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.

We present a novel benchtop-based microfabrication technology: 3D printing, ink casting, micromachined lamination (3D PICLμM) for rapid prototyping of lab-on-a-chip (LOC) and biological devices. The technology uses cost-effective, makerspace-type microfabrication processes, all of which are ideally suited for low resource settings, and utilizing a combination of these processes, we have demonstrated the following devices: (i) 2D microelectrode array (MEA) targeted at in vitro neural and cardiac electrophysiology, (ii) microneedle array targeted at drug delivery through a transdermal route and (iii) multi-layer microfluidic chip targeted at multiplexed assays for in vitro applications. The 3D printing process has been optimized for printing angle, temperature of the curing process and solvent polishing to address various biofunctional considerations of the three demonstrated devices. We have depicted that the 3D PICLμM process has the capability to fabricate 30 μm sized MEAs (average 1 kHz impedance of 140 kΩ with a double layer capacitance of 3 μF), robust and reliable microneedles having 30 μm radius of curvature and ~40 N mechanical fracture strength and microfluidic devices having 150 μm wide channels and 400 μm fluidic vias capable of fluid mixing and transmitted light microparticle visualization. We believe our 3D PICLμM is ideally suited for applications in areas such as electrophysiology, drug delivery, disease in a dish, organ on a chip, environmental monitoring, agricultural therapeutic delivery and genomic testing.

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 demonstrate a new fabrication technology to realize ``intelligent'', transdermal, minimally invasive microneedle array (iμNA) by crosslinking a hydrogel, Polyethylene Glycol Diacrylate (PEGDA) by photo-polymerization using Digital Light Processing (DLP) based 3D printing. The photo-polymerization conditions have been optimized so that the mutually exclusive requirements of excellent mechanical strength while retaining hydrogel properties of PEGDA are met which would allow swelling/delivery of therapeutic cargo of diclofenac sodium via diffusion. An array having 100 microneedles arranged in a 10x 10 array was successfully 3D printed which efficiently penetrated human skin during ex vivo characterization. In vitro drug release studies demonstrated that the PEGDA based iμNA behaves as a stimuli responsive device showing distinct release characteristics from external stimuli such as temperature and pH. [2020-0133]

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.

Conventional two-dimensional microelectrode arrays (2D MEAs) in the market involve long manufacturing timeframes, have cleanroom requirements, and need to be assembled from multiple parts to obtain the final packaged device. For MEAs to be “used and tossed”, manufacturing has to be moved from the cleanroom to makerspaces. In order to enable makerspace fabricated MEAs comparable to conventional MEAs, the microfabrication processes must be optimized to have similar electrical properties along with biocompatibility and number of recording sites. This work presents a makerspace microfabricated 2D MEA having electrode densities up to a commercially popular 8 × 8 array, all fabricated under four days. Additive manufacturing-based realization of the MEA devices provides immense flexibility in terms of meeting distinct design requirements. A unique non-planar MEA having meso-scale electrodes on the top side of a chip transitioning to traces onto the bottom side through electrical vias is presented in this work. This allows for (a) monolithic integration of a culture well for devices having up to a 6 × 6 MEA array, (b) selective electroplating of the meso-scale electrodes (500 μm diameter) defined by silver ink casting followed by pulsed electroplating of gold or platinum without any masking procedure, (c) casting of a uniform and planar insulation layer via a novel process of confined precision spin coating (CPSC) of SU-8 which acts as a biocompatible insulation atop the meso-scale electrodes; and (d) selective laser micromachining to define the 50 μm × 50 μm microelectrodes. For an 8 × 8 array, the culture well and MEA chip framework are 3D printed as two separate parts and sealed together with a biocompatible epoxy as in commercially available MEAs. The fabricated MEAs have an average 1 kHz impedance of 36.8 kΩ/16 kΩ with a double layer capacitance of 400 nF cm⁻²/520 nF cm⁻² for nano-porous platinum/nano-gold which is comparable to the state-of-art commercially available 2D MEAs. Additionally, it was found out that our 3D printing-based process compares very favorably with traditional glass MEAs in terms of design to device while representing a dramatic reduction in cost, timeline for fabrication, reduction in the number of steps and the need for sophisticated microfabrication and packaging equipment.