Lab-To-Marketplace: Commercialization of a stretchable microelectrode array

描述(由申请人提供)：建议的工作是针对可伸缩微电极阵列(BMSEED的sMEA)的商业化，这是一种新工具，提供了同时与体外细胞培养机械和电子接口的增强能力。脑或脊髓中神经元的机械拉伸通常是创伤性脑损伤(TBI)和脊髓损伤(SCI)的根源。机械应变也是干细胞分化的重要线索。目前，TBI、SCI或组织工程学的体外模型不可能在拉伸细胞的同时进行电生理测量。BMSEED的sMEA将通过具有与细胞一起弹性拉伸和放松的微电极来实现这一能力，从而允许(A)在拉伸细胞之前、期间和之后从相同位置记录和刺激电生理活动，(B)研究反复阈值以下损伤(例如，反复脑震荡)随时间的累积影响，以及(C)将损伤后的神经活动正常化到损伤前的水平。这些能力将极大地提高对药物评估和其他治疗策略的研究，将受伤后对神经系统的损害降至最低，从而节省动物的时间、金钱和生命。BMSEED的sMEA也可能成为控制机械诱导干细胞分化为电生理活性细胞(如神经元或心肌细胞)的有效工具，这是再生医学的主要目标。BMSEED的sMEA由嵌入微电极的弹性基板和与数据采集系统的接口组成。我们之前的研究已经证明了sMEA原型在创伤性脑损伤研究中的能力。因此，这项拟议的工作旨在通过改进现有的制造工艺将这种sMEA发展成商业产品。因此，这项提议的第一个具体目标是通过简化工艺和并行处理来降低生产sMEA的成本。我们将(A)评估三种沉积金膜的方法 就成本效益和可靠性而言，(B)用荫罩图案化取代目前的光刻方法来生产微电极图案，以及(C)用自动化工艺来取代手工电镀微电极的工艺。第二个具体目标是描述这些用于创伤性脑损伤研究的低成本sMEA。我们将首先从(I)其生物兼容性、(Ii)其功能性、(Iii)它们保持功能的最大应变以及(Iv)它们可重复使用的次数来比较所生产的sMEA与三种黄金沉积方法。然后，我们将用产生最高质量的sMEA的工艺制造70个sMEA，并使用相同的标准评估它们的重复性。这一目标的结果也将适用于其他应用，如脊髓损伤和组织工程。该项目的成功完成将为生产中小型企业提供一种具有成本效益的方法。BMSEED的长期目标是将SMEA柔软和顺应性微电极的应用扩展到机械活动(例如，心脏附近)和非常活跃的体内神经接口 软(例如，大脑)环境。

DESCRIPTION (provided by applicant): The proposed work is directed at the commercialization of a stretchable microelectrode array (BMSEED's sMEA), a new tool that provides enhanced capabilities to simultaneously interface mechanically and electrically with cell cultures in vitro. The mechanical stretching of neurons in the brain or spinal cord is often te root cause of traumatic brain injury (TBI) and spinal cord injury (SCI). Mechanical strain is also an important cue for the differentiation of stem cells. It is currently not possible for in vitro models of TBI, SCI, or tissue engineering to carry out electrophysiological measurements while stretching the cells. BMSEED's sMEAs will enable this capability by having microelectrodes that stretch and relax elastically with the cells, allowing to (a) record and stimulate electrophysiological activity from the same location before, during, and after stretching the cells (b) investigate the cumulative effects of repeated, sub-threshold injuries over time (e.g., repetitive concussions), and (c) normalize post-injury neural activity to pre-injury levels. These capabilities will greatly improve research on the evaluation of drugs and other treatment strategies to minimize the damage to the nervous system after an injury, saving time, money and lives of animals. BMSEED's sMEA could also be an effective tool for controlling the mechanically-induced differentiation of stem cells into electrophysiologically active cells, such a neurons or cardiomyocytes, which is a major goal of regenerative medicine. BMSEED's sMEA consists of an elastomeric substrate with embedded microelectrodes, and an interface to the data acquisition system. Our previous research has demonstrated the capabilities of sMEA prototypes in traumatic brain injury research. Therefore, this proposed work aims to develop this sMEA into a commercial product by improving the current fabrication process. The first specific aim of this proposal is therefore to reduce the cost to produce sMEA through process simplification and parallel processing. We will (a) evaluate three methods to deposit the gold film with respect to their cost-effectiveness and reliability, (b) replace the current lithographic methd to produce the microelectrode pattern with shadow mask patterning, and (c) replace the manual process to electroplate the microelectrodes with an automated one. The second specific aim is to characterize these low- cost sMEAs for traumatic brain injury research. We will first compare sMEAs produced with the three gold deposition methods for (i) their biocompatibility, (ii) their functionality, (iii) the maximum strain at which they remain functional, and (iv) how many times they can be re-used. We will then fabricate 70 sMEAs with the process that produces the highest quality sMEAs, and assess their repeatability using the same criteria. The results of this aim will also apply to other applications such as spinal cord injury and tissue engineering. The successful completion of this project will provide a cost-effective method to produce sMEAs. The long- term goal of BMSEED is to extend the application of the sMEAs' soft and compliant microelectrodes to in vivo neural interfaces in mechanically active (e.g., near the heart) and very soft (e.g., the brain) environment.