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

• 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
• 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

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. .

项目总结/摘要 周围神经损伤（PNI）导致的神经间隙（节段性丢失，消融）缺陷是最常见的 暂时性和永久性神经系统功能障碍的常见和昂贵的原因。目前最好的临床 修复消融PNI的实践是缝合宿主神经桥接器械，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的恢复 依赖于缓慢和不精确的轴突生长，通常需要数月至数年才能重新支配目标。可行 周围神经同种异体移植物（PNAs）很少在实验或临床上使用，这是由于以下风险： 免疫抑制治疗和移植排斥。 为了大大改善目前对节段性丢失PNI的治疗，我们的团队将把我们的协同作用转化为 局部免疫抑制和聚乙烯诱导的轴突融合（PEG融合）技术 PNAs. PNA的PEG融合迅速（在几分钟内）恢复细胞质/电连续性，并防止 沃勒变性到40-60%的轴突，立即重新支配失神经组织，并可靠地促进 在几周内迅速恢复自主行为。PEG融合的嵌合轴突段内 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。 用本地化ISN技术翻译PEG融合的PNA将产生从 目前的临床实践是等待几天到几个月才能用自体移植物、脱细胞神经同种异体移植物修复消融PNI 或导管，其中患者的结果仅取决于轴突再生。相比之下， 在损伤三天内通过PEG融合/供体同种异体移植物的局部ISN进行消融PNI， 显著改善PEG融合轴突产生的功能结果（数周而不是数月/年）， 通过由局部ISN增强的活PNA，非融合轴突的稳健再生。 .