Soft implantable drug delivery device integrated wirelessly with wearable devices to treat fatal seizures

Abstract

Personalized biomedical devices have enormous potential to solve clinical challenges in urgent medical situations. Despite this potential, a device for in situ treatment of fatal seizures using pharmaceutical methods has not been developed yet. Here, we present a novel treatment system for neurological medical emergencies, such as status epilepticus, a fatal epileptic condition that requires immediate treatment, using a soft implantable drug delivery device (SID). The SID is integrated wirelessly with wearable devices for monitoring electroencephalography signals and triggering subcutaneous drug release through wireless voltage induction. Because of the wireless integration, bulky rigid components such as sensors, batteries, and electronic circuits can be moved from the SID to wearables, and thus, the mechanical softness and miniaturization of the SID are achieved. The efficacy of the prompt treatment could be demonstrated with animal experiments in vivo, in which brain damages were reduced and survival rates were increased.

Fig. 1. SID wirelessly integrated with wearable devices.

(A) Schematic illustration of an SID in the subcutaneous region, which is wirelessly integrated with a wearable power transmitter and a wearable EEG monitoring device. Inset shows the wireless power transfer through the skin, which induces the subcutaneous drug release from the SID. (B) Image of the front side of the SID. LED, light-emitting diode. (C) Image of the backside of the SID. (D) Soft mechanical characteristics of the SID allows it to be freely twisted and bent (inset). (E) The SID can be implanted in the subcutaneous region of the mouse’s back with a minimal surgical incision. (F) Image of a wearable EEG monitoring device. (G) Image of a wearable power transmitter for the wireless power supply to the SID. Photo credit: Hyunwoo Joo, Seoul National University.

Fig. 2. Wireless coupling by the voltage induction.

(A) Simulation result of the efficiency versus frequency. (B) S11 measurement and simulation results of the transmitter coil. (C) Output voltage measurement and simulation results under different RF signal strengths with the lid resistance of 5 kilohms. (D) Simulated 1-g average specific absorption rate (SAR) when the 19-dBm RF signal was transmitted from the transmitter coil. (E) Schematic illustrations for brightness changes of LED indicators during device coupling and drug release. (F) Images for brightness changes of LED indicators during device coupling and drug release. (G) Simulation of normalized efficiency changes under displacements in the x, y, and z axes. (H) Output voltage measurement under displacements in the x, y, and z axes. (I) Simulation of normalized efficiency changes by tissue component variation. (J) Simulation of normalized output voltage affected by displacements (∣Δy∣≤ 1.5 mm, ∣Δz∣≤ 1 mm) and tissue composition changes (2 mm ≤fat thickness ≤10 mm) under various input powers. Photo credit: Hyunwoo Joo, Seoul National University.

Fig. 3. Drug release from the SID.

(A) Exploded schematic illustration of the backside of the SID to show its design. (B) Image of the lid and reservoir of the SID. (C) Magnified view with an optical camera image of the drug inlet and outlet of the SID. (D) Schematic illustration of the drug release process using the water electrolysis. (E) Time-lapse optical camera images of the drug release process. (F) Images of the fuse before (left) and after (right) the drug release. (G) Drug release profile from the SID in vitro. (H) Images of the drug release on porcine tissues ex vivo (left, before drug release; middle, during wireless power supply to the SID; right, after drug release). Evans blue was used as a model drug for easy visualization of the released drug. Photo credit: Hyunwoo Joo, Seoul National University.

Fig. 4. Mechanical stability and biological safety of the SID.

(A) Resistance change of the lid during the bending deformation of the SID. (B) Resistance change of the lid under application of the various vertical pressures. (C) Induced strain at the fuse as a function of bending radius, estimated through FEA. (D) Induced strain at the fuse as a function of the vertical pressure applied on the skin, estimated through FEA. Each thickness represents the skin thickness of the front of arm (red), scalp (blue), and back (green) (48, 49). (E) Image of the mouse skin under which the SID is implanted. (F) Image of indicator LEDs on the SID. LED lights are shown through the skin. (G) Image of the mouse muscle tissue on which the SID is implanted. No sign of the drug leakage was observed. (H) Image of the implanted SID after its extraction from the animal. (I) Immunohistology analysis results [hematoxylin and eosin (H&E), CD3, CD20, CD68] for the tissues that encase the implanted device after 4 weeks of the device implantation. Photo credit: Hyunwoo Joo, Seoul National University.

Fig. 5. Demonstration of the seizure suppression using wirelessly controlled subcutaneous drug release in vivo.

(A) Spectrogram of the EEG signals under the seizure obtained from the control (no treatment) group. (B) EEG signals from the control group at different time points. (C) Spectrogram of the EEG signals under the seizure obtained from the experimental (subcutaneous drug release) group. (D) EEG signals from the experimental group at different time points. (E) Survival rate of the experimental (red) and control (blue) groups. ***P < 0.001 by the log-rank test. (F) Experimental procedure to check the integrity of the blood-brain barrier (BBB) under SE. IV, intravenous. (G) Images of the brain (left) and its dissected samples (right) for the experimental (top) and control (bottom) groups. Evans blue was intravenously injected to check the integrity of the BBB. (H) Amount of Evans blue in the resected mouse brain for the experimental and control groups. **P < 0.01 by the Mann-Whitney U test. Box, standard error; line, median; whisker, minimum-maximum. Photo credit: Hyunwoo Joo, Seoul National University.

Fig. 6. Drug release demonstration from a large-size SID with human EEG signals ex vivo.

(A) Image of the backside of a large-size SID that is scaled-up to be compatible with the amount of drug required for the human application. (B) Experimental setup for the drug release demonstration from the large-size SID with human EEG signals ex vivo. (C) Spectrogram of the prerecorded EEG signals from a patient with SE. (D) Human EEG signals at different time points. (E) Image of the SID before the release of the model drug between the porcine skin and the muscle tissue. (F) Image of the SID after the release of the model drug. Evans blue was used as a model drug for easy visualization of the drug release. Photo credit: Hyunwoo Joo, Seoul National University.