Optically Controlled Drug Delivery Through Microscale Brain-Machine Interfaces Using Integrated Upconverting Nanoparticles

Abstract

The aim of this work is to incorporate lanthanide-cored upconversion nanoparticles (UCNP) into the surface of microengineered biomedical implants to create a spatially controlled and optically releasable model drug delivery device in an integrated fashion. Our approach enables silicone-based microelectrocorticography (ECoG) implants holding platinum/iridium recording sites to serve as a stable host of UCNPs. Nanoparticles excitable in the near-infrared (lower energy) regime and emitting visible (higher energy) light are utilized in a study. With the upconverted higher energy photons, we demonstrate the induction of photochemical (cleaving) reactions that enable the local release of specific dyes as a model system near the implant. The modified ECoG electrodes can be implanted in brain tissue to act as an uncaging system that releases small amounts of substance while simultaneously measuring the evoked neural response upon light activation. In this paper, several technological challenges like the surface modification of UCNPs, the immobilization of particles on the implantable platform, and measuring the stability of integrated UCNPs in in vitro and in vivo conditions are addressed in detail. Besides the chemical, mechanical, and optical characterization of the ready-to-use devices, the effect of nanoparticles on the original electrophysiological function is also evaluated. The results confirm that silicone-based brain-machine interfaces can be efficiently complemented with UCNPs to facilitate local model drug release.

Keywords: biomedical implant; brain–machine interfaces; drug delivery; electrocorticography; upconverting nanoparticles.

Figure 1

Schematic representation of the surface modification steps.

Figure 2

Uncaging (photocleavage) mechanism after NIR light exposure of the UCNPs.

Figure 3

The molecular structure of TetPPG-Rhod, the click and the uncaging process [44]. NMR spectrum of the dye system can be found in the Supporting Information of the cited article.

Figure 4

Contact angle of the modified silicone (PDMS) model substrate. (a) Bare substrate, (b) plasma treated substrate, (c) NPTES-treated substrate, (d) BCN-NHS-modified substrate (scalebars indicate 1 mm).

Figure 5

FTIR spectra recorded after each modification step of a PDMS disk. (a) Bare substrate, (b) plasma-treated substrate, (c) NPTES-treated substrate.

Figure 6

SEM images of the UCNP-ECoG system. (a) The whole probe surface with numbered recording sites, (b) a closer look at recording site 9 at larger magnification, (c) UCNP coverage on the substrate surface near site 4, (d) particles detected with Matlab, near site 4 (white scalebars show 1 mm, 50 µm and 2 µm, respectively).

Figure 7

EIS measurements of the ECoG systems, represented on Bode plots. (a) Resistance (magnitude) of the unmodified and UCNP-modified ECoGs, (b) reactance (phase angle) of the unmodified and UCNP-modified ECoGs.

Figure 8

Fluorescence spectroscopy measurements of the ECoG systems. (a) RFI (relative fluorescent intensity) changes due to the IR laser irradiation, (b) Observing the effect of natural light vs. IR laser light on the system.

Figure 9

Averages of the image histograms of 2P images taken on sample regions of unmodified PDMS discs and a fully modified UCNP-ECoG device with different light intensities. The histograms of UCNP devices (orange, 1.72 mW; red, 8.6 mW) show increased fluorescence on these images, suggesting successful uncaging.

Figure 10

Sample in vivo electrophysiological recording with a UCNP-modified ECoG device from a ketamine–xylazine anesthetized mouse, showing characteristic oscillations evoked by the anesthesia. The 8 traces are simultaneous recordings from the 8 channels of the device. The signal is low pass filtered to below 150 Hz. 50 Hz line-frequency noise was band-stop filtered.