% vs. 3% at day 3 and ~14% vs. 6% at day 7). Endothelial cells increased by about fivefold within the nerve gap, and axonal extension into the nerve gap increased almost twofold for fibrin+Mφ compared with fibrin control.DiscussionBMDM suspended within fibrin hydrogels at a nerve gap do not impair regeneration.

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The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration

Cited by 43 publications

References 40 publications

Advances in the repair of segmental nerve injuries and trends in reconstruction

Advances in the repair of segmental nerve injuries and trends in reconstruction

Preparation and assessment of an optimized multichannel acellular nerve allograft for peripheral nerve regeneration

A feasibility study transplanting macrophages to a segmental nerve injury

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