Comprehensive investigation of electrical interactions with biological system for biomedical applications

Abstract

Electroactivity is indispensable in physiological functions in the human body at both cellular and tissue levels. At a cellular level, electroactivity intrinsically involves membrane potential and electrical coupling. Also, body’s sensing, movement, and regulatory mechanisms rely on bioelectrical signals at tissue and organ levels. Bioelectronic devices have been extensively developed to either record internal electroactivity or deliver external electrical stimuli to regulate functions of the biological system. This research aimed to i) develop novel implantable bioelectrodes presenting superior performance and biocompatibility and ii) investigate responses of mesenchymal stem cells (MSCs) to electrical stimulation (ES) for potential tissue engineering applications. Implantable bioelectrodes are pivotal tools facilitating precise and efficient electrical/electrochemical interactions with biological systems for signal recording and/or stimulation. However, they frequently encounter challenges upon implantation and reliability, including adverse reactions such as non-specific protein and cell binding, leading to fibrotic scar tissue formation and impaired signal sensitivity post-implantation. To address these issues, this study proposed engineering strategies to prevent non-specific cell binding to biomimetic implantable electrodes for extended time periods. For instance, the combination of polypyrrole/hyaluronic acid (PPy/HA) serves as a promising model of biomimetic bioelectrodes, in which electrically conductive polymer (i.e., PPy) enhances surface area and charge injection and hydrophilic and polyanionic polysaccharide (i.e., HA) enhances biocompatibility. Nonetheless, HA degradation by hyaluronidase (HAase) and reactive oxygen species in vivo drastically impairs the original performance of PPy/HA electrodes, which is associated with biofouling and foreign body reaction. To tackle this issue, PPy/HA bioelectrodes were modified by incorporating hyaluronidase inhibitor (i.e., glycyrrhizin) or chemically modified HA (i.e., thiolated HA; HA-SH) to promote resistance to HA degradation and non-specific cell adhesion, which can prolong performance of PPy/HA electrodes in vivo environments. Moreover, MSCs were electrically stimulated to enhance their therapeutic activity. MSCs are known for their unique ability to self-renew and differentiate into various cell types (e.g., bone, cartilage, and adipose tissues) and secrete various growth factors and cytokines, which have made MSCs promising for tissue engineering applications. Numerous studies have focused on enhancing MSC functions through gene engineering, development of special culture condition, and treatment of specific biochemical molecules; however, the efficacy of MSC-based therapies remains still unsatisfactory. Thus, electrical stimulation (ES) was employed to modulate MSC’ behaviors. Specifically, enhanced paracrine effects and chondrogenic differentiation of ES-treated MSCs were demonstrated both in vitro and in vivo studies. In conclusion, this thesis has not only contributed the development of reliable, biocompatible, and implantable bioelectrodes and novel strategies to enhance therapeutic potentials of MSCs using ES. The investigation of interactions between biological elements and electrical activity explored in this research could potentially pave a new way for the development of next-generation therapies aimed at developing bioelectronics devices and MSC-based tissue regeneration.