The role of the inflammatory microenvironment in Acellular Nerve Allografts (ANAs) repairing nerve gaps

炎症微环境在无细胞神经同种异体移植物（ANA）修复神经间隙中的作用

• 批准号: 10678384
• 负责人: Jesús Alberto Acevedo Cintrón
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678384
• 关键词: Affect; Allogenic; Allografting; Autologous Transplantation; Axon; Biomedical Engineering; Blood Vessels; Caring; Cells; Chemicals; Chronic; Clinic; Clinical; Data; Defect; Detergents; Expenditure; Extracellular Matrix; FK506; Fellowship; Gene Expression; Goals; Harvest; Immunology; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; Learning; Length; Macrophage; Measures; Modeling; Modification; Molecular Target; Morbidity - disease rate; Morphology; Natural regeneration; Nerve; Nerve Regeneration; Neurobiology; Operative Surgical Procedures; Patients; Peripheral Nerves; Peripheral nerve injury; Process; Quality of life; Rattus; Recovery of Function; Research; Role; Scientist; Site; T-Lymphocyte; Tacrolimus; Techniques; Testing; Time; Training; Translating; Trauma; United States; angiogenesis; axon regeneration; cell motility; cytokine; experience; immunogenicity; inflammatory marker; inflammatory milieu; inflammatory modulation; migration; myelination; nerve autograft; nerve damage; nerve gap; nerve injury; nerve repair; novel; pharmacologic; reconstruction; regeneration potential; regenerative; repaired; sciatic nerve; single-cell RNA sequencing; standard of care; therapy development

PROJECT SUMMARY/ABSTRACT Reconstruction of peripheral nerve gap injuries continues to pose a challenge in the clinic due to their significant long-term functional morbidity. Multiple surgical approaches have been developed to promote nerve regeneration across a damaged nerve with a gap. In the clinic, nerve autografts are considered the standard of care in treating nerve gaps due to their superior capacity in promoting nerve regeneration. However, the use of nerve autografts is limited by their availability, increased surgery time, loss of nerve function from the lost nerve and donor site morbidity. Acellular nerve allografts (ANAs) have been proposed as a clinical alternative to autografts in repairing nerve gaps due to their capability in promoting regeneration across short gaps (< 3 cm). ANAs are allogenic nerves that are chemically processed to remove the cells, reducing immunogenicity, while maintaining the extracellular matrix (ECM) that will allow cell migration into the ANA and subsequent nerve regeneration. However, unlike autografts, ANAs do not support regeneration across long defects (> 3 cm). The reason why long ANAs do not promote regeneration or regenerate poorly is not completely understood. Previous studies have demonstrated the critical role of inflammatory cells, such as macrophages and T cells, in regulating and promoting the early stages of nerve regeneration in ANAs (before 4 weeks post-surgery). Specifically, macrophages will promote angiogenesis and T cells will promote axonal myelination. However, when compared to short ANAs capable of robust regeneration, preliminary data shows an increase in the expression of pro-inflammatory cytokines and changes in the morphology of blood vessels in long ANAs at the later stages of nerve regeneration (between 4- and 8- weeks post-surgery). The increase in the expression of pro-inflammatory cytokines and the changes in the morphology of blood vessels happen after angiogenesis has occurred and axons have started migrating into the ANAs. These changes suggest that a pro-inflammatory environment develops inside long ANAs in the later stages of nerve regeneration, and this correlates with changes in the morphology of blood vessels and a decrease in the number of myelinated axons. We hypothesize the state of chronic inflammation in long ANAs is disrupting the regenerative microenvironment in long ANAs. In brief, the proposed research aims to characterize and compare the inflammatory microenvironment that develops in the later stages of nerve regeneration in long ANAs with the microenvironment in the regenerated short ANAs and autografts. This project also explores the effect of reducing inflammation in long ANAs, using a pharmacological intervention, on axonal regeneration. An integral part of this study is to identify the cell subpopulations promoting the pro- inflammatory microenvironment in long ANAs. An in-depth analysis of these cell subpopulations may provide specific molecular targets used to develop therapies aimed to promote nerve regeneration in long ANAs.

项目摘要/摘要 周围神经间隙损伤的重建在临床上仍然是一个挑战，因为他们 严重的长期功能障碍。已经开发了多种手术方法来促进 有缝隙的受损神经的神经再生。在临床上，自体神经移植被认为是 治疗神经间隙的标准护理，因为它们在促进神经再生方面具有优越的能力。 然而，自体神经移植物的使用受到其可用性、手术时间延长、神经丢失等方面的限制。 功能由神经丢失和供区发病率引起。脱细胞同种异体神经移植已被提出。 作为临床上替代自体移植修复神经缺损的一种方法，因为它具有促进再生的能力 跨越短间隙(&lt；3厘米)。ANA是一种同种异体神经，经过化学处理后可以移除细胞， 降低免疫原性，同时维持细胞外基质(ECM)，使细胞迁移到 ANA和随后的神经再生。然而，与自体移植物不同的是，ANA不支持再生 跨过长缺陷(&gt；3厘米)。为什么长ANA不能促进再生或再生能力差 还没有完全被理解。以前的研究已经证明了炎症细胞的关键作用， 如巨噬细胞和T细胞，在调节和促进神经再生的早期阶段 ANAS(术后4周前)。具体地说，巨噬细胞将促进血管生成，T细胞将 促进轴突髓鞘形成。然而，与能够强健再生的短ANA相比， 初步数据显示，促炎症细胞因子的表达增加，并改变了 神经再生后期(4~8周)长管内血管的形态 术后数周)。促炎症细胞因子的表达增加及血管内皮细胞的变化 血管形态发生在血管生成和轴突开始迁移到 全日空。这些变化表明，在长ANAS内形成了一个促炎环境 神经再生的后期，这与血管形态的变化和 有髓轴突数量的减少。我们假设长期慢性炎症的状态 ANA正在扰乱Long ANA的再生微环境。简而言之，提出的研究目的 描述和比较神经发育后期的炎性微环境 长ANA的再生与再生的短ANA和自体移植的微环境。这 该项目还利用一种药物干预方法，探索了Long Anas减少炎症的效果， 关于轴突再生。这项研究的一个组成部分是确定促进促红细胞生成素前体的细胞亚群。 长静脉曲张的炎性微环境。对这些细胞亚群的深入分析可能会提供 特定的分子靶点用于开发旨在促进长ANA神经再生的治疗方法。