Periodic Reporting for period 3 - Living Bionics (Living bioelectronics: Bridging the interface between devices and tissues) Reporting period: 2021-05-01 to 2022-10-31 Summary of the context and overall objectives of the project Recent advances in biomedical engineering have made possible the development of medical devices that interface directly with the nervous system to provide therapeutic treatment for various conditions, such as cochlear implants and bionic eyes for hearing- and visually-impaired people, or deep brain stimulation for Parkinson’s disease. However, the electrodes in these invasive devices used to stimulate or record the nervous system are made of stiff, inorganic materials like metals. The body recognizes these as foreign objects and attempts to protect itself from the implant by inducing an inflammatory response. Immune cells create a capsule, called a glial scar, around the electrode to isolate it and neural cells move away from the area. Consequently, higher, unsafe currents are needed to activate the nervous system and produce a therapeutic response, and the device may fail in the long-term.In order to create a neural implant that is truly integrated by the body rather than tolerated, softer, organic materials are needed at the interface with the nervous system. The Living Bionics project aims to combine concepts from tissue engineering and regenerative medicine together with bionic device technologies to develop living bioelectronics: layered electrodes incorporating living cells encapsulated within a soft hydrogel to interface with the nervous system without eliciting a strong adverse immune reaction. The objectives of this project include:- Engineering a hydrogel that can support the growth of a neural network within it,- Understanding the effect of biological, electrical, and environmental cues on the cells and their capacity to create connections,- Implanting the resulting device in mice to show viable connections between the cells within the device and the host nervous tissue.The Living Bionics project will be a ground-breaking step towards safer, truly integrated neural implants, paving the way for breakthrough therapeutic treatments for many widespread neural conditions. 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 half of the project, the team focused on understanding the impact of hydrogel composition on neural cell survival and modifying the material to promote neuronal growth. They used a synthetic hydrogel made of poly(vinyl alcohol) (PVA) as the base material and incorporated natural proteins like gelatine to enhance cell growth. Through further research, the team discovered that astrocytes, which are supportive cells that aid in the survival and growth of neurons, played a crucial role in neural network development and had to be encapsulated in the hydrogel alongside neurons to produce functional neural networks. As a result the team developed a novel material, PVA-Norbornene-gelatine (PVA-NB-GEL), and characterised its mechanical and electrical properties. In the second phase of the project, it was demonstrated that this hydrogel can support the growth of neurons and astrocytes encapsulated within it, and that these encapsulated cells can form functional connections with explanted brain tissue. 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) This work has identified the importance of considering the mechanical and topographical properties of hydrogels used for 3D culture of cells when developing a hydrogel for cell encapsulation. Addition of biological molecules is not sufficient for cell survival, and a delicate balance of biological, mechanical, and topographical cues, together with the presence of crucial accessory cells, is needed to grow functional neural networks throughout a synthetic hydrogel. The in-depth study of cell response, not only of behaviour but also looking at gene and protein regulation, is critical to take decisions on how the material properties must be modified to support neural cell growth. Based on these findings, the team designed and characterised a novel synthetic hydrogel and demonstrated that encapsulated neural cells can grow within it and develop active synapses with brain slices placed on top of the gel.The project will now focus on producing the full layered device for implantation in mice where the functionality of connections between the encapsulated cells in the hydrogel and the neural tissue of the host will be investigated, along with chronic response to the device. Neuronal connections within a PVA-SG hydrogel
