Microelectronically Stimulating and Actuating Nanofibers for Muscle Replacement and Regeneration

目前对于大体积骨骼肌的损失还没有理想的修复方法。先前研究的解决方案包括自体肌肉移植和使用各种细胞来源（外源性肌源细胞、卫星细胞和成肌细胞）。虽然这些技术取得了一些成功，但它们也有缺点。例如，自体移植会导致发病、功能丧失、供体部位体积减小以及移植后的有效性有限。这些问题使得组织工程成为更受欢迎的肌肉再生方法。骨骼肌细胞可以在多种材料上生长，包括天然基质、合成聚合物和脱细胞组织。这些方法都能产生新的肌肉，但在组织再生之前，它们不能提供功能（运动的收缩）。这里介绍的系统被设计为在植入时收缩，以便在新组织发育时立即给予患者功能。该项目将研究聚合物驱动纳米纤维与植入式微电子刺激器结合的潜力，以形成用于骨骼肌组织工程的可收缩支架。纳米纤维被设计成离子聚合物复合材料，当放置在电场中时就会启动。当离子聚合物复合材料弯曲时，每根纳米纤维的组分将被排列成沿纳米纤维长度方向的弯曲转化为收缩。先前的研究表明，当肌肉细胞受到机械（通过张力）和电刺激时，肌肉细胞的生长和组织发育会加快。所提出的系统将利用这些现象，利用电刺激引起的支架收缩来刺激肌肉细胞和新肌肉的生长和发育。引起收缩的电场将由一个可植入的多级可编程电压调节器感应。微芯片被设计成产生不同的电压水平，让用户可以自由控制支架收缩的程度。微芯片运行所需的电力将通过无线链路提供。此外，所需的电压水平可以远程调节。该系统的潜力和适用性将通过其功能替代和再生肌肉组织的能力在体外和体内进行评估。提出的系统将通过完成以下目标来创建：改进纳米线组成-聚合物浓度和纳米颗粒浓度，并在体外评估支架组织再生能力；一种用于纳米纤维电刺激的高集成度皮下微芯片的研制纳米线支架与刺激芯片的集成；以及研究支架在体内促进组织愈合的能力。将调查脚手架的收缩性（强度、速度、收缩程度）。该支架还将研究其与骨骼肌细胞（用于肌肉再生）和血管细胞（用于潜在的血管化）的生物相容性和再生能力。这些测试将在有电刺激和没有电刺激的情况下进行。采用低差拓扑结构，研制了一种高集成度、低功耗、可控的多级稳压器。该芯片将包含一个精心设计的感应链接，使可植入的微系统能够无线供电和控制。芯片将被封装以确保其生物相容性。支架和刺激微芯片将通过烧结（通过加热粘合）纳米纤维与导线和导线周围相结合。完整的集成电刺激驱动支架装置将在肌肉袋模型中进行体内评估。创造一种无线、电刺激、可收缩的肌肉再生支架将使离子聚合物复合材料在组织工程中的应用成为可能。该系统还将通过开发可在生物介质中可靠运行的生物相容性低功耗电路来增强微电子领域。

Currently there is no ideal restoration method for large volume skeletal muscle loss. Previously investigated solutions include autologous muscle transplants and the use of various cell sources (exogenous myogenic cells, satellite cells, and myoblasts). While these techniques have had some success, they also have drawbacks. Autologous transplantation, for example, leads to morbidity, loss of function, decreased volume at the donor site, and limited effectiveness when transplanted. These problems have made tissue engineering a more popular approach for muscle regeneration. Skeletal muscle cells have been grown on numerous materials including natural substrates, synthetic polymers, and decellularized tissue. These options all develop new muscle, but they do not provide functionality (contraction for movement) until the tissue is regenerated. The system presented here is designed to contract upon implantation to give the patient immediate function as new tissue develops. The proposed project will investigate the potential of combining polymeric, actuating nanofibers with implantable microelectronic stimulators to form contractile scaffolds for skeletal muscle tissue engineering. The nanofibers are designed to behave as ionic polymeric composites that will actuate when placed inside an electric field. As ionic polymeric composites bend, the components of each nanofiber will be arranged to convert bending along the nanofiber length into contraction. Previous work has shown that muscle cell growth and tissue development increase when the muscle cells are stimulated mechanically (through strain) and electrically. The proposed system will take advantage of these phenomena by using the scaffold contraction caused by the electrical stimulation to stimulate the growth and development of muscle cells and new muscle.The electric field that causes the contraction will be induced by an implantable multi-level programmable voltage regulator. The microchip is designed to generate different voltage levels, giving the user the freedom to control the degree of scaffold contraction. The power required for the operation of the microchip will be provided through a wireless link. In addition, the required voltage level can be adjusted remotely. The potential and applicability of the system will be evaluated in vitro and in vivo by its ability to functionally replace and regenerate muscle tissue. The proposed system will be created through completion of the following objectives: Refining nanowire composition-polymer concentration and nanoparticle concentration and evaluating scaffold tissue regenerative capability in vitro; Developing a highly-integrated subcutaneous microchip for the electrical stimulation of nanofibers; Integrating the nanowire scaffold and the stimulation microchip; and Investigating the in vivo capability of the scaffolds to promote tissue healing. The scaffold will be investigated for contractility (strength, speed, degree of contraction). The scaffold will also be investigated for biocompatibility and regenerative ability with both skeletal muscle cells (for muscle regeneration) and vascular cells (for potential vascularization). These tests will be conducted both with and without electrical stimulation. A highly-integrated low power controllable multi-level voltage regulator will be developed using low-drop out topology. The chip will contain a carefully designed induction link that will enable the implantable microsystem to be powered and controlled wirelessly. The chip will be packaged to ensure its biocompatibility. The scaffold and stimulatory microchip will be integrated by sintering (bonding by heating) nanofibers to the wires and around the wires. The complete integrated electric stimulator-actuating scaffold device will be evaluated in vivo in a muscle pocket model. The creation of a wireless, electrically stimulated, contractile scaffold for muscle regeneration will enable the application of ionic polymeric composites for tissue engineering. The proposed system will also enhance the microelectronics field by developing biocompatible low power circuits that can operate reliably in biological media.