Periodic Reporting for period 2 - OPTEL-MED (Optoelectronic medicine - nerve cell regulation with light)
Période du rapport: 2022-07-01 au 2023-12-31
Bioelectronic medicine today is growing in leaps and bounds, with ambitious new technologies entering the clinic and already changing the lives of more than a million patients worldwide. Materials scientists are called to craft biomedical devices that are smaller, smarter, and less invasive. We propose to create implantable photovoltaic devices which can wirelessly stimulate the nervous system and enable a new type of minimally invasive optoelectronic medicine. To achieve this, we will use biocompatible organic semiconductors which can efficiently absorb light in the near infrared part of the spectrum, where biological tissues are transparent. By micropatterning stimulation pixels on ultrathin conformable substrates, we will create optoelectronic nerve cuff electrodes which will be orders-of-magnitude thinner than what is used clinically today. We will explore deeply the physics of this new type of electrolytic photovoltaic stimulator. The designs will be optimized to operate with safe light intensities delivered from outside of the body. Benchmarking the targeting of precise optoelectronic stimulation will be done in ex vivo and in vivo nerve models.
The project is driven by answering milestone scientific questions in device physics, photoelectrochemistry, and electrophysiology, however the project is simultaneously designed to tackle an important clinical application: vagus nerve stimulation (VNS). We will apply our findings to implement an implantable stimulator actuated transcutaneously by portable light sources. We will develop standard operating procedures for chronic optoelectronic VNS in rodent animal models, paving the way for future clinical trials. The application to VNS is motivated by the fact that at present the vagus nerve is the peripheral nerve with that largest number of patients receiving bioelectronic therapy. It is important to note that the science and technology developed in OPTEL-MED is not limited to the vagus nerve only, and can be deployed to other peripheral nerve targets. Success with vagus nerve models is expected to stimulate cross-over into other applications.
The project is driven by answering milestone scientific questions in device physics, photoelectrochemistry, and electrophysiology, however the project is simultaneously designed to tackle an important clinical application: vagus nerve stimulation (VNS). We will apply our findings to implement an implantable stimulator actuated transcutaneously by portable light sources. We will develop standard operating procedures for chronic optoelectronic VNS in rodent animal models, paving the way for future clinical trials. The application to VNS is motivated by the fact that at present the vagus nerve is the peripheral nerve with that largest number of patients receiving bioelectronic therapy. It is important to note that the science and technology developed in OPTEL-MED is not limited to the vagus nerve only, and can be deployed to other peripheral nerve targets. Success with vagus nerve models is expected to stimulate cross-over into other applications.
Using tissue-penetrating deep red light to electrically stimulate nerves and brain tissue is the main goal of the project. The critical result has been successful demonstration of this concept on the sciatic nerve in a rat model. We developed a minimalistic ultrathin implant based on biocompatible parylene plastic. This implant can be easily surgically implanted and immobilized around the sciatic nerve. The implant features a single photocapacitor pixel. This photocapacitor converts an impulse of red light into a capacitive pulse of current, which in turn is transmitted into the nerve and generates action potentials. Before the project started, we had in vitro verificaiton that this concept of photocapacitive stimulation worked. The OPTEL-MED project aimed to translate that preliminary finding into something that can be implanted. Therefore, the photocapacitor must be on a flexible compliant substrate, and must be efficient enough to generate charge using the limited light that can be safely transmitted through tissue. We proved that this is in fact possible. The sciatic nerve was stimulated successfully both acutely and chronically for a hundred days. We evaluated safety of the implant, and found no detriment to the nerve. We were able to reliably deliver stimulation to the nerve through a depth of tissue around 10 mm. We had to overcome materials science challenges of getting the photocapacitor device onto a compliant substrate. Our prototype (Nat. Biomed. Eng. 6, 741–753 (2022).) shows that this is indeed possible. There are many areas of improvement to work on which were outlined in the project plan: increasing charge-generation efficiency, proving long-term safety and stability, and form factors to be appropriate for different targets.
We had to develop different varieties of photocapacitors for VNS in mice. The first tests were challenging and not successful, and smaller different nerve interfaces had to be developed. In the end, we have been successful in acute VNS, and our findings are under review. We are now moving towards chronic experiments.
Aside from peripheral nerves, we proposed to explore photocapacitors for stimulation of the brain. We utilized photocapacitors as wireless cortical stimulation electrodes, and demonstrated that they can be actuated through the skull: J. Neural Eng. 18, 066016 (2021).
In paralel, we have made progress with the concepts for charge delivery which were anticipated in the proposal. One route is structuring of photocapacitors into micropyramid architectures: Nanotechnology 33, 245302 (2022). We continue with other routes of charge concentration by connecting charge generation elements to microelectrodes, which provide more spatial control of stimulation. A related aim is to create structures surfaces which can be better interfaced and immobilized to tissue. To this end, we have demonstrated the use of 3D foldable conductors: Adv. Electron. Mater. 2001236, (2021).
One of the primary aims of the project was more fundamental exploration of photoelectrical stimulation, mechanistically at the level of cell interfaces. We have made significant progress in two of the planned areas: studying reactive oxygen species formation at electrodes; and understanding of the mechanisms of capacitive coupling which govern the efficiency of stimulation.
In the topic of oxygen electrochemistry, we have conducted a detailed survey of many electrode materials and established a novel method of directly probing oxygen and hydrogen peroxide concentrations. We found, to our surprise, that established neurostimulation protocols produce very significant changes in local oxygen chemistry. We hypothesized that some conditions cause irreversible oxygen chemistry, but our findings exceeded our hypothesis: J. Neural Eng. 19, 036045 (2022). and have received a lot of feedback from the bioelectronics community due to this publication. As the findings are both surprising and generally applicable to all neurostimulation protocols (not just the photoelectrical work we concentrate on in OPTEL-MED).
Another important aspect of oxygen electrochemistry we studied at the level of peroxide-sensitive ion channels. We developed a unique tool for delivering "on demand" peroxide which was used to modify the behavior of potassium ion channels, which has important (electro)physiological consequences Adv. Sci. 9, 2103132 (2022). This work also surpassed our expectations in terms of results and response from the community, and we are actively pursuing this research direction.
We recently published a detailed study of understanding photocapacitive coupling with cells: doi:10.1002/admt.202101159. This is a fundamental and important milestone which guides development of photocapacitor technology.
We had to develop different varieties of photocapacitors for VNS in mice. The first tests were challenging and not successful, and smaller different nerve interfaces had to be developed. In the end, we have been successful in acute VNS, and our findings are under review. We are now moving towards chronic experiments.
Aside from peripheral nerves, we proposed to explore photocapacitors for stimulation of the brain. We utilized photocapacitors as wireless cortical stimulation electrodes, and demonstrated that they can be actuated through the skull: J. Neural Eng. 18, 066016 (2021).
In paralel, we have made progress with the concepts for charge delivery which were anticipated in the proposal. One route is structuring of photocapacitors into micropyramid architectures: Nanotechnology 33, 245302 (2022). We continue with other routes of charge concentration by connecting charge generation elements to microelectrodes, which provide more spatial control of stimulation. A related aim is to create structures surfaces which can be better interfaced and immobilized to tissue. To this end, we have demonstrated the use of 3D foldable conductors: Adv. Electron. Mater. 2001236, (2021).
One of the primary aims of the project was more fundamental exploration of photoelectrical stimulation, mechanistically at the level of cell interfaces. We have made significant progress in two of the planned areas: studying reactive oxygen species formation at electrodes; and understanding of the mechanisms of capacitive coupling which govern the efficiency of stimulation.
In the topic of oxygen electrochemistry, we have conducted a detailed survey of many electrode materials and established a novel method of directly probing oxygen and hydrogen peroxide concentrations. We found, to our surprise, that established neurostimulation protocols produce very significant changes in local oxygen chemistry. We hypothesized that some conditions cause irreversible oxygen chemistry, but our findings exceeded our hypothesis: J. Neural Eng. 19, 036045 (2022). and have received a lot of feedback from the bioelectronics community due to this publication. As the findings are both surprising and generally applicable to all neurostimulation protocols (not just the photoelectrical work we concentrate on in OPTEL-MED).
Another important aspect of oxygen electrochemistry we studied at the level of peroxide-sensitive ion channels. We developed a unique tool for delivering "on demand" peroxide which was used to modify the behavior of potassium ion channels, which has important (electro)physiological consequences Adv. Sci. 9, 2103132 (2022). This work also surpassed our expectations in terms of results and response from the community, and we are actively pursuing this research direction.
We recently published a detailed study of understanding photocapacitive coupling with cells: doi:10.1002/admt.202101159. This is a fundamental and important milestone which guides development of photocapacitor technology.
We have elaborated an unexpected new development that achieves the goals of less-invasive peripheral nerve stimulation: temporal interference stimulation. This technique is noninvasive as it uses on-skin electrodes. Multiple electrode pairs emitting high frequency fields cause a point of constructive interference which can be tuned to be at the position of a nerve target. This nerve is then stimulated at the offset, or beat frequency, between the high-frequency carriers. We have tested this successfully on the sciatic nerve. Adv. Healthc. Mater. 2200075, 2200075 (2022).