Focal, remote-controlled, chronic chemical modulation of brain microstructures

Abstract

Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients.

Steerable Microinvasive Probes for Localized Drug Delivery to Deep Tissue

“…This is demonstrated by the manual infusion of MRI contrast into the substantia nigra of adult rats. Syringe pumps can provide more precise control over the size of the bolus delivered and volume of brain covered, as demonstrated previously . The S‐MINI can be utilized for the focal delivery of neuroactive compounds to investigate neural circuit function or new therapeutic candidates while maintaining MRI capabilities.…”

“…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) .…”

“…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) . Immunohistochemical staining of astrocytes (GFAP), macrophages (Iba1), and neurons (NeuN) was quantified to appreciate the inflammatory response associated with implantation (Figure d,e; Figure S1c, Supporting Information).…”

“…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.…”

“…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.…”