Swaminathan Rajaraman

Micromachined three-dimensional electrode arrays for transcutaneous nerve tracking

We report the development of metal transfer micromolded (MTM) three-dimensional microelectrode arrays (3D MEAs) for a transcutaneous nerve tracking application. The measurements of electrode?skin?electrode impedance (ESEI), electromyography (EMG) and nerve conduction utilizing these minimally invasive 3D MEAs are demonstrated in this paper. The 3D MEAs used in these measurements consist of a metalized micro-tower array that can penetrate the outer layers of the skin in a painless fashion and are fabricated using MTM technology. Two techniques, an inclined UV lithography approach and a double-side exposure of thick negative tone resist, have been developed to fabricate the 3D MEA master structure. The MEAs themselves are fabricated from the master structure utilizing micromolding techniques. Metal patterns are transferred during the micromolding process, thereby ensuring reduced process steps compared to traditional silicon-based approaches. These 3D MEAs have been packaged utilizing biocompatible Kapton? substrates. ESEI measurements have been carried out on test human subjects with standard commercial wet electrodes as a reference. The 3D MEAs demonstrate an order of magnitude lower ESEI (normalized to area) compared to wet electrodes for an area that is 12.56 times smaller. This compares well with other demonstrated approaches in literature. For a nerve tracking demonstration, we have chosen EMG and nerve conduction measurements on test human subjects. The 3D MEAs show 100% improvement in signal power and SNR/?area as compared to standard electrodes. They also demonstrate larger amplitude signals and faster rise times during nerve conduction measurements. We believe that this microfabrication and packaging approach scales well to large-area, high-density arrays required for applications like nerve tracking. This development will increase the stimulation and recording fidelity of skin surface electrodes, while increasing their spatial resolution by an order of magnitude or more. Although biopotential electrode systems are not without their challenges, the non-invasive access to neural information, along with the potential for automation with associated electronic and software development, is precisely what makes this technology an excellent candidate for the next generation in diagnostic, therapeutic, and prosthetic devices.

Hollow polymer microneedle array fabricated by photolithography process combined with micromolding technique

Transdermal drug delivery through microneedles is a minimally invasive procedure causing little or no pain, and is a potentially attractive alternative to intramuscular and subdermal drug delivery methods. This paper demonstrates the fabrication of a hollow microneedle array using a polymer-based process combining UV photolithography and replica molding techniques. The key characteristic of the proposed fabrication process is to define a hollow lumen for microfluidic access via photopatterning, allowing a batch process as well as high throughput. A hollow SU-8 microneedle array, consisting of 825μm tall and 400 μm wide microneedles with 15-25 μm tip diameters and 120 μm diameter hollow lumens was designed, fabricated and characterized.

Fabrication and Characterization of Polymer Hollow Microneedle Array Using UV Lithography Into Micromolds

Drug delivery through micromachined needles is an attractive alternative to intramuscular and subdermal injection by hypodermic needles, due to the potential for reduced pain caused by the micro-sized needles. In this paper, a polymer-based fabrication process using UV lithography into micromolds is developed, allowing the fabrication of microneedle (MN) shafts, tips, lumens, and substrate baseplate using lithography. Using UV lithography into micromolds allows complex three-dimensional structures to be defined, since both mask patterns and mold topography are available to define the structures. A hollow MN array and baseplate, in which the needle lumens extend through the thickness of the baseplate, are demonstrated. Fabricated SU-8 MNs are 825 μm in height and 400 μm in width, with a pyramidal tip; the needle lumen, 120 μm in diameter, intersects with one of the faces of the pyramidal tip. Mechanical characterization of the fabricated MNs shows that the fracture force of a single needle against a rigid surface is 12.0 N. The insertion force of a single needle into porcine skin is empirically determined to be 2.4 N. The fracture force of the needle against porcine skin is observed to be in excess of 90 N.

Three-Dimensional Metal Transfer Micromolded Microelectrode Arrays (MEAS) for In-Vitro Brain Slice Recordings

We report successful electrical characterization and electrophysiological recordings from hippocampal brain slices using metal transfer micromolded three-dimensional microelectrode arrays (3-D MEAs). These MEAs have been fabricated on polymer substrates using metal transfer micromolding. They have further been packaged on glass substrates and insulated using parylene deposition. Recording sites have been defined using laser micromachining and RIE etching. Initial electrical and electrophysiological characterization of the MEAs has been successfully demonstrated in this paper. We believe this fabrication approach enables manufacturing-friendly batch fabrication of truly disposable, biocompatible and cost-effective MEAs, which will be indispensable to the neurophysiology and pharmacology communities.

Metal-Transfer-Micromolded Three-Dimensional Microelectrode Arrays for in-vitro Brain-Slice Recordings

We report the development of metal-transfer-micromolded 3-D microelectrode arrays (3-D MEAs) and demonstrate successful electrical characterization, biocompatibility measurements, and electrophysiological recordings from rat hippocampal brain slices with these MEAs. Metal transfer micromolding is introduced as a manufacturing technology for producing nonplanar metallized patterned microelectromechanical-systems devices such as MEAs on polymeric substrates. This technology provides a self-aligned metallization scheme that eliminates the need for complex 3-D lithography. Two techniques, i.e., an intentionally formed nonplanar mold and a shadow mask, are demonstrated for the self-aligned metallization scheme. The MEAs have further been packaged using custom-designed commercial printed circuit boards and insulated using parylene deposition. Recording sites have been defined using two techniques: laser micromachining/reactive ion etching (RIE) of parylene and selective deposition of parylene using a “capping” technique. Electrical (impedance spectroscopy), biocompatibility (2-D planar cultures of neurons), electrophysiological (tissue slice recordings) characterizations of the MEAs are successfully demonstrated in this paper. The impedance of the electrodes was modeled based on a classical equivalent circuit, and high-frequency impedance estimation techniques were studied. We believe this fabrication approach offers an attractive route to disposable and biocompatible 3-D MEAs, utilizable by the neurophysiology and pharmacology communities.

Electrodeposited Metal Structures in High Aspect Ratio Cavities using Vapor Deposited Polymer Molds and Laser Micromachining

This paper reports a laser-assisted fabrication scheme for three-dimensional (3-D) electrodeposited metal structures into high aspect ratio trenches. A polymer (parylene C) is conformally deposited onto a highly nonplanar surface, selectively laser ablated, and used as an electroplating mold to fabricate metallic structures. Laser ablation of high-resolution (< 10 mum) features is performed using a 248 nm KrF Excimer laser. The ablation parameters for the parylene layer have been characterized for various film thicknesses. Metal lines of 2 mum thickness, and 2.5 mum width have been electroplated into 300 mum deep silicon trenches. The minimum resolution achieved is less than 5 mum. This process can potentially be applied toward the fabrication of embedded inductors, high density electrodes, buried interconnects or high voltage circuitry in CMOS and MEMS devices.

A Stretchable Microneedle Electrode Array for Stimulating and Measuring Intramuscular Electromyographic Activity

We have developed a stretchablemicroneedle electrode array (sMEA) to stimulate andmeasure the electrical activity of muscle across multiple sites. The technology provides the signal fidelity and spatial resolution of intramuscular electrodesacross a large area of tissue. Our sMEA is composed of a polydimethylsiloxane (PDMS) substrate, conductive-PDMS traces, and stainless-steel penetrating electrodes. The traces and microneedles maintain a resistance of less than 10 [Formula: see text] when stretched up to a ~63% tensile strain, which allows for the full range of physiological motion of felinemuscle. The device and its constituent materials are cytocompatible for at least 28 days in vivo. When implanted in vivo, the device measures electromyographic (EMG) activity with clear compound motor unit action potentials. The sMEA also maintains a stable connection with moving muscle while electrically stimulating the tissue. This technology has direct application to wearable sensors, neuroprostheses, and electrophysiological studies of animals and humans.

Polydimethylsiloxane Microstencils Molded on 3-D-Printed Templates

Microstencils have been utilized in biomedical engineering to pattern cell cultures, engineer tissues, and pattern conductive materials in microelectronics for the measurement of bioelectric activity. However, fabricating these microstencils can be considerably time consuming, expensive, and cleanroom processing or laser micromachining intensive. We present microfabrication strategies for producing stencils rapidly and cost effectively, with minimal use of cleanroom facilities, ideal for prototyping or applications where microfabrication costs need to be conserved. The process utilizes 3-D-printed templates as master structures from, which polydimethylsiloxane (PDMS) microstencils are molded. The entire process, from concept to completed stencil, requires approximately one day; however, the majority of this time is budgeted for PDMS curing cycles, so it requires only ~1-2 person hours to complete. These microstencils were used to pattern metal traces ~160-1000-μm wide, on three commonly used BioMEMS substrate materials- to pattern rat cortical neuronal cell cultures with radii between ~300 and 1000 μm-and to pattern organic materials. With the advancement of 3-D-printing technologies, we anticipate that our presented processes will improve in resolution and gain a greater cost advantage over traditional microstencilling methods.

3D Printing, Ink Casting and Micromachined Lamination (3D PICLμM): A Makerspace Approach to the Fabrication of Biological Microdevices

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.

Micromachining on and of Transparent Polymers for Patterning Electrodes and Growing Electrically Active Cells for Biosensor Applications

We report on microfabrication and assembly process development on transparent, biocompatible polymers for patterning electrodes and growing electrically active cells for in vitro cell-based biosensor applications. Such biosensors are typically fabricated on silicon or glass wafers with traditional microelectronic processes that can be cost-prohibitive without imparting necessary biological traits on the devices, such as transparency and compatibility for the measurement of electrical activity of electrogenic cells and other biological functions. We have developed and optimized several methods that utilize traditional micromachining and non-traditional approaches such as printed circuit board (PCB) processing for fabrication of electrodes and growing cells on the transparent polymers polyethylene naphthalate (PEN) and polyethylene terephthalate (PET). PEN-based biosensors are fabricated utilizing lithography, metal lift-off, electroplating, wire bonding, inkjet printing, conformal polymer deposition and laser micromachining, while PET-based biosensors are fabricated utilizing post-processing technologies on modified PCBs. The PEN-based biosensors demonstrate 85–100% yield of microelectrodes, and 1-kHz impedance of 59.6 kOhms in a manner comparable to other traditional approaches, with excellent biofunctionality established with an ATP assay. Additional process characterization of the microelectrodes depicts expected metal integrity and trace widths and thicknesses. PET-based biosensors are optimized for a membrane bow of 6.9 to 15.75 µm and 92% electrode yield on a large area. Additional qualitative optical assay for biomaterial recognition with transmitted light microscopy and growth of rat cortical cells for 7 days in vitro (DIV) targeted at biological functionalities such as electrophysiology measurements are demonstrated in this paper.