Microfabricated Implantable Parylene-Based Wireless Passive Intraocular Pressure Sensors

This paper presents an implantable parylene-based wireless pressure sensor for biomedical pressure sensing applications specifically designed for continuous intraocular pressure (IOP) monitoring in glaucoma patients. It has an electrical LC tank resonant circuit formed by an integrated capacitor and an inductor coil to facilitate passive wireless sensing using an external interrogating coil connected to a readout unit. Two surface-micromachined sensor designs incorporating variable capacitor and variable capacitor/inductor resonant circuits have been implemented to realize the pressure-sensitive components. The sensor is monolithically microfabricated by exploiting parylene as a biocompatible structural material in a suitable form factor for minimally invasive intraocular implantation. Pressure responses of the microsensor have been characterized to demonstrate its high pressure sensitivity (> 7000 ppm/mmHg) in both sensor designs, which confirms the feasibility of pressure sensing with smaller than 1 mmHg of resolution for practical biomedical applications. A six-month animal study verifies the in vivo bioefficacy and biostability of the implant in the intraocular environment with no surgical or postoperative complications. Preliminary ex vivo experimental results verify the IOP sensing feasibility of such device. This sensor will ultimately be implanted at the pars plana or on the iris of the eye to fulfill continuous, convenient, direct, and faithful IOP monitoring

Integration technologies for implantable microsystems

Microsystems targeted for implantation require careful consideration of power, thermals, size, reliability, and biocompatibility. The presented research explored appropriate integration technologies for an implantable drug delivery system suitable for use in mice weighing less than 20 grams. Microsystems technology advancements include in situ pump diaphragm formation; integrated, low volume microfluidic coupling technologies; and incorporation of a low voltage, low-power pump actuation with a zero-power off state. Utility of the developed integration technologies have been tested through in vitro reliability and validation experiments. A four-chamber peristaltic pump was created using micromachining (e.g. thin film deposition and Si etching) and direct write techniques. A novel phase change material based actuator was designed and fabricated to deflect deformable diaphragms into and out of four pump chambers while the diaphragms isolated the pumped fluid from the working material. Polyimide capillary tubing with 140-μm OD was integrated in-plane and acted as fluidic interconnects to a drug supply and to the pharmaceutical delivery site. Parylene C conformal coating and the design for gap occlusion provided sealed, flexible tubing connections to the micropump. The per chamber actuation power of 10.1 mW at 0.083 Hz resulted in fluid flow of over 100 nL/min with an efficiency of 11 mJ/nL

Microfluidic device for triggered chip transience

pre-printThis paper presents the fabrication and testing of a microfluidic device for the triggered destruction (transience) of microchips. The device consists of a thin film array of sealed reservoirs patterned on a polymer film. Each reservoir encloses a corrosive chemical agent which upon release dissolves the surface of a microchip placed beneath. When transience is activated, an integrated micro-heater melts the bottom of the reservoirs thus releasing the chemical agent, which in a matter of minutes destroys key layers on the underlying electronic/sensor chip. Each reservoir consists of a 16 μm-tall cavity holding 1 μL/cm2 of 1000:1 BHF. The measured energy required to burst open a filled reservoir was ~35mJ/cm2 when the device rests on top of a glass substrate and ~100mJ/cm2 when the device rests on top of a 0.5 μm-layer of silicon dioxide on a 0.5 mm silicon wafer

Micromachined three-dimensional electrode arrays for in-vitro and in-vivo electrogenic cellular networks

This dissertation presents an investigation of micromachined three-dimensional microelectrode arrays (3-D MEAs) targeted toward in-vitro and in-vivo biomedical applications. Current 3-D MEAs are predominantly silicon-based, fabricated in a planar fashion, and are assembled to achieve a true 3-D form: a technique that cannot be extended to micro-manufacturing. The integrated 3-D MEAs developed in this work are polymer-based and thus offer potential for large-scale, high volume manufacturing. Two different techniques are developed for microfabrication of these MEAs - laser micromachining of a conformally deposited polymer on a non-planar surface to create 3-D molds for metal electrodeposition; and metal transfer micromolding, where functional metal layers are transferred from one polymer to another during the process of micromolding thus eliminating the need for complex and non-repeatable 3-D lithography processes. In-vitro and in-vivo 3-D MEAs are microfabricated using these techniques and are packaged utilizing Printed Circuit Boards (PCB) or other low-cost manufacturing techniques. To demonstrate in-vitro applications, growth of 3-D co-cultures of neurons/astrocytes and tissue-slice electrophysiology with brain tissue of rat pups were implemented. To demonstrate in-vivo application, measurements of nerve conduction were implemented. Microelectrode impedance models, noise models and various process models were evaluated. The results confirmed biocompatibility of the polymers involved, acceptable impedance range and noise of the microelectrodes, and potential to improve upon an archaic clinical diagnostic application utilizing these 3-D MEAs.Ph.D.Committee Chair: Mark G. Allen; Committee Member: Elliot L. Chaikof; Committee Member: Ionnis (John) Papapolymerou; Committee Member: Maysam Ghovanloo; Committee Member: Oliver Bran

3-Dimensional Intracortical Neural Interface For The Study Of Epilepsy

Epilepsy is a chronic disease characterized by recurrent, unprovoked seizures, where seizures are described as storms of uncontrollable neuro-electrical activity within the brain. Seizures are therefore identified by observation of electrical spiking observed through electrical contacts (electrodes) placed on the scalp or the cortex above the epileptic regions. Current epilepsy research is identifying several specific molecular markers that appear at specific layers of the epilepsy-affected cortex. However, technology is limited in allowing for live observation of electrical spiking across these layers. The underlying hypothesis of this project is that electrical interictal activity is generated in a layer- and lateral-specific pattern. This work reports a novel neural probe technology for the manufacturing of 3D arrays of electrodes with integrated microchannels. This new technology is based on a silicon island structure and a simple folding procedure. This method simplifies the assembly or packaging process of 3D neural probes, leading to higher yield and lower cost. Various types of 3D arrays of electrodes, including acute and chronic devices, have been successfully developed. Microchannels have been successfully integrated into the 3D neural probes via isotropic XeF2 gas phase etching and a parylene resealing process. This work describes in detail the development of neural devices targeted towards the study of layer-specific interictal discharges in an animal model of epilepsy. Devices were designed utilizing parameters derived from the rat model of epilepsy. The progression of device design is described from 1st prototype to final chronic device. The fabrication process and potential pitfall are described in detail. Devices have been characterized by SEM (scanning electron microscope) imaging, optical imaging, various types of impedance analysis, and AFM (atomic force microscopy) characterization of the electrode surface. Flow characteristics of the microchannels were also analyzed. Various animal tests have been carried out to demonstrate the recording functionality of the probes, preliminary biocompatibility studies, and the reliability of the final chronic device package. These devices are expected to be of great use to the study of epilepsy as well as various other neurological diseases

A Digital Microfluidics Platform for Loop-Mediated Isothermal Amplification of DNA

Digital Microfluidics (DMF) is an innovative technology for liquid manipulation at microliter- to picoliter-scale, with tremendous potential of application in biosensing. DMF allows maneuvering single droplets over an electrode array, by means of electrowetting-on-dielectric (EWOD), that allows changing the contact angle of a droplet over a dielectric. Each droplet is thus considered a microreactor, with an unparalleled potential to perform chemical and biological reactions. Several aspects inherent to DMF platforms, such as multiplex assay capability and integration capability, make them promising for lab-on-chip and point-of-care (PoC) applications, e.g. DNA amplification assays or disease detection. DNA detection strategies for PoC have been profiting from recent development of isothermal amplification schemes, of which Loop-mediated Isothermal Amplification (LAMP) is a major methodology, allowing a 109-fold amplification efficiency in one hour. Here, I demonstrate for the first time the effective coupling of DMF and LAMP, resulting in a DMF device capable of performing LAMP reactions. This novel DMF platform has been developed and characterised, which allows successful amplification of a c-Myc gene fragment by LAMP. Precise temperature control is achieved by using a transparent heating element, connected to a looping feedback control system. This platform is able to amplify just 0.5 ng/μL of the target DNA, in only 45 minutes, for a device temperature of 65 °C and a reaction volume of 1.62 μL, one of the lowest volumes ever reported. Moreover, the electrophoretic analysis indicates that the amplification efficiency of the on-chip LAMP is considerably higher than that from the bench-top reaction

Non-volatile liquid-film-embedded microfluidic valve for microscopic evaporation control and contactless bio-fluid delivery applications

Quick evaporation speed of microfluids can cause many unexpected problems and failures in various microfluidic devices and systems. In this dissertation, a new evaporation speed controlling method is demonstrated using a thin liquid-film based microfluidic valve. Microfluidic droplet ejectors were designed, fabricated and integrated with the liquid-film based microfluidic valve. The thin liquid film with nonvolatility and immiscibility exhibited excellent microfluidic valve functionality without any stiction problem between valve components, and provided a very effective evaporation protection barrier for the microfluids in the device. Successful evaporation control by the liquid-film-embedded (LiFE) microfluidic valve has been demonstrated. In addition, guided actuation of the microfluidic valve along predefined paths was successfully achieved using newly developed oil-repellent surfaces, which were later used for developing ‘virtual walls’ for confining low surface tension liquids within predefined areas. Moreover, bioinspired slippery surfaces for aiding the microfluidic valve along the ejector surface have also been developed. These slippery surfaces were evaluated for their effectiveness in reducing microfluidic valve driving voltages. Finally, a sliding liquid drop (SLID) shutter technique has been developed for a normally closed functionality with aid from nanostructures. The SLID shutter resolves many issues found in the previous LiFE microfluidic valve. Smooth and successful printing results of highly volatile bio-fluids have been demonstrated using the SLID shutter technique. I envision that these demonstrated techniques and developed tools have immense potential in various microfluidic applications

Development of a Digital Microfluidic Toolkit: Alternative Fabrication Technologies for Chemical and Biological Assay Platforms

This thesis proposes the development of a digital microfluidics (DMF) device using alternative fabrication methods and materials for application in chemical and biological assays. DMF technology which relies on electrowetting-on-dielectric (EWOD) mechanism, offers several advantages such as reduced sample volume, faster analysis, device flexibility, and portability. It is however not without shortcomings as the fabrication of DMF devices is expensive while the reliability of such devices is reduced due to surface contamination when highly concentrated biomolecular samples (e.g. protein and cells) are used. The first experimental work in this thesis aims to reduce the cost of electrode patterning of DMF devices by investigating the use of inkjet printing method in conjunction with several combinations of conductive ink and substrate. It has been found that EWOD device made of PEDOT:PSS, a type of conductive polymer ink printed on Melinex®, a polyethylene terephthalate substrate presents the most reliable droplet actuation performance with velocity comparable to the standard chrome-on-glass device. Two types of inkjet-printed PEDOT:PSS-on-Melinex® device have been fabricated; one is a 3D 4 × 4 electrode array device and the other is a magnetic micro-immunoassay device establishing the feasibility of the proposed method. The 3D 4 × 4 electrode array device which utilises both sides of the substrate (i.e. top and bottom surfaces) for electrode patterning allows for future construction of multi-level DMF devices with large functional area. Implementation of such electrode design increases throughput as it made multiple parallel assays possible. The second inkjet-printed device demonstrates the possibility of employing the PEDOT:PSS-on-Melinex® device in heterogeneous immunoassay by successfully performing mixing and merging of two droplets and more importantly the magnetic beads separation operation. The second experimental investigation concerns the search for substitute materials for the dielectric and hydrophobic components of EWOD device using off-the-shelf products. For the dielectric component, the best performing material in terms of electrowetting reversibility is Rust-Oleum® Polyurethane Finish while for the hydrophobic surface is Top Coating of NeverWet® superhydrophobic material. Both are low-cost materials which employ a very simple spraying technique as their fabrication method. The NeverWet® superhydrophobic material has been selected for detailed investigation due to its other potential function as an anti-biofouling surface to either eliminate or minimise the biomolecules adsorption problem. The superhydrophobic material has shown great potential by demonstrating droplet contact angle reversibility and low roll-off angle for highly concentrated protein solution indicating low adsorption of protein on its surface. A superhydrophobic EWOD device has been fabricated using the Top Coating of NeverWet® as the actuating surface and the device has reliably transported concentrated protein droplets across its surface. It is hoped that the findings in the thesis will assist towards the future realisation of low-cost and robust DMF devices for a wide range of biological and chemical assays applications outside of conventional laboratory environment

MICROPARTICLE SAMPLING AND SEAPARATIONENABLED BY DROPLET MICROFLUIDICS

This work reports design, device fabrication, modeling and experimental results on newsampling and separation principles in which liquid is transported in a droplet form on a plannerhydrophobic surface with no moving parts. The presented particle sampler and separatorconstitute core units for the handheld lab-on-a-chip-based airborne particle monitoring system.For the airborne particle sampling, a novel method is developed by which the particles onthe solid surface are swept and sampled by electrowetting-actuated moving droplets. Theoreticalanalysis and experimental works along with microfabricated testing devices are carried out toinvestigate the underlying physics and to optimize the sampling conditions. The samplingconcepts are examined and proved on a solid surface and perforated filter membrane showinghigh sampling efficiencies.For the particle separation, a new separation scheme is developed in which the mixedparticles are separated within a mother droplet by traveling-wave dielectrophoresis (tw-DEP).Using the subsequent operation of droplet splitting by way of electrowetting, the separatedparticles can be isolated into each split droplet according to the DEP properties of the particles.This in-droplet separation is examined with many combinations of particles in microfabricateddevices. By investigating the particle behavior as function of the frequency of the traveling waveDEP signal, the separation efficiencies are optimized.The above microfluidic units constitute key components for upstream particle sampling anddownstream sample processing in the lab on a chip system, providing the following advantages:extremely small amount use of samples/reagents (2) no external pressure source required forfluidic operations, (3) simple design and fabrication since no mechanical moving structure