Periodic Reporting for period 2 - STARDUST (in vivo optogeneticS, elecTrophysiology and phArmacology with an ultRasonically-powered DUST for Parkinson's Disease)
Reporting period: 2018-10-01 to 2020-03-31
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 the brain affected by Parkinson's Disease and effectively responding to optogenetics techniques, development of new opsins increasing the sensitivity of neurons to the light and finally a light-enabled drug-delivery to the target.
Within optogenetics for Parkinson’s disease the following progress has been made:
1. Validation of the External Globus Pallidus (GPe) optogenetic stimulation to alleviate motor deficits in a mouse model of Parkinson’s disease.
2. We have produced the behavioral readouts to assess our model of PD in rodents and non-human primates, by unilateral lesions of the nigrostriatal pathway with the neurotoxin 6-OHDA.
3. We have determined the optimal conditions to efficiently reverse the motor deficits produced by 6-OHDA lesions without altering baseline motor activity of control animals (nonlesioned).
4. We have shown that restricting photostimulation to a selective GPe neuronal subpopulation (parvalbumin neurons) produces comparable antiparkinsonian action in the mice PD model.
5. Identification of the motor cortical area to implant and test the basic Dust.
6. We have characterized the effects of optogenetic stimulation of the secondary motor cortical area (M2) on discrete forelimb movements and circling behavior in control mice. This will allow testing the first prototypes of basic dust which will be placed within the M2 motor cortex.
7. We have selected from our colony, by age, all the six subjects to be used in the project, and performed successfully the habituation and training protocols for self-positioning of the animals on the primate chair;
8. We have determined the baseline of motor performances of all subjects in tasks for fine and gross motor coordination, motor learning patterns and handedness through behavioral tasks;
9. We performed essays for Parkinsonism induction in 2 animals to decide the best sites for 6-OHDA injection together with dosage, followed by regular clinical evaluations through the adapted UPDRS protocol for primates. However, due to the spontaneous recovery of the symptoms, these protocols need to be revised;
10 We proceeded the acquisition of the constructs for optogenetic manipulations and designed a pilot test for the determination of their viability in mice before submitting the NHPs to surgical intervention. The pilot project is under evaluation through the Ethics Committee and will be conducted as soon as the permission will be granted.
Within Opsin Engineering the following progress has been made.
11. Na conducting ChR with red light sensitivity (Chrimson-S)
12. Chrimson with even further red-shifted absorption (Chrimson-SA, lmax= 608 nm)
13. Chloride selective ChRs (ACRS) with red-shifted absorption
14. a ChR with improved K-selectivity is in progress
From the drug-delivery point-of-view, the following progress has been made:
15. Developing a new drug delivery system (DDS) which can be miniaturized.
16. The DDS is compatible with local delivery for sustained treatment.
17. The DDS can be triggered to obtain the desired dosing.
18. The DDS has been shown to function with key drugs for integration in the Stardust project.
Within hardware design and miniaturization, the following progress has been made.
19. Design, fabrication, and testing of different integrated chips for LED driving, power management and drug deliver
20. UPIB design to power implantable dusts
21. Multiple MEMS transducers (MRUT and SMRUT) for powering dusts at different depths and directivities
22. Communication and recording circuitries for the advanced dust
23. Testing the dusts (two versions) in a water tank after covering them with PDMS
24. Demonstrated high-efficiency micro-LEDs (>33 % wall-plug efficiency) delivering sufficient power density for optogenetic applications at low (~1mA) currents.
25. Developed and demonstrated an integration strategy for ultrasonically powered light delivery dusts with volume <<1mm3.
26. Developing a strategy for compact integration of different colour LEDs with rectifier
27 A setup for poling of the biocompatible piezoelectric material
28. An autoclave synthesis route for pure KN and NN has been designed.
29. The obtained synthesized KNN has been characterized structurally using X-ray diffraction and electrically from measurements of polarization, strain, permittivity and d33 as a function of the electric field.
30. A Nb-slurry, h-Nb2O5, t-Nb2O5 and mixed Nb2O5 polymorph Nb-precursors have been tested in flow and autoclave synthesis for their ability to produce KN, NN, and KNN.
31 Methods for mechanical micro processing of the piezoelectric ceramic have been tested.
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 tumor 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 applications. 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 society, too.