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in vivo optogeneticS, elecTrophysiology and phArmacology with an ultRasonically-powered DUST for Parkinson's Disease

Periodic Reporting for period 1 - STARDUST (in vivo optogeneticS, elecTrophysiology and phArmacology with an ultRasonically-powered DUST for Parkinson's Disease)

Reporting period: 2017-10-01 to 2018-09-30

The main goal of STARDUST project is to realize a novel wireless implantable micro-scale device enabling in-vivo optogenetic, electrophysiology and drug-delivery with a focus on Parkinson's Disease. To achieve this ambitious goal, we have defined some objectives and milestones within this project. In general, such a device is not available although there are several on-going researches to achieve such a device for different purposes, which will be within the interest of research lab testing such a device on free-moving animals as well as the neurological disorder's society (In STARDUST, Parkinson's Disease).

Development of a fully implantable device entails different technological challenges including the volume/size of the device, delivering enough power to drive the electronics and light emitting diodes on the device, a trustable recording and communication schemes, and so on, as well as biological challenges including finding a proper target in brain affected by Parkinson's Disease and effectively responding to optogentics techniques, development of new opsins increasing the sensitivity of neurons to the light and finally a light-enabled drug-delivery to the target.

within STARDUST project, 4 scientific objectives to achieve the overall goal of the project has been defined:
1. Identification of a novel way and target for treating PD symptoms
2. Realization of the ultrasonically-powered Dusts with light power delivery of >1mW/mm^2
3. Enabling drug-delivery integrated with Dusts activated by blue light
4. Engineering ion-specific (H+, Na+, K+, Cl-) channelrhodopsins with higher red light sensitivity than currently available

In summary, the project aims to offer an alternative treatment for the over 6 million people suffering from Parkinson’s Disease worldwide and therein help reducing the 13.9 B€ annual costs from treatments and missing labour by developing completely new and improved approaches to Parkinson’s Disease research and treatment.
From neurological disorders, that are globally the main cause for disability, Parkinson’s Disease is growing the fastest. Aging population and increasing life expectancy leads to increase of prevalence, and therefore the number of people affected by PD globally has more than doubled from 1990 to 2015. In 2016, PD caused 3.2 million DALYs (disability-adjusted life years), of which about 500 000 in European Union. Currently, there are various approaches to treating Parkinson’s Disease: amongst others anti-Parkison’s drugs (such as dopaminergic, dopamine agonists and enzyme inhibitors), deep brain stimulation (DBS), neural implantation and use of e.g. growth factors. About 90 clinical trials related to PD and implants are found at of which currently active 30. Most of them utilize DBS .
STARDUST envisions a new device taking the optogenetic technologies approach to another level easing the animal study not only for PD but other diseases.
During the first period of the project, following progress have been made:

1. Using optogenetic manipulations, we have identified the external Globus Pallidus (GPe) as a critical locus in regulating motor activity that could be targeted for optogenetic therapy in PD conditions, which was the first milestone of the project, successfully achieved.
2. We have successfully tested (in Lab on PCB) a basic prototype assessing the power required for optogenetics. The first prototype's integrated electronics are under production. The integration of all components will be done in the next phase of the project.
3. Light-enabled drug-delivery has been thoroughly researched. We have developed a triggered drug delivery system.
4. We have slowed down the kinetics and thereby increased the sensitivity of the cells. This has been done for the anion conducting ACRs and the red-light absorbing Chrimson. Using this will ease the downscaling of the designed prototype achieving smaller device's sizes, thereby, less damage to the tissues during in-vivo testing. The results have been published in
Oda, K., Vierock, J., Oishi, S., Rodriguez-Rozada, S., Taniguchi, R., Yamashita, K., Wiegert, J.S. Nishizawa, T., Hegemann, P., Nureki, O. (2018) Crystal structure of the red light-activated channelrhodopsin Chrimson. Nature Comm. 9(1):3949. doi: 10.1038/s41467-018-06421-9.
STARDUST explores, for the first time, a wireless device for optogenetics purposes that includes recording and drug-delivery as well. The envisioned device, if successful, can be a starting point for many other applications from neurological disorders to cancer photodynamic therapy. During the first year of the project, obtained results are promising not only to provide enough power for optogenetics using μLEDs, but also applicable to drive lasers for applications, where a higher power using laser is required. The envisioned device can be used also for drug-delivery for interventions where local drug delivery is important. This approach, now, is just to make a proof of concept of the drug-delivery in the brain. In case of success, it can be used to deliver anti-inflammatory drugs and/or CNS stimulating active pharmaceutical ingredients at the targeted site.

From the technology-point-of-view, more research groups have started to work on development of implantable devices powered by ultrasonic harvesting. The main goal of these different research groups is to transfer the maximum power to the implants. Within STARDUST consortium, we are working hand-in-hand with others to develop not only a novel technology with maximum efficiency compared to the state-of-the-art, but also finding new techniques to ease the use of our envisioned technology. Such examples include synthesis of new biocompatible materials for implants, new MEMS techniques for transducers and receivers, discovery of new opsins with higher sensitivity to the emitted light and finding new targets related to Parkinson's Disease.

In summary the main expected impacts of STARDUST are as follow:
a. To develop a novel neural interface technology that will allow the creation of artificial physiological feedback loops, with great potential for disease treatment, dissection of neural systems, cell control and management, not only for restorative but also functional enhancement approaches.
b. The ability to control cell activity through a miniaturized, untethered device opens up enormous unprecedented possibilities for clinical management with substantial impact for neuroprosthetics, treatment of neurodegenerative and psychiatric disorders, probing neural circuits, neural function enhancement, effective control of epileptic seizures, development of retinal prostheses and reprogramming of cell activity to reverse cancerous tumour growth.
c. STARDUST is flexible and can target different brain areas, representing an important step for making optogenetics a tool more suitable for human trials. This can change the course of clinical neuroscience.
d. The technology developed in STARDUST can impact other fields such as Lab-on-Chip technology for future healthcare by biosensor add-on to the STARDUST platform for enormous application. These potentials will be studied as a future roadmap for STARDUST.
e. The technology can potentially have a huge effect on the psychiatric health care and on the European pharma industry and medical device industry. All these will also deliver remarkable, transformable impacts on the society, too.