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. .

项目摘要/摘要导致神经间隙（分段，消融）缺陷的周围神经损伤（PNIS）最多暂时和永久性神经系统功能障碍的常见和昂贵的原因。当前最好的临床修复消融PNI的练习是为了缝合缝合神经桥接设备，例如自体移植，细胞神经同种异体移植或合成导管。结果很差，因为任何感觉或行为恢复的回报取决于缓慢和不精确的轴突生长，通常需要数月到几年才能重新定位目标。可行外周神经同种异体移植（PNA）很少在实验或临床上使用免疫抑制疗法和移植排斥。为了极大地改善当前对分段损失PNI的治疗，我们的团队将翻译我们的协同作用可行的局部免疫抑制和聚乙烯诱导的轴突融合（PEG融合）的技术 PNAS。 PNAS的PEG融合迅速（几分钟之内）恢复细胞质/电气连续性并防止沃勒（Wallerian）变性至40-60％的轴突，立即重新启动了无效的组织，可靠地促进几周内，自愿行为的高度加速回归。 PEG融合的嵌合轴突段即使没有免疫抑制（ISN）和组织匹配，宿主也不会拒绝PNA。本地化进一步降低了免疫反应。用局部IS技术的PEG融合PNA的翻译将产生范式转变当前等待几天到几个月的临床实践，以自体移植，细胞神经同种异体移植修复消融PNI 或导管，患者预后仅取决于轴突再生。相反，修理 peg融合/局部化的pNIS在受伤后三天内应用的同种异体移植物的IS 钉融合轴突和通过局部ISN增强的可行PNA对非融合轴突的稳健再生。。