Peripheral Nerve Regeneration using Electrical Stimulation

神经损伤是一种使人衰弱的病症，通常需要手术干预以桥接神经损伤部位，以促进切断的轴突朝向下游肌肉和其他器官再生。神经组织的再生可以潜在地使用生物材料来增强，所述生物材料保持与内源性组织相似的机械特性，同时还提供指导神经生长的拓扑结构。研究表明，可以通过电刺激以及神经营养生长因子和小分子的局部递送来实现进一步的增强，但是这些递送的时机、剂量和机制需要与再生的进展相匹配，因此目前临床上没有这样的治疗方法。与当前神经修复相关的另一个基本挑战是无法检测再生进展的程度，这对临床决策至关重要。目前，再生进展的检测是粗糙的，并且依赖于医生使用100多年前开发的方法沿着皮肤物理地敲击沿着。因此，该项目旨在通过开发新型生物材料来应对这些挑战，这些生物材料可以感知神经再生的进展，并通过分子和/或电线索来增强局部再生微环境。这种方法将建立在独特的生物物理和电化学性质的有机聚合物为基础的。使用这些聚合物的主要好处是将电刺激直接引入再生部位，以改善治疗效果。下一步将是保留所开发的半导体的电化学和生物物理特性，同时将其整合到与组织的电化学和物理特性相匹配的生物相容性系统中。一旦成功合成了基于生物素的结构，该材料将使用自组装肽进行封装。这将有助于半导体的生物相容性，并为再生神经提供指导。此外，肽可以容易地用成像模式功能化，并用于治疗化合物的持续释放。这种方法将被探索，以开拓新一代的神经修复管道，可以感知再生，并通过相应地增强局部再生微环境作出反应。成功设计生物相容性聚合物后，将使用先进的3D细胞培养模型对材料进行测试，该模型可以准确模拟神经损伤部位的体内环境。这种方法将用于评估再生，预测宿主细胞反应，并测试不同成像方式的可行性，这些成像方式可以检测组织再生的程度以及电刺激对再生的影响。如果材料开发和体外测试工作进展迅速，并且还有足够的时间，那么接下来的步骤将推动该技术进行体内测试，尽管这可能会形成后续项目，因为三种不同功能的开发和体外测试（再生支持，成像检测进展，电刺激）可能是博士学位的一个足够雄心勃勃的目标。因此，该项目将开创用于治疗神经损伤的先进新医疗技术，为特定的患者和损伤情况量身定制。该项目涵盖了先进产品设计和复杂产品特性的ESPRC两个项目。通过尝试设计一种治疗解决方案，该解决方案结合了肽构建体的医学益处和通过有机电子器件进行电刺激的传递机制，以及随后的广泛表征工作，这两个领域都将被项目期间所需的工作所覆盖。

Nerve injury is a debilitating condition that often requires surgical intervention to bridge the nerve injury site to promote regeneration of severed axons towards downstream muscles and other organs. Regeneration of neural tissue can potentially be enhanced using biomaterials which maintain similar mechanical properties to that of endogenous tissue whilst also providing topology which directs nerve growth. Research has shown that further enhancements can be achieved through electrical stimulation, and the local delivery of neurotrophic growth factors and small molecules, however the timing, dosage and mechanism of delivery of these needs to be matched to the progression of regeneration so no such treatments are currently available clinically. Another fundamental challenge associated with current nerve repair is the inability to detect the extent to which regeneration is progressing, which is essential to clinical decision making. Currently detection of regeneration progression is crude and relies on the physician physically tapping along the skin, using a method developed over 100 years ago. This project therefore aims to address these challenges through developing novel biomaterials that can sense progression of nerve regeneration and respond to enhance the local regenerative microenvironment through molecular and/or electrical cues. This approach will be built upon the unique photophysical and electrochemical properties of organic semiconductor-based polymers. The main benefit of using these polymers is to introduce electric stimulation directly to the site of regeneration to improve therapeutic outcomes. The next step would be retaining the electrochemical and photophysical features of the semiconductors developed whilst integrating them into a biocompatible system matching the electrochemical and physical properties of the tissue. Once a semiconductor-based structure has been successfully synthesized, the material will be encapsulated using self-assembling peptides. This will aid biocompatibility of the semiconductor and provide guidance for the regenerating nerves. Furthermore, peptides can be readily functionalized with imaging modalities, and used in the sustained release of therapeutic compounds. This approach will be explored in order to pioneer a new generation of nerve repair conduits that can sense regeneration and respond by enhancing the local regenerative microenvironment accordingly. Upon successful design of a biocompatible polymer(s) the materials will be tested using advanced 3D cell culture models that can accurately model the in vivo environment at the site of nerve injury. This approach will be used to assess regeneration, predict host cell responses, and test feasibility of different imaging modalities that could detect the extent of tissue regeneration as well as the effect of electrical stimulation on regeneration. If the material development and in vitro testing work progresses rapidly and there is sufficient time remaining then next steps will take the technology forward for testing in vivo, although this is likely to form a subsequent project since the development and in vitro testing of the three different functionalities (regeneration support, imaging to detect progression, electrical stimulation) is likely to be a sufficiently ambitious aim for a PhD. This project will therefore pioneer sophisticated new healthcare technology for treating nerve injuries, tailored to the specific patient and injury scenario. The project covers the 2 of the ESPRC remits of Advanced Product Design & Complex Product Characterisation. By attempting to design a therapeutic solution that incorporates the medicinal benefits of peptide constructs and a delivery mechanism of electrical stimulation through organic electronics and, subsequently the extensive characterization work, both of the remits will be covered by the work required during the project.