Periodic Reporting for period 3 - STARDUST (in vivo optogeneticS, elecTrophysiology and phArmacology with an ultRasonically-powered DUST for Parkinson's Disease)
Período documentado: 2020-04-01 hasta 2022-09-30
The main goal of STARDUST project is to realize a novel wireless implantable micro-scale device enabling in-vivo optogenetics, 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 research 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).
Opsin Engineering:
At UBER (Humboldt-University of Berlin), we have developed a set of molecular optogenetic tools for excitatory or inhibitory application. We optimized these channelrhodopsins to be selective for anions or cations and to function with diverse channel kinetics at higher wavelengths. Further, we have been able to discover and characterize the channelrhodopsin with the highest selectivity for K+ available to date. Among others, we demonstrated its superiority for action potential suppression in mouse hippocampal neurons. Thus new K-selective ChR named WiChR should improve the development STARDUST technology for low-invasive treatment of PD patients.
Neuroscience:
By photoactivation of GPe neurons in a mouse model of PD, we could alleviate a wide range of abnormal motor behaviours (ipsilateral circling, bradykinesia and akinesia) reminiscent of Parkinson’s symptoms in patients. We further demonstrated that similar beneficial effects can be achieved by selectively targeting a subpopulation of GPe GABA neurons expressing a specific marker (parvalbumin). These results highlight the importance of GPe in the pathophysiology of PD and show that selectively targeting PV-expressing neurons with optogenetic, unlike electrical deep brain stimulation, is a promising therapy for restoring motor function.
Drug Delivery
We have developed a light triggered drug delivery system (DDS) based on polymers containing photoswitchable spiropyran (SP, hydrophobic) group. When the polymer is exposed to UV light it isomerizes into its merocyanine (MC, hydrophilic) form, the system returns to the SP form when exposed to green light. Drug release is a result of the intermolecular interactions between drug, polymer and solvent. In order to improve the biocompatibility of the DUSTs and prevent foreign body reactions (FBR), we developed and optimized biomimicking polymers, that mimic the chemical composition of the human endothelial cell membrane. Brain-adhesive top-coating: A bio-adhesive chitosan coating has been developed and the bio-adhesiveness has been documented experimentally in terms of peak removal force and total work of removal.
Electronics and photonics:
At UCC/Tyndall we have developed blue-emitting microLEDs with very small dimensions (130 mm x 330 mm x130 mm) and have demonstrated their integration with custom electronic circuits from Aarhus. The LEDs have very high conversion efficiency between electrical power and optical power and, as such, represent the state of the art. The devices have been integrated with piezoelectric elements into total volume < 0.33 mm3 and the devices have been demonstrated functioning in mouse brain tissue at CNRS remotely powered by a compact ultrasound generator from Aarhus. Integrated dual LED configurations (blue + red as well as UV+ blue), matching the electronic drive chips, were developed to enable activation and inhibition of different opsins developed at Humboldt. The integrated devices had similar sizes to the individual ones due to the use of transfer printing, where the thickness of the devices is reduced to 5mm. Successful demonstration of the devices were shown. Devices have been supplied to Fraunhofer for integration with their flexible polymer backplane technology. We have developed custom UV microLEDs in order to match the absorption spectrum of Biomodics spiropyran drug delivery polymer. These devices have similar dimensions to the blue devices and also are very efficient.
At AU, we have developed several chips including Low-power chips for harvesting energy from ultrasonic waves and drive LEDs for optogenetics, chip for driving two LEDs for dual optogenetics, a chip for neural recording, communication, and driving LEDs for optogenetics and drug delivery. This is ready to be integrated and can be used for any implant. The chip has been tested successfully.
We have also developed transducer driver using discrete components (used for in vitro and in vivo test and can drive the PZT well), an integrated version of the UPIB (version 1 to prove that we have the drivability of the transducer to very high voltages), and finally an advanced UPIB working in different ranges of frequencies up to 5MHz. These UPIBs can be used for many ultrasonic applications
Furthermore, AU has been heavily involved in material development as well as new MEMS-based devices, including new material called LKNN used instead of PZT opening a path to biocompatible US devices, and several MEMS-based devices used for beam steering to implantable devices at different depths and locations in the brain.
Integrated Device development:
Currently, we have three Dusts that are described several times during the project reviews and also in the reports. Since we were not able to do the in vivo test, then there is no clinical evidence as such. However, we, in total developed three Dust prototypes:
Basic Dust version 1 (Only for Optogenetics) with the dimension of 1x3x0.5 mm3 (PZT)
Basic Dust version 2 (Only for optogenetics) with the dimension of 0.5x0.7x0.9 mm3 (PZT)
Basic Dust Version 3 (only for optogenetics) with the same dimension of version 1 (Biocompatible LKNN)
It is worth mentioning that all the components for advanced dusts are ready and sent to Fraunhofer but no integration was done at Fraunhofer.
At UBER (Humboldt-University of Berlin), we have developed a set of molecular optogenetic tools for excitatory or inhibitory application. We optimized these channelrhodopsins to be selective for anions or cations and to function with diverse channel kinetics at higher wavelengths. Further, we have been able to discover and characterize the channelrhodopsin with the highest selectivity for K+ available to date. Among others, we demonstrated its superiority for action potential suppression in mouse hippocampal neurons. Thus new K-selective ChR named WiChR should improve the development STARDUST technology for low-invasive treatment of PD patients.
Neuroscience:
By photoactivation of GPe neurons in a mouse model of PD, we could alleviate a wide range of abnormal motor behaviours (ipsilateral circling, bradykinesia and akinesia) reminiscent of Parkinson’s symptoms in patients. We further demonstrated that similar beneficial effects can be achieved by selectively targeting a subpopulation of GPe GABA neurons expressing a specific marker (parvalbumin). These results highlight the importance of GPe in the pathophysiology of PD and show that selectively targeting PV-expressing neurons with optogenetic, unlike electrical deep brain stimulation, is a promising therapy for restoring motor function.
Drug Delivery
We have developed a light triggered drug delivery system (DDS) based on polymers containing photoswitchable spiropyran (SP, hydrophobic) group. When the polymer is exposed to UV light it isomerizes into its merocyanine (MC, hydrophilic) form, the system returns to the SP form when exposed to green light. Drug release is a result of the intermolecular interactions between drug, polymer and solvent. In order to improve the biocompatibility of the DUSTs and prevent foreign body reactions (FBR), we developed and optimized biomimicking polymers, that mimic the chemical composition of the human endothelial cell membrane. Brain-adhesive top-coating: A bio-adhesive chitosan coating has been developed and the bio-adhesiveness has been documented experimentally in terms of peak removal force and total work of removal.
Electronics and photonics:
At UCC/Tyndall we have developed blue-emitting microLEDs with very small dimensions (130 mm x 330 mm x130 mm) and have demonstrated their integration with custom electronic circuits from Aarhus. The LEDs have very high conversion efficiency between electrical power and optical power and, as such, represent the state of the art. The devices have been integrated with piezoelectric elements into total volume < 0.33 mm3 and the devices have been demonstrated functioning in mouse brain tissue at CNRS remotely powered by a compact ultrasound generator from Aarhus. Integrated dual LED configurations (blue + red as well as UV+ blue), matching the electronic drive chips, were developed to enable activation and inhibition of different opsins developed at Humboldt. The integrated devices had similar sizes to the individual ones due to the use of transfer printing, where the thickness of the devices is reduced to 5mm. Successful demonstration of the devices were shown. Devices have been supplied to Fraunhofer for integration with their flexible polymer backplane technology. We have developed custom UV microLEDs in order to match the absorption spectrum of Biomodics spiropyran drug delivery polymer. These devices have similar dimensions to the blue devices and also are very efficient.
At AU, we have developed several chips including Low-power chips for harvesting energy from ultrasonic waves and drive LEDs for optogenetics, chip for driving two LEDs for dual optogenetics, a chip for neural recording, communication, and driving LEDs for optogenetics and drug delivery. This is ready to be integrated and can be used for any implant. The chip has been tested successfully.
We have also developed transducer driver using discrete components (used for in vitro and in vivo test and can drive the PZT well), an integrated version of the UPIB (version 1 to prove that we have the drivability of the transducer to very high voltages), and finally an advanced UPIB working in different ranges of frequencies up to 5MHz. These UPIBs can be used for many ultrasonic applications
Furthermore, AU has been heavily involved in material development as well as new MEMS-based devices, including new material called LKNN used instead of PZT opening a path to biocompatible US devices, and several MEMS-based devices used for beam steering to implantable devices at different depths and locations in the brain.
Integrated Device development:
Currently, we have three Dusts that are described several times during the project reviews and also in the reports. Since we were not able to do the in vivo test, then there is no clinical evidence as such. However, we, in total developed three Dust prototypes:
Basic Dust version 1 (Only for Optogenetics) with the dimension of 1x3x0.5 mm3 (PZT)
Basic Dust version 2 (Only for optogenetics) with the dimension of 0.5x0.7x0.9 mm3 (PZT)
Basic Dust Version 3 (only for optogenetics) with the same dimension of version 1 (Biocompatible LKNN)
It is worth mentioning that all the components for advanced dusts are ready and sent to Fraunhofer but no integration was done at Fraunhofer.
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 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.
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.