The development of microelectrode arrays (MEAs) along with complementary advances in electronics, mechanics and software to connect with these arrays has led to the in vitro interfacing and benchtop electrophysiological models of several electrically active cells such as neurons and cardiomyocytes proving vital models and testing of human disease conditions in a dish/on a chip. This topical review deals with the micro/nanofabrication technology development of Microelectrodes Arrays from early silicon based developments to today’s additive manufacturing technologies that have been employed to address bio-micro-electro-mechanical systems tool development in this space. Specifically 2D and 3D MEAs technologies have been reviewed in this paper along with a broad overview of some of the biological applications using these devices that are advancing the very state of biomedical research.

The widespread adaptation of 3D printing in the microfluidic, bioelectronic, and Bio-MEMS communities has been stifled by the lack of investigation into the biocompatibility of commercially available printer resins. By introducing an in-depth post-printing treatment of these resins, their biocompatibility can be dramatically improved up to that of a standard cell culture vessel (99.99%). Additionally, encapsulating resins that are less biocompatible with materials that are common constituents in biosensors further enhances the biocompatibility of the material. This investigation provides a clear pathway toward developing fully functional and biocompatible 3D printed biosensor devices, especially for interfacing with electrogenic cells, utilizing benchtop-based microfabrication, and post-processing techniques.

We explore the capabilities and limitations of 3D printed microserpentines (µserpentines) and utilize these structures to develop dynamic 3D microelectrodes for potential applications in in vitro, wearable, and implantable microelectrode arrays (MEAs). The device incorporates optimized 3D printed µserpentine designs with out-of-plane microelectrode structures, integrated on to a flexible Kapton® package with micromolded PDMS insulation. The flexibility of the optimized, printed µserpentine design was calculated through effective stiffness and effective strain equations, so as to allow for analysis of various designs for enhanced flexibility. The optimized, down selected µserpentine design was further sputter coated with 7–70 nm-thick gold and the performance of these coatings was studied for maintenance of conductivity during uniaxial strain application. Bending/conforming analysis of the final devices (3D MEAs with a Kapton® package and PDMS insulation) were performed to qualitatively assess the robustness of the finished device toward dynamic MEA applications. 3D microelectrode impedance measurements varied from 4.2 to 5.2 kΩ during the bending process demonstrating a small change and an example application with artificial agarose skin composite model to assess feasibility for basic transdermal electrical recording was further demonstrated.

Benchtop tissue cultures have become increasingly complex in recent years, as more on-a-chip biological technologies, such as microphysiological systems (MPS), are developed to incorporate cellular constructs that more accurately represent their respective biological systems. Such MPS have begun facilitating major breakthroughs in biological research and are poised to shape the field in the coming decades. These biological systems require integrated sensing modalities to procure complex, multiplexed datasets with unprecedented combinatorial biological detail. In this work, we expanded upon our polymer-metal biosensor approach by demonstrating a facile technology for compound biosensing that was characterized through custom modeling approaches. As reported herein, we developed a compound chip with 3D microelectrodes, 3D microfluidics, interdigitated electrodes (IDEs) and a microheater. The chip was subsequently tested using the electrical/electrochemical characterization of 3D microelectrodes with 1 kHz impedance and phase recordings and IDE-based high-frequency (~1 MHz frequencies) impedimetric analysis of differential localized temperature recordings, both of which were modeled through equivalent electrical circuits for process parameter extraction. Additionally, a simplified antibody-conjugation strategy was employed for a similar IDE-based analysis of the implications of a key analyte (l-glutamine) binding to the equivalent electrical circuit. Finally, acute microfluidic perfusion modeling was performed to demonstrate the ease of microfluidics integration into such a polymer-metal biosensor platform for potential complimentary localized chemical stimulation. Overall, our work demonstrates the design, development, and characterization of an accessibly designed polymer-metal compound biosensor for electrogenic cellular constructs to facilitate comprehensive MPS data collection.

Microfabrication and assembly of 3D MEA based on a glass-stainless steel platform is shown utilizing non-traditional “Makerspace Microfabrication” techniques featuring cost-effective, rapid fabrication and an assorted biocompatible material palette.