Miniaturized neural system for chronic, local intracerebral drug delivery

Abstract

Recent advances in medications for neurodegenerative disorders are expanding opportunities for improving the debilitating symptoms suffered by patients. Existing pharmacologic treatments, however, often rely on systemic drug administration, which result in broad drug distribution and consequent increased risk for toxicity. Given that many key neural circuitries have sub-cubic millimeter volumes and cell-specific characteristics, small-volume drug administration into affected brain areas with minimal diffusion and leakage is essential. We report the development of an implantable, remotely controllable, miniaturized neural drug delivery system permitting dynamic adjustment of therapy with pinpoint spatial accuracy. We demonstrate that this device can chemically modulate local neuronal activity in small (rodent) and large (nonhuman primate) animal models, while simultaneously allowing the recording of neural activity to enable feedback control.

Steerable Microinvasive Probes for Localized Drug Delivery to Deep Tissue

“…Our group has previously demonstrated reduced glial scarring in response to smaller implant diameters, down to 150 µm . Implants that incorporate highly flexible, low‐diameter materials to reduce associated inflammation are thus termed “microinvasive.” Microinvasive implants are capable of targeting deep‐brain structures with increased spatial resolution and minimal scarring . These studies reinforce the necessity for further reducing implant diameter to improve chronic viability and spatial resolution.…”

“…A custom 3D‐printed cap was fabricated as a coimplant to prevent device migration during chronic implantation (Figure S1a, Supporting Information). S‐MINIs were implanted into the substantia nigra (anteroposterior (AP): −5.0 mm, mediolateral (ML): −2.2 mm, dorsoventral (DV): −8.2 mm) of rats using previously established implantation procedures (Figure b; Figure S1b, Supporting Information) . Histological analysis of glial scarring was performed after 8 weeks of implantation using previously developed methods (Figure c) .…”

“…Guide tubes and protective sheaths have often been necessary to improve implant stability and prevent buckling during insertion when designs require long, thin implants . The use of thick exterior coatings removes the benefit of size reduction in glial scarring granted by smaller implants.…”

“…S‐MINI Implantation : All in vivo studies were completed following previously reported methods . Briefly, F344 (SAS Fischer) female rats were purchased form Charles River Laboratories and sustained under 12 h light/dark cycles.…”

“…Reliably guiding small‐diameter implants with high aspect ratios to deep structures is challenging and often requires external control to predictably guide the long, thin implants to a final location . Many devices employ shuttles to facilitate insertion, such as hydrogel coatings and guide tubes . The use of such shuttles increases device diameter, potentially mitigating the benefits to gliosis reduction.…”