Khalil Ramadi1 2 Michael Cima3 2 1

1, Harvard-MIT Health Sciences & Technology, Cambridge, Massachusetts, United States
2, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
3, Department of Materials Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

Brain pathologies often arise from the dysfunction of specific neural circuit nodes. Interrogation of these nodes is a primary goal of neuroscience research. Reliable targeting of these microstructures can be difficult, however. Nodes are often small (sub-mm) and irregularly shaped. Current approaches employ stereotactic mapping and rely on large (>300μm) guide cannulas to ensure minimal deflection of probes during insertion. Such techniques can result in extensive glial scarring. This can substantially modify the local microenvironment to be investigated and limit chronic viability of implants. This is especially the case for fluidic targeting and drug delivery. Acutely inserted needles used for drug microinfusions (100nl-2μl) are large (23-28G), causing insertion trauma and backflow of infusate.

We present a toolkit for manufacturing multimodal neural probes (termed Miniaturized Neural drug Delivery systems (MiNDs)) for use in both small and large animal models. Probes can be customized according to desired functionalities. Here we show in vivo functionality of MiNDs containing fluidic and electrical functionalities and an MRI-compatible MiNDs with 2 fluidic channels in a 200μm footprint. We also report the ability to independently insert and steer individual 60μm fibers of various materials, allowing access to multiple brain sites from a single burr hole. We characterize the mechanical insertion properties of different probe sizes and materials, elucidating the various advantages of each. The microinvasive footprint of the probes limits gliosis and enhances neural regeneration, allowing for chronic viability and functionality up to 1 year post-implantation.

High sensitivity MicroPET was used to characterize distinct infusion dynamics of nanoliter fluid infusions through chronic implants, emphasizing the ability to finely tune volume to target brain microstructures. We supported this by inducing volume-dependent behavior modulation in rodents with unilateral stimulation of GABA circuitry in the substantia nigra. These techniques are readily transferable to other laboratories seeking to develop custom neural probes for multimodal chronic neural interfacing. MiNDs is a powerful tool for the dissection of deep brain microstructures in small and large preclinical models.