Translating Novel Peripheral Nerve Allograft Technologies Toward Clinical Use

将新型周围神经同种异体移植技术转化为临床应用

基本信息

批准号：
10660790
负责人：
GEORGE Davis BITTNER
金额：
$ 61.02万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660790
关键词：
3-Dimensional Ablation Acceleration Allogenic Allografting Animal Model Applied Research Autologous Transplantation Axon Behavior Behavioral Biological Models Biological Products Biomedical Engineering Cadaver Cells Clinical Collaborations Cytoplasm Defect Development Devices Distal Doctor of Philosophy Esthesia Family suidae Functional disorder Funding Opportunities Goals Graft Rejection Health Human Hydrogels Immune response Immunologist Immunosuppression Injury International Legal patent Licensing Malignant Neoplasms Methods Microsurgery Mission Myelin Natural regeneration Nerve Nerve Regeneration Nervous System Operative Surgical Procedures Organ Transplantation Orthopedics Outcome Patient-Focused Outcomes Peer Review Peripheral Nerves Peripheral nerve injury Pharmaceutical Preparations Polyethylene Glycols Polyethylenes Process Publishing Rattus Recovery Regenerative Medicine Regulatory T-Lymphocyte Risk Series Surgeon Surgical sutures Techniques Technology Therapeutic Therapeutic immunosuppression Time Tissue Procurements Tissues Translating Translations Trauma United States National Institutes of Health Universities Wallerian Degeneration acronyms axon regeneration clinical practice clinical translation clinically significant cost design experience functional improvement human tissue implantation improved improved outcome median nerve motor behavior nerve gap novel pathogen porcine model prevent programs reinnervation repaired sciatic nerve standard care standard of care success supportive environment technology development

项目摘要

PROJECT SUMMARY/ABSTRACT Peripheral nerve injuries (PNIs) that result in nerve gap (segmental-loss, ablation) defects are the most common and costly cause of temporary and permanent nervous system dysfunction. The current best clinical practice to repair ablation PNIs is to suture to host nerves bridging devices such as autografts, acellular nerve allografts or synthetic conduits. Outcomes are poor because the return of any sensation or behavioral recovery depends upon slow and imprecise axonal outgrowths, often taking months to years to re-innervate targets. Viable peripheral nerve allografts (PNAs) are rarely used experimentally or clinically due to the risks of immunosuppressive therapy and graft rejection. To greatly improve current treatments for segmental-loss PNIs, our team will translate our synergistic technologies of localized immunosuppression and polyethylene -induced axon fusion (PEG-fusion) of viable PNAs. PEG-fusion of PNAs rapidly (within minutes) restores cytoplasmic/electrical continuity and prevents Wallerian Degeneration to 40-60% of axons, immediately re-innervates denervated tissues and reliably promotes a highly accelerated return of voluntary behaviors within weeks. PEG-fused chimeric axonal segments within PNAs are not rejected by the host even without immune suppression (ISN) and tissue matching. Localized ISN further reduces the immune response. Translation of PEG-fused PNAs with localized ISN technologies would produce a paradigm shift from current clinical practice of waiting days to months to repair ablation PNIs with autografts, acellular nerve allografts or conduits, where the patient outcome is solely dependent upon axon regeneration. In contrast, repairing ablation PNIs by PEG-fusion/localized ISN of donor allografts applied within three days of injury would generate significantly improved functional outcomes (weeks instead of months/years) produced by PEG- fusion axons and robust regeneration of non-fused axons through the viable PNA enhanced by localized ISN. .

项目概要/摘要导致神经间隙（节段丢失、消融）缺陷的周围神经损伤 (PNI) 是最常见的暂时性和永久性神经系统功能障碍的常见且昂贵的原因。目前最好的临床修复消融 PNI 的做法是缝合宿主神经桥接装置，例如自体移植物、脱细胞神经同种异体移植物或合成导管。结果很差，因为任何感觉或行为恢复都恢复了依赖于缓慢且不精确的轴突生长，通常需要数月至数年才能重新激活目标。可行的由于存在以下风险，同种周围神经移植物（PNA）很少在实验或临床上使用免疫抑制治疗和移植物排斥反应。为了大大改善目前对节段性损失 PNI 的治疗，我们的团队将转化我们的协同作用活细胞的局部免疫抑制和聚乙烯诱导轴突融合（PEG-融合）技术 PNAs。 PNA 的 PEG 融合快速（几分钟内）恢复细胞质/电连续性并防止 40-60% 的轴突发生华勒变性，立即重新激活失神经组织并可靠地促进几周内自愿行为的高度加速恢复。 PEG融合嵌合轴突片段即使没有免疫抑制 (ISN) 和组织匹配，PNA 也不会被宿主排斥。本地化 ISN 进一步降低免疫反应。 PEG 融合 PNA 与本地化 ISN 技术的翻译将产生范式转变目前的临床实践需要等待数天到数月才能用自体移植物、无细胞同种异体神经移植物修复消融 PNI 或导管，其中患者的结果仅取决于轴突再生。相比之下，修复在损伤三天内应用供体同种异体移植物的 PEG 融合/局部 ISN 消融 PNI 将产生 PEG 融合轴突产生的功能结果显着改善（几周而不是几个月/几年）通过局部 ISN 增强的可行 PNA 实现非融合轴突的稳健再生。。