Neural Interfaces towards a Treatment of Epilepsy – Merging Photopharmacology with Implantable Optoelectronics and Electrophoretic Drug Delivery

与人脑的接口是深入了解神经元过程的关键挑战，也是治疗癫痫等神经疾病的医学进展的关键。兴奋性和抑制性信号之间的不平衡被认为是癫痫发作的一个原因。结合皮质内注射抗惊厥药物，绕过血脑屏障等障碍，以及近距离测量神经元活动，是一种很有前途的治疗策略。药物在目标脑区通过有机离子泵进行电泳性的“干式”输送后的扩散限制了这种方法的时间分辨率。尽管对大脑活动进行精确的皮质内测量是可能的，但对癫痫的发生和强度的准确预测仍然达不到，这一事实加剧了这种情况。这使得对靶区内抗癫痫药物浓度的高时间控制变得更加重要。光的使用似乎是实现这种控制的一种有效方法，因为它具有非侵入性、无害的性质，并实现了高空间和时间分辨率。光药理学的概念是基于药理活性物质与分子光开关的结构互连。人们已经对用于中枢神经系统的光开关兴奋性和抑制性神经递质进行了广泛的研究，利用光可逆地灭活/激活药物的药理作用。光遗传学领域的发展势头导致了一系列植入式光电探针用于体内生物组织的照明，这些学科的融合，即光药理学、皮质内注射和测量以及植入型光电子学，可能会克服每个单独方法的问题，为抗癫痫治疗提供强有力的工具。为了实现这一点，发光二极管将被集成在植入物中，带有一个灵活的有机电极和一个微流控离子泵，注入一种可光切换的谷氨酸受体拮抗剂。通过该设备对神经活动的持续监测，可以预测癫痫发作的可能性。如果预测表明癫痫事件的可能性增加，将注射非活性药物，对神经活动没有影响。在实际癫痫发作的情况下，红光照射将按需发生，通过抑制谷氨酸能突触的信号传递来抑制主动电位的放电。根据所测量的癫痫发作强度，组织内的药理活性药物浓度将分别在红光或蓝光照射下增加或降低，从而提供精确的控制。植入物中所有系统组件的集成，特别是其设计、微制造、表征和应用优化将是该项目的主要任务

Interfacing with the human brain is a critical challenge for a deep understanding of neuronal processes and is the key for medicinal progress in treatment of neurological diseases, like epilepsy. An imbalance between excitatory and inhibitory signals has been discussed as a reason for epileptic seizures. The incorporation of an intracortical injection of anticonvulsants, bypassing obstacles like the blood–brain barrier, and a close-by measurement of neuronal activity is a promising therapeutic strategy. The diffusion of the drug after its electrophoretic, "dry" delivery via an organic ion pump in the targeted brain area limits the temporal resolution of this approach. This circumstance is aggravated by the fact that the exact prediction of seizure’s occurrence and intensity is still out reached, even though precise, intracortical measurements of the brain activity are possible. This makes a high temporal control over the antiseizure drug concentration within the target area even more important. The use of light appears to be a potent way to accomplish such a control, due to its non-invasive, harmless nature and achievement of high spatial and temporal resolution. The concept of photopharmacology is based on the structural interconnection of pharmacologic active agents with molecular photoswitches. Extensive studies on photoswitchable excitatory as well as inhibitory neurotransmitters for use in the central nervous system have been conducted, using light to reversibly de-/activate the pharmacological effect of the drug. The momentum in the field of optogenetics led to a wide range of implantable optoelectronic probes for in vivo illumination of biologic tissue.The merging of those disciplines, namely: photopharmacology, intracortical injection and measurement as well as implantable optoelectronics, might overcome the problems of each individual approach and provide a powerful tool for antiseizure therapy. To achieve this, light emitting diodes will be integrated in an implant with a flexible, organic electrode and a microfluidic ion pump, injecting a photoswitchable antagonist of a glutamate receptor. A constant monitoring of the neural activity by the device will allow the prediction of the seizure’s likelihood. If the forecast indicates an increased likelihood of an epileptic event inactive drug will be injected, having no effect on the neural activity. In case of actual seizure, red light irradiation will occur on demand, suppressing active potential firing by inhibiting the signal transmission in the glutamatergic synapses. Depending on the measured intensity of the seizure, the pharmacologically active drug concentration within the tissue will be increased by red light or decreased by blue light illumination, respectively, affording precise control.The integration of all system components in an implant, in particular its design, microfabrication, characterization and optimization towards the application will be the main task of this project