Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices

Khalil B Ramadi; Ashvin Bashyam; Chris J Frangieh; Erin B Rousseau; Max J Cotler; Robert Langer; Ann M Graybiel; Michael J Cima

doi:10.1016/j.celrep.2020.107734

Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices

Cell Rep. 2020 Jun 9;31(10):107734. doi: 10.1016/j.celrep.2020.107734.

Authors

Khalil B Ramadi¹, Ashvin Bashyam², Chris J Frangieh², Erin B Rousseau¹, Max J Cotler¹, Robert Langer³, Ann M Graybiel⁴, Michael J Cima⁵

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Health Sciences and Technology Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Health Sciences and Technology Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard-MIT Health Sciences and Technology Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: mjcima@mit.edu.

PMID: 32521259
DOI: 10.1016/j.celrep.2020.107734

Abstract

Treatments for neurologic diseases are often limited in efficacy due to poor spatial and temporal control over their delivery. Intracerebral delivery partially overcomes this by directly infusing therapeutics to the brain. Brain structures, however, are nonuniform and irregularly shaped, precluding complete target coverage by a single bolus without significant off-target effects and possible toxicity. Nearly complete coverage is crucial for effective modulation of these structures. We present a framework with computational mapping algorithms for neural drug delivery (COMMAND) to guide multi-bolus targeting of brain structures that maximizes coverage and minimizes off-target leakage. Custom-fabricated chronic neural implants leverage rational fluidic design to achieve multi-bolus delivery in rodents through a single infusion of radioactive tracer (Cu-64). The resulting spatial distributions replicate computed spatial coverage with 5% error in vivo, as detected by positron emission tomography. COMMAND potentially enables accurate, efficacious targeting of discrete brain regions.

Keywords: brain; computational method/algorithm; drug delivery; intracerebral infusion; microdevice; microprobe.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Algorithms
Animals
Computational Biology / methods*
Drug Delivery Systems / methods*
Drug Implants / metabolism*
Humans
Mice
Pharmaceutical Preparations / metabolism*

Substances

Drug Implants
Pharmaceutical Preparations

Grants and funding

R01 EB016101/EB/NIBIB NIH HHS/United States