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.

项目摘要 该提案旨在揭示叶酸的未置换表观遗传和生物力学作用（FA，维生素B9） 用于神经元的形态发生和发展新颖的表观遗传刺激，可生物降解和光声 神经引导导管（NGC）修复关键大小的周围神经（PN）缺陷。假设 是（1）局部递送廉价且稳定的（半衰期超过100天）的叶酸（也称为维生素 b9）直接以临界浓度水平的Mg/L的直接到达外周损伤部位可以增强神经再生 和通过有趣的表观遗传调节恢复的功能恢复； （2）叶酸释放的NGC可以编排 引人入胜的生化到生物力学力转导，以促进神经元分化和再生； （3）将FA纳入POC会导致聚合物，该聚合物可以在组织反式中实现光声成像（PAI） 父母的近红外（NIR）窗口，用于无创，实时的，现场的神经脚手架降解的原地监测 和神经再生。该项目的创新在于1）合成新的叶酸释放和光声 用于神经支架的柠檬酸盐可生物降解聚合物（POCFA）； 2）阐明未置换的基因 叶酸的特定表观遗传学和生化对生物力学转导影响神经创变； 3） 第一次，通过直接以临界浓度（mg/l）的方式探索PN再生 伤害部位； 4）在体内实时双模式光声和超声（PAU）神经支架的成像 降解和神经再生。超声成像提供潜在的解剖或结构信息 组织的序列，而光谱光声成像（PAI）映射了吸收光聚合物 利用差异滥用的组织的血管结构和相关的功能氧饱和 NIR窗口中的氧气和脱氧血红蛋白。先前研究的严格包括1）我们以前有 开发了多功能的多功能可生物降解的弹性CUPE NGC，可用于PN再生； 2） 我们获得了令人信服的数据，以支持生物学稳定的叶酸显示出有趣的剂量依赖性 表观遗传和生物力学作用，以促进两只大鼠的神经元分化迁移和增殖 Schwann和Neuron细胞，以及大鼠20 mM坐骨神经缺损的再生和功能恢复 植入后4周； 3）POCFA在近红外I中表现出意外的强滥用 （NIR-I，700-1000 nm），甚至在NIR-II（1000-1700 nm）的窗口中。这一亲戚的预期结果 Posal是一种实用方法，用于具有合适表观遗传学的可成像NGC的最佳设计 批判性神经缺陷的再生和功能恢复的地形线索和地形线索。