Periodic Reporting for period 3 - IntegraBrain (Integrated Implant Technology for Multi-modal Brain Interfaces) Reporting period: 2021-04-01 to 2022-09-30 Summary of the context and overall objectives of the project Neuroprosthetic technologies aim to restore functions of the nervous system affected by injury or disease. They are often implantable electronic devices that establish communication between brain and machine using small electrical impulses. Future implants are likely to be multi-modal, i.e. additionally enabled in the biochemical, optical, thermal and mechanical domains and seamlessly integrated in the soft tissues of the nervous system. Technologically this is challenging to achieve. For example, neural electrode arrays available today are rarely customisable in a way that allows the clinician to adapt them to the specific anatomy of a patient, the mechanical environment or the multiple modalities of information flow in neural tissue. This may result in sub-optimal biointegration and limit the effectiveness and possibilities for personalised therapies.Bioelectronic implants can be applied in soft tissue organs, especially in the nervous system, where injury or degeneration can result 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.A key objective of the action is the development of additive manufacture (3D printing) methods for rapid prototyping of implants that are mechanically soft, multi-modal and customised. We will validate the capacities of the technology in vivo. In the central nervous system, we will demonstrate multi-modal neuromodulation in a pre-clinical model of epilepsy. In the periphery, we will demonstrate soft implants tailored to specific niches of the neuromuscular system. Overall, with the IntegraBrain project, we hope to catalyse pre-clinical development of implantable human-machine interfaces. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far In the first three years of the action we focused on adapting additive manufacturing technologies for the prototyping of sensors and actuator arrays for applications in bioelectronics. This involved the development of a palette of functional inks that support electrical optical and microfluidic functionalities. The inks are based on soft materials such as silicone composites and hydrogels that exhibit mechanical properties similar to those of the soft tissues/cells we are aiming to interface. One useful type of composite ink was developed by combining platinum microparticles with silicone elastomer which is used to print biocompatible and stretchable electrodes. They have electrical properties that make them 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 inside the body of skeletal muscles (in preclinical models) [1]. Our printing approaches enable the fabrication of mesoscopic features (sub-millimetre dimensions) which is sufficient for many bioelectronics applications including some cell culture applications. To this end, we demonstrated an array containing electrodes, optical fibres and microfluidics for pacing and recording stem-cell derived cardiomyocytes [2]. The hydrogel class of materials is also promising (in the context of bioelectronics), because these materials are ultra-soft, hydrated and can contain bioactive molecules that may improve biointegration of the device. We demonstrated several approaches to render hydrogels electrically conductive by incorporating conductive polymers as interpenetrating networks [3]. Further, we developed methods to print the hydrogels using electro-assisted gelation. For example we demonstrated alginate hydrogels containing the conductive polymer poly(3,4-ethylenedioxythiophene) [4,5].Besides implants and cell culture, we realised our printed stretchable electronics can be applied in wearable sensor devices. We used commercially available cotton gloves onto which we directly printed stretch, pressure and electromyography sensors. When the glove is worn, it is able to pick up various indicators of hand function/dexterity/strength. The gloves are customisable, inexpensive and simple in design (Figure 1) [6]. We have therefore considered them for use in diagnostics or monitoring of progressive neurological conditions. Currently the team is collaborating with a clinical partner at the host institution to develop user friendly wearable sensors that patients can use at home.During the last reporting period we were active in integrating the novel materials into devices and systems. The objective is to demonstrate a multimodal and closed loop implantable system [7]. We have integrated and bench-tested a system consisting of a (passive) implantable unit linked with an (active) external driver. The system is capable of delivering focal cooling to an area approximately 2x2 mm2 in a fast and controlled manner. The significance is that rapid, deep, prolonged and spatially confined cooling can now be implemented on the brain surface. This is a key capacity needed for starting the last work package where focal brain cooling will be applied for epileptic seizure suppression (in a preclinical model). In addition to the cooling function, the system is equipped with a microfluidic channel for drug delivery and electrodes for collecting surface field potentials. These capacities allow the implant to deliver multimodal neuromodulation. The action of the driver is coordinated by a microcontroller (e.g. control loops for cooling stabilisation). The controller has enough computational power for the implementation of autonomous decision making. To this end we have designed a machine learning algorithm (a classifier) that is capable of recognising seizure activity and switching on the cooling program. Although the system is not yet functioning autonomously, it is expected that this will be implemented during the next reporting period. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The materials and fabrication technologies we developed enable rapid customisation and tailoring of bioelectronic devices that communicate with living systems. The wide range of materials we can process enables interfacing modes that go beyond electrical stimulation/recording and include thermal, optical, and pharmacological modulation of the biological system. The use of soft materials better matched the mechanics/softness of cells and tissues, which is challenging to achieve with standard rigid materials used in electronics.By the end of the action, we will achieve an integrated and autonomous implantable system that will be capable of multimodal neuromodulation in vivo. In a preclinical model of epilepsy, we will demonstrate seizure suppression. The system will autonomously detect the emergence of a seizure and will deploy a combination of focal cooling and drug release or stop its spread. By the end of the action, we will have demonstrated the full design cycle for a proof-of-concept multimodal neuromodulation system. This starts with the materials and technologies to fabricate the implant hardware, proceeds through system integration and programming and will conclude with a demonstration in a rodent disease model. We hope our work will catalyse further interest and clinical translation of technology for bioelectronic medicine Related documents cover_art_no_writing.jpg Printed sensors for monitoring hand function.png
