Pre-clinical validation of 3D-printed nerve conduits for pediatric peripheral nerve repair

项目摘要 周围神经损伤，由于创伤，肿瘤或其他医疗条件，需要50000 - 200000 手术，并可能导致完全或部分瘫痪。自体移植是目前的“金标准” 但是需要额外的程序来获取移植物，在儿科人群中进行可能具有挑战性， 并且经常导致供体部位的神经瘤形成和功能丧失。这个项目的目标是验证 本发明提供了制造临床前聚合物三维（3D）神经导管的材料和方法， 嵌入式无线传感器，用于连续监测婴儿/儿童的功能恢复。的 3D打印的可血管化神经导管模仿神经组织的微结构，嵌入有 用于原位监测的无线传感器，并且可以执行仿生功能以增强神经再生 治疗目前，还没有临床解决方案用于监测神经移植物治疗后的成功。 手术具体目标1将专注于优化3D生物打印神经导管的制造和性能， 用于临床转化的商业级生物材料。为了实现这一目标，我们将使用 快速投影，图像引导，直接打印（RaPID）平台，可以3D打印整个神经导管， 只需几秒钟，并将匹配患者的特定大小和形状。导管将具有线性微通道 沿着长度用于轴突生长和侧面微孔用于血管化。特定目标2将验证生成 儿科患者特定导管的体积缺陷。为此，我们将协调收集 出生至18岁儿童患者的MRI数据，包括性别和周围神经损伤 包括头颈部、上肢和下肢。根据收集的MRI数据， 儿科神经导管将进行3D生物打印，以验证RaPID系统，并为计划的 FDA监管审查。Specific Aim 3将开发一种无线供电和控制的传感器， 通过神经缺损的电脉冲在这个目标中，我们将通过聚合物袖口设计连接无线传感器 以评估神经纤维生长的速率和稳健性 穿过治疗修复部位。开发这种植入式传感器将为集成 诊断和治疗用于外科手术干预。本提案完成时的最终交付成果 将具有制造质量标准、源材料质量标准、尺寸限制、测试和放行 具有无线传感功能的3D生物打印神经导管的规格，以支持提交前会议， FDA随后提交了510（k）文件。

Project Summary Peripheral nerve injuries, as a result of trauma, tumors, or other medical conditions, require 50,000-200,000 surgeries annually, and may cause complete or partial paralysis. The autograft is the current "gold standard" but requires additional procedures to harvest the graft, can be challenging to perform in a pediatric population, and often leads to neuroma formation and loss of function at the donor site. The goal of this project is to validate the materials and methods to fabricate pre-clinical polymeric three-dimensional (3D) nerve conduits with an embedded wireless sensor for continuous monitoring of functional recovery to be used in infants/children. The 3D printed vascularizable nerve conduits mimic the micro-architecture of nerve tissues, are embedded with wireless sensors for in situ monitoring, and can perform biomimetic functions to augment nerve regeneration therapies. Currently, there is no clinical solution for monitoring the success of a neural graft therapy after surgery. Specific Aim 1 will focus on optimizing 3D-bioprinted nerve conduit fabrication and performance using commercial-grade biomaterials for clinical translation. To fabricate such a conduit in this aim, we will use a Rapid Projection, Image-guided, Direct-printing (RaPID) platform that can 3D-print the entire nerve conduit in mere seconds and will match the patient’s specific size and shape. The conduit will have linear micro-channels along the length for axon growth and side micro-holes for vascularization. Specific Aim 2 will validate generation of pediatric patient-specific conduits based on volumetric defect. In this aim, we will coordinate the collection of MRI data among pediatric patients from birth to 18 years of age, both sexes, and with peripheral nerve injuries involving the head and neck, upper limbs, and lower limbs. Based upon the MRI data collected, personalized pediatric nerve conduits will be 3D bioprinted to validate the RaPID system and provide evidence for planned FDA regulatory review. Specific Aim 3 will develop a wirelessly powered and controlled sensor to detect electrical impulses across a nerve defect. In this aim, we will attach wireless sensors via a polymeric cuff design to the distal end of an injured mouse sciatic nerve to assess the rate and robustness of nerve fiber growth across the therapeutic repair site. Developing this implantable sensor will pave the way for integrating diagnostics with therapeutics for surgical interventions. The final deliverable at the completion of this proposal will be to have the manufacturing specifications, source material specifications, sizing limits, testing and release specifications for 3D bioprinted nerve conduits with wireless sensing to support a pre-submission meeting with FDA followed by a 510(k) filing.