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

Implantable Microsystem Technologies For Nanoliter-Resolution Inner Ear Drug Delivery

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. The present work demonstrates a novel biocompatible, implantable, and scalable microsystem consisted of a thermal phase-change peristaltic micropump with wireless control and a refillable reservoir. The micropump is fabricated around a catheter microtubing (250 μm OD, 125 μm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Direct-write micro-scale printing technology was used to build the mechanical components of the pump around the microtubing directly on the back of a printed circuit board assembly. In vitro characterization results indicated nanoliter resolution control over the desired flow rates of 10–100 nL/min by changing the actuation frequency, with negligible deviations in presence of up to 10× greater than physiological backpressures and ±3°C ambient temperature variation. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. A stand-alone, refillable, in-plane, scalable, and fully implantable microreservoir platform was designed and fabricated to be integrated with the micropump. The microreservoir consists two main components: a cavity for storing the drug and a septum for refilling. The cavity membrane is fabricated with thin Parylene-C layers, using a polyethylene glycol (PEG) sacrificial layer. The septum thickness is minimized by pre-compression down to 1 mm. The results of in vitro characterization indicated negligible restoring force for the optimized cavity membrane and thousands of punctures through the septum without leakage. The micropump and microreservoir were integrated into microsystems which were implanted in mice. The microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. The results match with syringe pump gold standard. For the first time a miniature and yet scalable microsystem for inner ear drug delivery was developed, enabling drug discovery opportunities and translation to human

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

Design of a Customized multipurpose nano-enabled implantable system for in-vivo theranostics

The first part of this paper reviews the current development and key issues on implantable multi-sensor devices for in vivo theranostics. Afterwards, the authors propose an innovative biomedical multisensory system for in vivo biomarker monitoring that could be suitable for customized theranostics applications. At this point, findings suggest that cross-cutting Key Enabling Technologies (KETs) could improve the overall performance of the system given that the convergence of technologies in nanotechnology, biotechnology, micro&nanoelectronics and advanced materials permit the development of new medical devices of small dimensions, using biocompatible materials, and embedding reliable and targeted biosensors, high speed data communication, and even energy autonomy. Therefore, this article deals with new research and market challenges of implantable sensor devices, from the point of view of the pervasive system, and time-to-market. The remote clinical monitoring approach introduced in this paper could be based on an array of biosensors to extract information from the patient. A key contribution of the authors is that the general architecture introduced in this paper would require minor modifications for the final customized bio-implantable medical device

Laser-assisted processing of multilayer films for inexpensive and flexible biomedical microsystems

Flexible/stretchable electronics offer ideal properties for emerging health monitoring devices that can seamlessly integrate with the soft, curvilinear, and dynamic surfaces of the human body. The resulting capabilities have allowed novel devices for monitoring physiological parameters, improving surgical procedures, and human-machine interfaces. While the attractiveness of these devices are indubitable, their fabrication by conventional cleanroom techniques makes them expensive and incompatible with rapid large-scale (e.g., roll-to-roll) production. The purpose of this research is to develop inexpensive fabrication technologies using low-cost commercial films such as polyimide, paper, and metalized paper that can be utilized for developing various flexible/stretchable physical and chemical sensors for wearable and lab-on-chip applications. The demonstrated techniques focus on an array of laser assisted surfaces modification and micromachining strategies with the two commonly used CO2 and Nd: YAG laser systems. The first section of this dissertation demonstrates the use of localized pulsed CO2 laser irradiation to selectively convert thermoset polymer films (e.g., polyimide) into electrically conductive highly porous carbon micro/nanostructures.Thisprocessprovidesauniqueandfacileapproachfordirect writing of carbonized conductive patterns on flexible polyimide sheets in ambient conditions, eliminating complexities of current methods such as expensive CVD processes and complicated formulation/preparation of conductive carbon based inks used in ink jet printing. The highly porous laser carbonized layer can be transferred to stretchable elastomer or further functionalized with various chemical substances such as ionic solutions, nanoparticles, and chemically conductive polymers to create different mechanical and chemical sensors. The second section of this dissertation describes the use of laser ablation for selective removal of material from multilayer films such as ITO-coated PET, parchment paper, and metalized paper to create disposable diagnostic platforms and in-vitro models for lab-on-chip based studies. The ablated areas were analyzed using electrical, mechanical, and surface analysis tools to understand change in physical structure and chemical properties of the laser ablated films. As proof-of-concept demonstrations of these technologies, four different devices are presented here: mechanical, electrochemical, and environmental sensors along with an in-vitro cell culture platform. All four devices are designed, fabricated, and characterized to highlight the capability of commercial laser processing systems in the production of the next generation, low-cost and flexible biomedical devices

Conformable transistors for bioelectronics

The diversity of network disruptions that occur in patients with neuropsychiatric disorders creates a strong demand for personalized medicine. Such approaches often take the form of implantable bioelectronic devices that are capable of monitoring pathophysiological activity for identifying biomarkers to allow for local and responsive delivery of intervention. They are also required to transmit this data outside of the body for evaluation of the treatment’s efficacy. However, the ability to perform these demanding electronic functions in the complex physiological environment with minimum disruption to the biological tissue remains a big challenge. An optimal fully implantable bioelectronic device would require each component from the front-end to the data transmission to be conformable and biocompatible. For this reason, organic material-based conformable electronics are ideal candidates for components of bioelectronic circuits due to their inherent flexibility, and soft nature. In this work, first an organic mixed-conducting particulate composite material (MCP) able to form functional electronic components and non-invasively acquire high–spatiotemporal resolution electrophysiological signals by directly interfacing human skin is presented. Secondly, we introduce organic electrochemical internal ion-gated transistors (IGTs) as a high-density, high-amplification sensing component as well as a low leakage, high-speed processing unit. Finally, a novel wireless, battery-free strategy for electrophysiological signal acquisition, processing, and transmission that employs IGTs and an ionic communication circuit (IC) is introduced. We show that the wirelessly-powered IGTs are able to acquire and modulate neurophysiological data in-vivo and transmit them transdermally, eliminating the need for any hard Si-based electronics in the implant

An Optofluidic Lens Biochip and an x-ray Readable Blood Pressure Microsensor: Versatile Tools for in vitro and in vivo Diagnostics.

Three different microfabricated devices were presented for use in vivo and in vitro diagnostic biomedical applications: an optofluidic-lens biochip, a hand held digital imaging system and an x-ray readable blood pressure sensor for monitoring restenosis. An optofluidic biochip–termed the ‘Microfluidic-based Oil-Immersion Lens’ (mOIL) biochip were designed, fabricated and test for high-resolution imaging of various biological samples. The biochip consists of an array of high refractive index (n = 1.77) sapphire ball lenses sitting on top of an oil-filled microfluidic network of microchambers. The combination of the high optical quality lenses with the immersion oil results in a numerical aperture (NA) of 1.2 which is comparable to the high NA of oil immersion microscope objectives. The biochip can be used as an add-on-module to a stereoscope to improve the resolution from 10 microns down to 0.7 microns. It also has a scalable field of view (FOV) as the total FOV increases linearly with the number of lenses in the biochip (each lens has ~200 microns FOV). By combining the mOIL biochip with a CMOS sensor, a LED light source in 3D printed housing, a compact (40 grams, 4cmx4cmx4cm) high resolution (~0.4 microns) hand held imaging system was developed. The applicability of this system was demonstrated by counting red and white blood cells and imaging fluorescently labelled cells. In blood smear samples, blood cells, sickle cells, and malaria-infected cells were easily identified. To monitor restenosis, an x-ray readable implantable blood pressure sensor was developed. The sensor is based on the use of an x-ray absorbing liquid contained in a microchamber. The microchamber has a flexible membrane that is exposed to blood pressure. When the membrane deflects, the liquid moves into the microfluidic-gauge. The length of the microfluidic-gauge can be measured and consequently the applied pressure exerted on the diaphragm can be calculated. The prototype sensor has dimensions of 1x0.6x10mm and adequate resolution (19mmHg) to detect restenosis in coronary artery stents from a standard chest x-ray. Further improvements of our prototype will open up the possibility of measuring pressure drop in a coronary artery stent in a non-invasively manner.PhDMacromolecular Science and EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111384/1/toning_1.pd

Intracortical Neural Probes with Post-Implant Self-Deployed Electrodes for Improved Chronic Stability.

This thesis presents a new class of implantable intracortical neural probe with small recording electrodes that deploy away from a larger main shank after insertion. This concept is hypothesized to enhance the performance of the electrodes in chronic applications. Today, electrodes that can be implanted into the brain for months or years, are an irreplaceable tool for brain machine interfaces and neuroscience studies. However, these chronically implanted neural probes suffer from continuous loss of signal quality, limiting their utility. Histological studies found a sheath of scar tissue with decreased neural density forming around probe shanks as part of an ongoing chronic inflammation. This was hypothesized to contribute to the deterioration of recorded signals. The neural probes developed in this thesis are designed to deploy electrodes outside this sheath such that they interface with healthier neurons. To achieve this, an actuation mechanism based on starch-hydrogel coated microsprings was integrated into the shank of neural probes. Recording electrodes were positioned at the tip of micrometer fine and flexible needles that were attached to the springs. Before insertion, the hydrogel dehydrates, retracting the springs. After insertion, the gel rehydrates, releasing the springs, which then deploy the electrodes. The actuation mechanism functions in a one-time release fashion, triggered by contact with biological fluids at body temperature. The deployment of the electrodes occurred over the course of two hours and can be divided into three stages: For the first 20 s, the electrodes did not deploy. Within the first three minutes they deployed by roughly 100 µm (0.5 µm/s). Tor the following two hours they deployed an additional 20 µm (0.17 µm/min). The employed design supported six deploying electrodes, each at the end of a 5 µm wide and thick, and 100 µm long needle. These were attached to a shank with 290 µm width, 12 µm thickness and 3 mm length. The shanks could be inserted into the cortex of rats through an opening in the pia without breaking. The acquired waveforms indicate that some of the deployed electrodes were able to record neural action potentials.PhDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113317/1/egertd_1.pd