Photoacoustic and epigenetic nerve scaffold for nerve regeneration

用于神经再生的光声和表观遗传神经支架

• 批准号: 10445552
• 负责人: Jian Yang
• 金额: $ 42.94万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-18 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445552
• 关键词: Affect; Anatomy; Ankle; Athletic Injuries; Autologous Transplantation; Biochemical; Biocompatible Materials; Biomechanics; Blood Vessels; Bone Screws; Caliber; Cells; Citrates; Clinical; Cues; Data; Defect; Development; Diagnosis; Disadvantaged; Dose; Elastomers; Elbow; Epigenetic Process; Evolution; FDA approved; Fiber; Folic Acid; Genes; Goals; Gold; Half-Life; Hemoglobin; Image; In Situ; Injury; Knee; Light; Maps; Medical Device; Methodology; Modality; Monitor; Morbidity - disease rate; Morphogenesis; Natural regeneration; Nerve; Nerve Regeneration; Neuroma; Neuronal Differentiation; Neurons; Numbness; Operative Surgical Procedures; Orthopedics; Outcome; Parents; Peripheral; Peripheral Nerves; Peripheral nerve injury; Persons; Polyesters; Polymers; Postoperative Period; Process; Rattus; Recovery of Function; Regenerative capacity; Regulation; Research; Resistance; Role; Series; Shoulder; Site; Speed; Spinal Ganglia; Structure; Surgical sutures; Time; Tissues; Ultrasonography; United States; Urethane; Vitamins; Wrist; Yang; absorption; base; biodegradable polymer; bioimaging; cell regeneration; crosslink; design; foot; implantation; improved; in situ imaging; in vivo; in vivo evaluation; injury and repair; innovation; interest; migration; nerve gap; neuron regeneration; novel; peripheral nerve regeneration; photoacoustic imaging; regenerative; repaired; scaffold; sciatic nerve; sciatic nerve injury; success; tissue oxygenation

Project Summary This proposal aims to uncover the underexplored epigenetic and biomechanical roles of folate (FA, Vitamin B9) for neuronal morphogenesis and develop novel epigenetically stimulating, biodegradable, and photoacoustic nerve guidance conduits (NGCs) for the repair of critical-sized peripheral nerve (PN) defects. The hypotheses are that (1) local delivery of an inexpensive and stable (half-life of over 100 days) folate (also known as vitamin B9) directly to the peripheral injury site at a critical concentration level of mg/L can enhance nerve regeneration and functional recovery through an intriguing epigenetic modulation; (2) folate-releasing NGCs could orchestrate intriguing biochemical-to-biomechanical force transduction to promote neuronal differentiation and regeneration; (3) incorporating FA into POC results in a polymer that enables photoacoustic imaging (PAI) in the tissue trans- parent near-infrared (NIR) window for non-invasive, real-time, in-situ monitoring of nerve scaffold degradation and nerve regeneration. The project’s innovation lie in 1) synthesizing new folate-releasing and photoacoustic citrate biodegradable polymers (POCFA) for nerve scaffold fabrication; 2) elucidating the underexplored gene- specific epigenetic and biochemical-to-biomechanical transduction effects of folate for neuroregeneration; 3) for the first time, exploring the PN regeneration by delivering folate at critical concentrations (mg/L) directly to the injury site; and 4) in vivo real-time dual-modality photoacoustic and ultrasound (PAUS) imaging of nerve scaffold degradation and nerve regeneration. Ultrasound imaging provides underlying anatomical or structural infor- mation of the tissue, whereas spectral photoacoustic imaging (PAI) maps light-absorbing polymers along with vascular structure and associated functional oxygen saturation of the tissue exploiting differential absorption of oxy- and deoxy- hemoglobin’s in the NIR window. The Rigor of Prior Research includes 1) we have previously developed multifunctional multi-channeled biodegradable elastic CUPE NGCs promising for PN regeneration; 2) we have obtained compelling data to support that biologically stable folate displayed intriguing dose-dependent epigenetic and biomechanical effects to promote neuronal differentiation migration and proliferation of both rat Schwann and neuron cells, and the regeneration and functional recovery of 20 mm sciatic nerve defects in rats as early as 4 weeks post-implantation; 3) POCFA displayed unexpected strong absorption in near-infrared-I (NIR-I, 700-1000 nm) and even in NIR-II (1000-1700 nm) window for PAI. The expected outcome of this pro- posal is a practical methodology for the optimal design of imageable NGCs with suitable epigenetic, biomechan- ical, and topographical cues for the regeneration and functional recovery of critically sized nerve defects.

项目概要 该提案旨在揭示叶酸（FA、维生素 B9）未被充分探索的表观遗传和生物力学作用 用于神经元形态发生并开发新型表观遗传刺激、可生物降解和光声 神经引导导管（NGC）用于修复临界大小的周围神经（PN）缺陷。假设 (1) 本地提供廉价且稳定（半衰期超过 100 天）的叶酸（也称为维生素 B9) 以mg/L的临界浓度水平直接到达外周损伤部位可增强神经再生 通过有趣的表观遗传调节实现功能恢复； (2) 释放叶酸的 NGC 可以协调 有趣的生物化学到生物力学的力传导，以促进神经元分化和再生； (3) 将 FA 掺入 POC 中，形成一种聚合物，可在组织中进行光声成像 (PAI) 母近红外 (NIR) 窗口，用于非侵入性、实时、原位监测神经支架降解 和神经再生。该项目的创新点在于1）合成了新型叶酸释放和光声材料 用于神经支架制造的柠檬酸盐生物可降解聚合物（POCFA）； 2）阐明未被充分研究的基因- 叶酸对神经再生的特定表观遗传和生物化学到生物力学转导作用； 3）对于 首次通过将临界浓度 (mg/L) 的叶酸直接输送至 PN 来探索 PN 再生 受伤部位； 4）神经支架的体内实时双模态光声和超声（PAUS）成像 退化和神经再生。超声成像提供基础解剖或结构信息 组织的合成，而光谱光声成像（PAI）则将光吸收聚合物与 利用不同吸收的组织的血管结构和相关的功能性氧饱和度 NIR 窗口中的氧合血红蛋白和脱氧血红蛋白。先前研究的严谨性包括 1）我们之前 开发了多功能、多通道、可生物降解的弹性 CUPE NGC，有望用于 PN 再生； 2） 我们已经获得了令人信服的数据来支持生物稳定的叶酸表现出有趣的剂量依赖性 表观遗传和生物力学效应促进大鼠神经元分化、迁移和增殖 雪旺与神经元细胞以及大鼠20mm坐骨神经缺损的再生和功能恢复 最早在植入后 4 周； 3）POCFA对近红外-I表现出意想不到的强吸收 （NIR-I，700-1000 nm），甚至在 PAI 的 NIR-II（1000-1700 nm）窗口中。本次会议的预期成果 posal 是一种实用的方法，用于优化设计具有合适的表观遗传、生物力学的可成像 NGC。 临界尺寸神经缺损的再生和功能恢复的临床和地形线索。