Hydrogel-base Bioelectronic System for Intelligent Disease Treatment

Abstract

Bioelectronic systems provide faithful, minimally invasive, and chronic recordings from neurological tissues, where such technologies might have wider clinical applications from electrical signals generation units (CNS system and PNS system) to the electrically active organs. Soft hydrogel-based electronic systems have been developed at the laboratory-level which can collect and deliver various bioelectric signals in different parts of the human body. Despite the remarkable advances in recent years, a key challenge for bioelectronic technologies is recognizing subtle pathological symptoms and reacting to the disorders promptly in a closed-loop manner. On the other hand, many bioelectronic systems have been developed as intervention devices in clinical trials, including chemical intervention, electrical therapy, etc. Despite the fact that the effectiveness of electroporation devices has been demonstrated in certain diseases, particularly tumors. However, in addition to rapid clearance and low transfection efficiency, current electrode-based electroporation devices exhibited complex application methods due to drug intramuscular pre-injection. In comparison, hydrogel-based bioelectronics with modulus comparable to human tissues offer a new avenue for improving current electroporation therapy.

In this study, we aim to develop a series of soft conductive hydrogel-based bioelectronic devices for electrophysiological signals detection, pharmacological intervention, as well as electroporation therapy. The formatted conductive hydrogel could be empowered with adjustable conductivity through conductive polymer induction, and their signal recording function could be used in bioelectrode fabrication. Furthermore, these well-designed hydrogel networks could be used as an intelligent drug delivery/release system to control the rate of drug release in response to external electrical stimuli, which is critical to the goal of "precise medicine". Specifically, depending on the applied electrical impulses, various types of drug cargo can be transported, ranging from small-molecule chemotherapy drugs to high-molecule biological reagents such as nucleic acids, antibodies, and so on. Furthermore, with a strong electrical field, the electroactive hydrogel-formed device could directly deliver high-molecule reagents into the cell cytoplasm, enabling reversible electroporation for disease treatment and vaccination. As a result, given the critical need for hydrogel-based bioelectronic systems, I developed two types of devices and investigated their potential biomedicine applications in order to provide more creative solutions for intelligent disease treatment.

In the first part, we developed a series of soft, biocompatible, and biostable hydrogel-based neural interface that allows complete integration with neural tissues to acquire high-quality neural signals, as well as realizing pharmacological intervention synchronously. The recorded neural spiking signal acts as closed-loop feedback to trigger a voltage-driven drug release in detected pathological conditions, where seizure occurrence is predicted by real-time electrophysiology analysis. When implanted into epileptic animals, the device enables autonomous preventative anti-seizure management, in which the dosing of the anti-epileptic drug was intelligently controlled in a time-sensitive, region-selective, and dose-adaptive way, thus the epileptic animals could recover to healthy state promptly.

In the second part, we developed a soft, biocompatible, and electroactive hydrogel electroporation platform to in-situ produce PD1-deficient engineered T cells on lymph nodes. We leverage the conductive hydrogel electrode as a CRISPR-Cas9 plasmid (delete PDCD1 loci) garage and traffic accelerator to contact with the lymph node directly, where preloaded CRISPR-Cas9 plasmid cargo could be released from the hydrogel matrix quickly and then driven into T cells cytoplasm upon external electric fields without physical damage. The melanoma tumor-bearing mice treated with our hydrogel electroporation platform exhibited obvious tumor elimination due to the effective engineered T-cell-mediated immune responses. Thus, such a hydrogel electroporation system could provide a broad platform to expand current immune therapy.

We believe that this series of electroactive hydrogel-based bioelectronic systems could be extended for smart administrations in many other diseased conditions, including but not limited to heart disease, infectious diseases, autoimmune diseases, etc. The development of hydrogel bioelectronics will present more exciting opportunities for biomedical research and technology translation and make significant contributions to clinical trials.

Date of Award	19 Dec 2022
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Peng SHI (Supervisor)