Engineering electroactive materials for macrophage immunomodulation and implantable bioelectronics

Abstract

Implantable bioelectrodes directly interact with surrounding biological systems, allowing for precise recording and stimulation of electrical signals. However, a fundamental challenge arises in their long-term utilization, as implanted bioelectrodes frequently lose their performance due to adverse inflammatory tissue responses, primarily orchestrated by macrophages. This thesis introduces engineering strategies of electroactive materials to modulate macrophage responses, with the ultimate aim of developing immunocompatible bioelectrodes. Specifically, conductive polymer bioelectrodes were engineered to exhibit immune-friendly characteristics, including surface topography, anti-inflammatory cytokine presentation, or antioxidant activity. Additionally, I explored the optimal features of electrically conductive hydrogels to minimize host immune responses, taking into consideration conductivity and stiffness, as electrically conductive hydrogels have recently been recognized as new types of implantable tissue engineering and electrode materials. First, the surface roughness of polypyrrole/heparin (PPy/Hep) was controlled, and the optimal roughness for mitigating macrophage-driven inflammation was investigated. Ra values of PPy/Hep electrodes were adjusted from 5.5 nm to 17.6 nm by varying applied charge density during electrochemical synthesis. The PPy/Hep with an Ra of 14.5 nm was determined to be the optimal electrode, as it exhibited the most effective reduction in cell recruitment and pro-inflammatory polarization of host macrophages, while not affecting cell viability. Second, the PPy/Hep was functionalized with interleukin-4 (IL-4), an anti-inflammatory cytokine, to directly induce anti-inflammatory polarization of macrophages. Heparin chains exposed on PPy/Hep electrodes allowed for facile and effective IL-4 immobilization via non-covalent interactions. The IL-4 immobilized PPy/Hep successfully induced macrophage phenotype toward anti-inflammatory state. Third, enzymatic antioxidant activity was introduced to PPy electrodes by employing heparin-hemin conjugates (HepH) as dopants. HepH-incorporated PPy electrodes reduced intracellular reactive oxygen species (ROS) levels and directed macrophage polarization toward anti-inflammatory phenotype. I have demonstrated that these strategies for controlling surface topography, cytokine immobilization, and introducing antioxidant activity successfully mitigated adverse tissue responses (e.g., scar tissue formation) around the implants and importantly enabled extended in vivo performance as electrocardiography signal recording electrodes. Finally, I prepared four electrically conductive hydrogels (graphene oxide-incorporated polyacrylamide) with varying stiffness (10 or 100 kPa) and electrical conductivities (0.07 or 0.2 mS/cm), and examined their interactions with macrophages and host tissues. Both stiffness and electrical conductivity exerted individual and combinatorial effects on macrophage polarization and host tissue responses, including cell recruitment, cytokine production, phenotypic marker expression, and scar tissue formation. In conclusion, the findings in this thesis offer promising approaches for enhancing the tissue compatibility and long-term performance of implantable bioelectrodes, thereby facilitating their application in biomedical devices.