Microelectronically Stimulating and Actuating Nanofibers for Muscle Replacement and Regeneration

目前尚无理想的大体积骨骼肌损伤修复方法。以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(外源性肌源性细胞、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率、功能丧失、供体部位体积减少，以及移植时的效果有限。这些问题使组织工程成为一种更受欢迎的肌肉再生方法。骨骼肌细胞已经在多种材料上生长，包括天然基质、合成聚合物和脱细胞组织。这些选择都会形成新的肌肉，但在组织再生之前，它们不会提供功能(收缩运动)。这里介绍的系统被设计成在植入时收缩，以在新组织发育时为患者提供即时功能。这项拟议的项目将研究将聚合物驱动纳米纤维与可植入的微电子刺激器相结合，形成用于骨骼肌组织工程的收缩支架的可能性。这种纳米纤维被设计成离子聚合物复合材料，当放置在电场中时会被激活。当离子聚合物复合材料弯曲时，每个纳米纤维的组件将被安排成将沿纳米纤维长度的弯曲转变为收缩。以前的工作表明，当肌肉细胞受到机械刺激(通过拉伸)和电刺激时，肌肉细胞的生长和组织发育都会增加。该系统将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，并通过可植入的多电平可编程电压调节器来诱导导致收缩的电场。这种微芯片可以产生不同的电压水平，让用户可以自由控制脚手架收缩的程度。微芯片运行所需的电力将通过无线链路提供。此外，还可以远程调整所需的电压电平。该系统的潜力和适用性将通过其在功能上取代和再生肌肉组织的能力在体外和体内进行评估。拟议的系统将通过完成以下目标来创建：提炼纳米线组成-聚合物浓度和纳米颗粒浓度，并评估支架组织的体外再生能力；开发用于电刺激纳米纤维的高度集成的皮下微芯片；整合纳米线支架和刺激微芯片；以及研究支架促进组织愈合的体内能力。将对脚手架的收缩性能(强度、速度、收缩程度)进行调查。该支架还将与骨骼肌细胞(用于肌肉再生)和血管细胞(用于潜在的血管形成)的生物相容性和再生能力进行研究。这些测试将在有电刺激和无电刺激两种情况下进行。采用低漏失的拓扑结构，设计了一种高集成度的低功耗可控多电平电压调节器。该芯片将包含一个精心设计的感应链路，使植入式微系统能够无线供电和控制。芯片将进行封装，以确保其生物兼容性。支架和刺激性微芯片将通过将纳米纤维烧结(通过加热结合)到导线和导线周围来集成。完整集成的电刺激器-致动支架装置将在肌袋模型中进行体内评估。用于肌肉再生的无线、电刺激、可收缩支架的创建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兼容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.