Enhancing Functional Recovery after Segmental Nerve Defect Using Nerve Allograft Treated with Plasma-Derived Exosome

Abstract

Background: Nerve injuries can result in detrimental functional outcomes. Currently, autologous nerve graft offers the best outcome for segmental peripheral nerve injury. Allografts are alternatives, but do not have comparable results. This study evaluated whether plasma-derived exosome can improve nerve regeneration and functional recovery when combined with decellularized nerve allografts. Methods: The effect of exosomes on Schwann cell proliferation and migration were evaluated. A rat model of sciatic nerve repair was used to evaluate the effect on nerve regeneration and functional recovery. A fibrin sealant was used as the scaffold for exosome. Eighty-four Lewis rats were divided into autograft, allograft, and allograft with exosome groups. Gene expression of nerve regeneration factors was analyzed on postoperative day 7. At 12 and 16 weeks, rats were subjected to maximum isometric tetanic force and compound muscle action potential. Nerve specimens were then analyzed by means of histology and immunohistochemistry. Results: Exosomes were readily taken up by Schwann cells that resulted in improved Schwann cell viability and migration. The treated allograft group had functional recovery (compound muscle action potential, isometric tetanic force) comparable to that of the autograft group. Similar results were observed in gene expression analysis of nerve regenerating factors. Histologic analysis showed no statistically significant differences between treated allograft and autograft groups in terms of axonal density, fascicular area, and myelin sheath thickness. Conclusions: Plasma-derived exosome treatment of decellularized nerve allograft may provide comparable clinical outcomes to that of an autograft. This can be a promising strategy in the future as an alternative for segmental peripheral nerve repair.

Dose–response analysis after administration of a human platelet‐derived exosome product on neurite outgrowth in vitro

“…Challenges in clinical translation include logistical and technical difficulties of cell culturing, cellular stability, tumorigenesis, and a feasible delivery method (Saffari, Saffari, Ulrich, et al, 2021). PEP, an off-the-shelf exosome product, has the potential to overcome these limitations as it is readily available, easily accessible, less immunogenic, less time invasive, and with minimal risks of cell contamination (Dong et al, 2019;Liu et al, 2020;Qing et al, 2018) as well as human-derived PEP, resulted in enhanced neuroregenerative effects (Bucan et al, 2019;Dong et al, 2019;Ikumi et al, 2021;Wang et al, 2023). Second, this in vitro model lacks the 3D, chemical and mechanical cues of nerve regeneration and an in vivo model (Clements et al, 2017;Saffari, Saffari, Chan, et al, 2021), and lacks the evaluation of the effect of PEP on nerve regeneration over time.…”

“…Exosomes can mediate intercellular communication and regulate cell biological behavior by delivering genomic cargo, including proteins, lipids, DNA, messenger RNA, micro-RNA, and other subtypes of RNA (Blanc & Vidal, 2018;Corrado et al, 2013;Li et al, 2017;Rezaie et al, 2018;Saffari, Saffari, Ulrich, et al, 2021). Modulating the nerve reconstruction site microenvironment with platelet-derived exosomes has demonstrated improved nerve regeneration (Ikumi et al, 2021;Saffari, Saffari, Ulrich, et al, 2021;Wang et al, 2023).…”

Discussion: Enhancing Functional Recovery after Segmental Nerve Defect Using Nerve Allograft Treated with Plasma-Derived Exosome

“…Strangely, the current literature is trending backward to search for alternatives that can only closely match autografts, yet there is a lack of newer studies to overcome the limitations of chronic nerve injuries, long nerve gaps, and long-term muscle denervation. A novel study reporting administration of insulin-like growth factor 1 by means of a nanoparticle to (1) the distal nerve of an injured nerve site before nerve transfer and (2) concomitantly to the distal target muscles, at 8 weeks after injury, is a well-designed study that is highly relevant to the problems we encounter clinically. 8 Such experimental studies with more clinical relevance will be welcomed more with anticipation by clinicians, rather than scrutiny.…”

“…In this study, the authors detail the use of plasma-derived exosomes (PEP) into allografts in a 1-cm gap rat sciatic nerve experimental model. 1 The authors made comparisons between (1) autografts, (2) allografts only, and (3) allografts treated with PEP and fibrin glue. The functional (electrodiagnostic), morphologic (muscle mass, nerve histology, immunohistochemical), and gene expression outcomes are shown.…”

“…This study further validates our belief that a processed allograft can only come close or reach the potentials of an autograft, but not exceed it. New ideas such as increasing the vascularity of an allograft, 7 or increasing stem cell quantity in the allografts 1 are being published, and yet clinical studies such as the use of free vascularized nerve grafts in long nerve gaps with proven clinical effects are being scrutinized for not producing enough evidence. Strangely, the current literature is trending backward to search for alternatives that can only closely match autografts, yet there is a lack of newer studies to overcome the limitations of chronic nerve injuries, long nerve gaps, and long-term muscle denervation.…”