Periodic Reporting for period 4 - IntegraBrain (Integrated Implant Technology for Multi-modal Brain Interfaces)
Reporting period: 2022-10-01 to 2024-06-30
Neuroprosthetic technologies restore functions of the nervous system affected by injury or disease. They are often implantable electronic devices that establish communication between brain and machine. Future implants are likely to be multi-modal (enabled in the biochemical, optical, thermal and mechanical domains) personalised and seamlessly integrated in tissues. Bioelectronic implants can be applied where injury or degeneration have resulted in chronic disability. They can become an alternative strategy for treating epilepsy, Parkinson’s disease, stroke, acute and chronic neurotrauma, where presently only systemic pharmacological or surgical approaches exist.
In the IntegraBrain project, additive fabrication combined with soft functional inks enabled us to demonstrate multimodal sensor-actuator-arrays. We printed arrays of electrodes, optical fibres and microfluidics enabling electrical recording, optogenetic stimulation and drug delivery in cell cultures. We demonstrated a highly integrated implant that is capable of delivering focal cooling, recording biopotentials and handling liquids in microfluidics, fabricated using additive fabrication (printing) and discrete electronic elements. In a third example we printed sensors on textile for detecting electromyographic signals from muscles, hand forces and joint angles. We tested the developed technologies in living systems ranging from cell cultures, a rat model of epilepsy (focal cooling for seizure suppression) to healthy human volunteers (sensorized glove). Overall, we demonstrated the great potential for additive fabrication and made significant progress towards the integration of multimodal systems for neuromodulation.
In the IntegraBrain project, additive fabrication combined with soft functional inks enabled us to demonstrate multimodal sensor-actuator-arrays. We printed arrays of electrodes, optical fibres and microfluidics enabling electrical recording, optogenetic stimulation and drug delivery in cell cultures. We demonstrated a highly integrated implant that is capable of delivering focal cooling, recording biopotentials and handling liquids in microfluidics, fabricated using additive fabrication (printing) and discrete electronic elements. In a third example we printed sensors on textile for detecting electromyographic signals from muscles, hand forces and joint angles. We tested the developed technologies in living systems ranging from cell cultures, a rat model of epilepsy (focal cooling for seizure suppression) to healthy human volunteers (sensorized glove). Overall, we demonstrated the great potential for additive fabrication and made significant progress towards the integration of multimodal systems for neuromodulation.
We explored additive fabrication technologies for the prototyping of sensors and actuator arrays for applications in bioelectronics. This involved the development of a palette of functional inks supporting electrical optical and microfluidic functionalities (1). The inks are based on soft materials such as silicone composites and hydrogels that exhibit mechanical properties similar to those of soft tissues or cells. Printed electrodes were suitable for recording or stimulation from various niches of the neuromuscular system in vivo such as the surface of the brain, spinal cord or from skeletal muscles which we demonstrated in preclinical models (Fig. 1 & 2) (2, 3). In a demonstration of a multimodal interface we fabricated electrodes, optical fibres and microfluidics for pacing and recording stem-cell derived cardiomyocytes (Fig. 3) (4). In the context of bioelectronics, another promising class of materials are electrically conductive hydrogels (5). They are ultra-soft, hydrated and can contain bioactive molecules that may improve biointegration. We demonstrated several approaches to render hydrogels electrically conductive by incorporating conductive polymers as interpenetrating networks (6). Further, we developed methods to print the hydrogels using electro-assisted gelation (Fig. 4) (7, 8). For example, we demonstrated alginate hydrogels containing the conductive polymer poly(3,4-ethylenedioxythiophene) (9, 10).
Besides implants and cell culture, we realised printed stretchable electronics can be applied in wearable sensor devices. We used cotton gloves onto which we directly printed stretch, pressure and electromyography sensors. The sensor gloves are customisable, inexpensive and simple to fabricate (Fig. 5) (11). We have considered them for use in diagnostics or monitoring of progressive neurological conditions (ongoing collaboration with a clinician).
A key objective of the IntegraBrain project was to engineer implantable multimodal systems for neuromodulation. In clinical systems today, neuromodulation is typically restricted to electrical pulses. Here we explored focal thermal cooling as an alternative. We used a hybrid fabrication approach that combines our printing approaches (and inks) with assembly of discrete electronic components. We integrated a miniature thermoelectric cooler (Peltier element), recording electrodes and microfluidics in a compact device (9 x 9 x 2.5 mm3). We then developed an auxiliary driver (size of a small lunchbox) to underpin the functionalities of the implant by supplying power, thermal management and acquisition of neural recordings. The auxiliary driver links to the implant via an umbilical connection. Although this does not reach the miniaturisation needed for an implantable system, considering the complexity of electrical, thermal and fluidic functions, we achieved a major step in integration. The focal cooling system was validated in an acute rodent model of focal cortical epilepsy where brain activity reminiscent of that seen in affected humans was generated. The emergence and progression of seizures were easily observed in neural recordings. Upon activation focal cooling, we decrease the cortical surface temperature in a controlled way (to approx. 18°C). We observed reduced power in the theta and alpha bands. This was accompanied by a marked reduction in overall amplitude of neural activity. This validates the promise of multimodal neuromodulation in future neuroprosthetic and electroceuticals based therapies.
1. https://doi.org/10.1002/admt.201800659
2. https://doi.org/10.1038/s41551-020-00615-7
3. https://doi.org/10.3389/fbioe.2021.770274
4. https://doi.org /10.1038/s41528-020-0075-z
5. https://doi.org/10.1002/pol.20230111
6. https://doi.org/10.1002/smll.201901406
7. https://doi.org /10.20517/ss.2022.25
8. https://doi.org/10.1002/mame.202300263
9. https://doi.org/10.1002/marc.202200557
10. https://doi.org /10.1038/s41467-022-29037-6
11. https://doi.org /10.1088/2058-8585/ac7dd1
Besides implants and cell culture, we realised printed stretchable electronics can be applied in wearable sensor devices. We used cotton gloves onto which we directly printed stretch, pressure and electromyography sensors. The sensor gloves are customisable, inexpensive and simple to fabricate (Fig. 5) (11). We have considered them for use in diagnostics or monitoring of progressive neurological conditions (ongoing collaboration with a clinician).
A key objective of the IntegraBrain project was to engineer implantable multimodal systems for neuromodulation. In clinical systems today, neuromodulation is typically restricted to electrical pulses. Here we explored focal thermal cooling as an alternative. We used a hybrid fabrication approach that combines our printing approaches (and inks) with assembly of discrete electronic components. We integrated a miniature thermoelectric cooler (Peltier element), recording electrodes and microfluidics in a compact device (9 x 9 x 2.5 mm3). We then developed an auxiliary driver (size of a small lunchbox) to underpin the functionalities of the implant by supplying power, thermal management and acquisition of neural recordings. The auxiliary driver links to the implant via an umbilical connection. Although this does not reach the miniaturisation needed for an implantable system, considering the complexity of electrical, thermal and fluidic functions, we achieved a major step in integration. The focal cooling system was validated in an acute rodent model of focal cortical epilepsy where brain activity reminiscent of that seen in affected humans was generated. The emergence and progression of seizures were easily observed in neural recordings. Upon activation focal cooling, we decrease the cortical surface temperature in a controlled way (to approx. 18°C). We observed reduced power in the theta and alpha bands. This was accompanied by a marked reduction in overall amplitude of neural activity. This validates the promise of multimodal neuromodulation in future neuroprosthetic and electroceuticals based therapies.
1. https://doi.org/10.1002/admt.201800659
2. https://doi.org/10.1038/s41551-020-00615-7
3. https://doi.org/10.3389/fbioe.2021.770274
4. https://doi.org /10.1038/s41528-020-0075-z
5. https://doi.org/10.1002/pol.20230111
6. https://doi.org/10.1002/smll.201901406
7. https://doi.org /10.20517/ss.2022.25
8. https://doi.org/10.1002/mame.202300263
9. https://doi.org/10.1002/marc.202200557
10. https://doi.org /10.1038/s41467-022-29037-6
11. https://doi.org /10.1088/2058-8585/ac7dd1
The materials and fabrication technologies we developed enable rapid customisation of bioelectronic devices. The wide range of materials we can process enables interfacing modes beyond electrical stimulation/recording and include thermal, optical, and pharmacological modulation of the biological system. Soft materials better matched the biomechanics of cells and tissues, which is challenging to achieve with standard rigid materials used in electronics.
We demonstrated unprecedented level of integration of electrical, thermal, microfluidic and optical elements for devices with multimodal sensing and actuation capability. This was made possible by novel 3D printing. functional inks and discrete electronic components. We implemented the focal cooling modality exceeding the state-of-the-art in terms of speed and precision of cooling.
We made a pioneering demonstration of customizable, soft and implantable electrode arrays. This is significant because up to now, the only way to produce such devices involved complex, multi-step processes that requiring specialized fabrication equipment (photolithographic processes).
The project advanced the field of biomaterials with applications in bioelectronics. We developed electrically conductive hydrogels which demonstrated tissue-like softness, stretchability and high electrical conductivity. We developed novel ways to assemble and pattern hydrogels using printing combined with electrochemical reactions.
Our results demonstrate that innovations in bioelectronics can be driven by novel high-performance, biologically compatible electronic materials, non-standard fabrication technologies and interfacing modalities.
We demonstrated unprecedented level of integration of electrical, thermal, microfluidic and optical elements for devices with multimodal sensing and actuation capability. This was made possible by novel 3D printing. functional inks and discrete electronic components. We implemented the focal cooling modality exceeding the state-of-the-art in terms of speed and precision of cooling.
We made a pioneering demonstration of customizable, soft and implantable electrode arrays. This is significant because up to now, the only way to produce such devices involved complex, multi-step processes that requiring specialized fabrication equipment (photolithographic processes).
The project advanced the field of biomaterials with applications in bioelectronics. We developed electrically conductive hydrogels which demonstrated tissue-like softness, stretchability and high electrical conductivity. We developed novel ways to assemble and pattern hydrogels using printing combined with electrochemical reactions.
Our results demonstrate that innovations in bioelectronics can be driven by novel high-performance, biologically compatible electronic materials, non-standard fabrication technologies and interfacing modalities.