Hydrogel Neural Interfaces—A Robust and Modular Toolbox for Neuroscience

The most common electrical and optical interrogation modalities in neuroscience are more than five orders of magnitude stiffer than the mammalian brain^1-2. Creating bioelectronics that are both capable of chronic interrogation of neural circuits and soft enough to prevent excessive tissue scarring remains an active area of research. In this work, we present a new modular strategy to create soft bioelectronics capable of electrical, optical, and chemical interrogation of the murine brain utilizing a hydrogel integration approach.<br/>Thermal drawing has been leveraged by us and others to obtain fiber-based neural interfaces at &gt;100 m length scales³. Despite these advantages, key challenges remain that limit the utility of thermal drawing for neuroscience, including 1) co-drawn materials’ compatibility constraints and 2) labor-intensive connectorization of each modality to backend hardware. Additionally, in these polymer-based neural interfaces, passive cladding comprises a significant fraction of the device and serves only insulation or structural roles. To overcome these disadvantages, our lab recently reported a modular and robust approach to creating multi-functional neural devices using a solvent evaporation or entrapment-driven (SEED) integration process⁴.<br/>In this process, a copolymer containing hydrophilic poly(ethylene glycol) covalently linked to hydrophobic poly(urethane) (PU-PEG) is used to combine multiple electrical, optical and microfluidic modalities together. When exposed to aqueous solutions, this copolymer will also spontaneously form a physical hydrogel. This property expands the functionality of the cladding material from not only serving as the integration matrix, but also allowing it to be a depot for small molecule drugs and nanoparticles. We employ these neural interfaces for chronic, simultaneous optogenetics and electrophysiology in mice and demonstrate that the microfluidic modality within multifunctional neural probes can be used to deliver high-viability cellular cargo. Finally, we synthesized a custom nanoparticle-forming block co-polymer and demonstrate that embedding this type of material within the hydrogel cladding of the neural interface enables delivery of poorly water-soluble small molecule drugs <i>in vitro</i> and <i>in vivo</i>. Our SEED integration approach overcomes the limitations of thermal drawing and we show here that it can be used to create a new class of multifunctional neural interfaces.<br/>¹Tabet et al, <i>Adv Healthcare Mater </i>(2019). ²Frank et al, <i>Nat Biotech</i> (2019). ³Canales et al, <i>Nat Biotech </i>(2015). ⁴Tabet et al, <i>ACS Central Science</i> (2021).