Photoacoustic and epigenetic nerve scaffold for nerve regeneration

项目摘要 该提案旨在揭示叶酸(FA，维生素B9)的表观遗传学和生物力学作用。 用于神经元形态发生和开发新的表观遗传刺激、生物可降解和光声 神经引导导管(NGCs)用于修复临界大小的周围神经(PN)缺损。假说 是：(1)当地提供一种廉价和稳定的(半衰期超过100天)叶酸(也称为维生素 B9)直接到周围损伤部位临界浓度水平的mg/L可促进神经再生 通过耐人寻味的表观遗传调节实现功能恢复；(2)释放叶酸的NGCs可以协调 激发生物化学到生物力学的力量传导，促进神经元分化和再生； (3)将FA加入到POC中会产生一种聚合物，该聚合物能够在组织中进行光声成像(PAI)。 无创、实时、原位监测神经支架降解的父近红外(NIR)窗口 和神经再生。该项目的创新之处在于1)合成了新的叶酸释放和光声 柠檬酸盐可生物降解聚合物(POCFA)用于构建神经支架；2)阐明未被探索的基因- 叶酸对神经再生的特殊表观遗传学和生物化学-生物力学转导作用；3) 第一次，通过将临界浓度的叶酸(mg/L)直接输送到 4)神经支架的在体实时双模式光声和超声成像 退化和神经再生。超声成像提供了潜在的解剖或结构信息- 组织的成像，而光谱光声成像(PAI)将光吸收聚合物与 利用差示吸收的组织的血管结构和相关的功能氧饱和度 近红外窗口中有氧合和脱氧血红蛋白。之前研究的严谨性包括1)我们之前 开发多功能多通道可生物降解弹性CuPE NGCs，有望实现净光再生；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耐人寻味的剂量依赖性 表观遗传学和生物力学效应促进大鼠神经元分化、迁移和增殖 雪旺和神经细胞与大鼠坐骨神经20 mm缺损区的再生和功能恢复 早在植入后4周，POCFA在近红外区表现出意想不到的强吸收 (NIR-I，700-1000 nm)，甚至在近IR-II(1000-1700 nm)窗口。这项计划的预期结果是- POSAL是一种实用的方法，用于优化设计具有合适的表观遗传学、生物力学和生物力学特性的可成像NGCs。 对于严重神经缺损区的再生和功能恢复的生理、局部和局部线索。

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.