A generic packaging technique using fluidic isolation for low-drift implantable pressure sensors

This paper reports on a generic packaging method for reducing drift in implantable pressure sensors. The described technique uses fluidic isolation by encasing the pressure sensor in a liquid-filled medical-grade polyurethane balloon; thus, isolating it from surrounding aqueous environment that is the major source of baseline drift. In-vitro tests using commercial micromachined piezoresistive pressure sensors show an average baseline drift of 0.006 cmH2O/day (0.13 mmHg/month) for over 100 days of saline soak test, as compared to 0.101 cmH2O/day (2.23 mmHg/month) for a non-fluidic-isolated one soaked for 18 days. To our knowledge, this is the lowest reported drift for an implantable pressure sensor

Long Term Implantable Pressure Sensors

The benefits of implantable pressure sensors for continuous monitoring of diseases like glaucoma or hydrocephalus has been well established, but it has been difficult to achieve accurate pressure sensing in the body for more than one month. In this thesis, a general MEMS pressure sensor packaging method called parylene-oil-encapsulation is developed and analyzed in order to make commercial barometers for use in air suitable for implantation inside the body long term. Accelerated aging bench top data is presented and a wireless implantable intraocular pressure sensor has been built towards proving the viability of the packaging method in vivo.</p

Design, manufacturing and characterisation of a wireless flexible pressure sensor system for the monitoring of the gastro-intestinal tract

Ingestible motility capsule (IMC) endoscopy holds a strong potential in providing advanced diagnostic capabilities within the small intestine with higher patient tolerance for pathologies such as irritable bowel syndrome, gastroparesis and chronic abdominal amongst others. Currently state-of-the art IMCs are limited by the use of obstructive off-the-shelf sensing modules that are unable to provide multi-site tactile monitoring of the Gastro-Intestinal tract. In this work a novel 12 mm in diameter by 30 mm in length IMC is presented that utilises custom-built flexible, thin-film, biocompatible, wireless and highly sensitive tactile pressure sensors arrays functionalising the capsule shell. The 150 μm thick, microstructured, PDMS flexible passive pressure sensors are wirelessly powered and interrogated, and are capable of detecting pressure values ranging from 0.1 kPa up to 30 kPa with a 0.1 kPa resolution. A novel bottom-up wafer-scale microfabrication process is presented which enables the development of these ultra-dense, self-aligned, scalable and uniquely addressable flexible wireless sensors with high yield (>80%). This thesis also presents an innovative metallisation microfabrication process on soft-elastomeric substrates capable to withstand without failure of the tracks 180o bending, folding and iterative deformation such as to allow conformable mapping of these sensors. A custom-built and low-cost reflectometer system was also designed, built and tested within the capsule that can provide a fast (100 ms) and accurate extraction (±0.1 kPa) of their response. In vitro and in vivo characterisation of the developed IMC device is also presented, facilitated respectively via the use of a biomimetic phantom gut and via live porcine subjects. The capsule device was found to successfully capture respiration, low-amplitude and peristaltic motility of the GI tract from multiple sites of the capsule.UK Engineering & Physical Sciences Research Council (EPSRC) through the Programme Grant Sonopill (EP/K034537/2)James Watt Scholarshi

Bio-Micro-Systems for Diagnostic Applications, Disease Prevention and Creating Tools for Biological Research

This thesis, divided into two parts, describes the development of 5 novel Bio-Micro-System devices. The term Bio-Micro-System has been used here to describe BioMEMS and 3D printed devices, with the dimensions of key components ranging from micrometers to a millimeter. Part A is focused on ‘Medical’ Micro-System devices that can potentially solve common medical problems. Part B is focused on ‘Biological’ Micro-System devices/tools for facilitating/enabling biological research. Specifically, Part A describes two implantable, electronics-free intraocular pressure (IOP) microsensors for the medical management of glaucoma: 1) Near Infrared Fluorescence-based Optomechanical (NiFO) technology - Consists of an implantable, pressure sensor that ‘optically encodes’ pressure in the near infrared (NIR) regime. A non-implantable, portable and compact optical head is used to excite the sensor and collect the emitted NIR light. The thesis discusses optimized device architecture and microfabrication approaches for best performance commercialization. 2) Displacement based Contrast Imaging (DCI) technology - A proof of concept, fluid pressure sensing scheme is shown to operate over a pressure range of 0–100 mbar (∼2 mbar resolution between 0–20 mbar,∼10 mbar resolution between 20–100 mbar), with a maximum error of <7% throughout its dynamic range. The thesis introduces the DCI technology and discusses its application as an IOP sensor. Moreover, Part A also describes a Touch-activated Sanitizer Dispensing (TSD) system for combating community acquired infections. The TSD can be mounted on any surface that is exposed to high human traffic and consists of an array of human-powered, miniaturized valves that deliver a small amount of disinfectant when touch actuated. The device disinfects the person’s hand that is touching it while being self-sterilized at the same time. The thesis describes the design and implementation of a proof of concept TSD that can disinfect an area equivalent to the size of a thumb. A significant (~ 10 fold) reduction in microbiological load is demonstrated on the fingertip and device surface within the first 24 hours. The size and footprint of the TSD can be scaled up as needed to improve hand hygiene compliance. In Part B, we developed a microfluidic chip for immobilizing Drosophila melanogaster larva by creating a cold micro-environment around the larva. After characterizing on chip temperature distribution and larval body movement, results indicate that the method is appropriate for repetitive and reversible, short-term (several minutes) immobilization. The method offers the added advantage of using the same chip to accommodate and immobilize larvae across all developmental stages (1st instar-late 3rd instar). Besides the demonstrated applications of the chip in high resolution observation of sub cellular events such as mitochondrial trafficking in neurons and neuro-synaptic growth, we envision the use of this method in a wide variety of biological imaging studies employing the Drosophila larval system, including cellular development and other studies. Finally, Part B also describes a 3D printed millifluidic device for CO2 immobilization of Caenorhabditis elegans populations. We developed a novel 3D printed device for immobilizing populations of Caenorhabditis elegans by creating a localized CO2 environment while the animals are maintained on the surface of agar. The results indicate that the method is easy to implement, is appropriate for short-term (20 minutes) immobilization and allows recovery within a few minutes. We envision its use in a wide variety of biological studies in Caenorhabditis elegan, including cellular development and neuronal regeneration studies.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144050/1/amritarc_1.pd

Application of Parylene C thin films in cardiac cell culturing

There are two main challenges when producing in vitro cell systems: first, to reconstitute the in situ cellular microenvironment, thus delivering more representative and reliable cell models for drug screening and disease modelling studies. Second, to record and quantify the electrical and chemical gradients across the culture. Ideally, both challenges should be accomplished within a single platform towards a lab-on-chip implementation. This research work investigates the application of Parylene C in cardiac cell scaffolding and its integrability with electrochemical monitoring technologies for measuring extracellular action potentials and pH. The surface properties of Parylene C in terms of water affinity, chemical composition and nanotopography were characterised before and after modifying the material's inherent hydrophobicity through oxygen plasma. A technology was developed to selectively alter the surface hydrophobicity of Parylene C through standard lithography and oxygen plasma, which is characterised by μm-resolution and long-term pattern stability, and can accurately control the extent of induced hydrophilicity, the pattern layout and 3-D geometry. The micro-engineered Parylene C films were employed as scaffolds for cardiac cells with immature physiological properties, such as neonatal rat ventricular myocytes (NRVM). The scaffolds promoted a more in situ cellular structure and organisation, while they improved important calcium (Ca2+) cycling parameters such as fluorescent amplitude, time to peak (Tp), time to 50% (T50) and 90% (T90) decay at 0.5-2 Hz field stimulation. The thickness of the patterned Parylene C films was found to regulate the shape of the cells by controlling their adhesion area on the Parylene substrate through a thickness-dependent hydrophobicity. NRVM on thin (2 μm) membranes tended to bridge across the hydrophobic areas and adopt a spread-out shape (average contact angle at the level of the nucleus was 64.51o). On the other hand, cells on thick (10 μm) films were mostly constrained on the hydrophilic areas and demonstrated a more elongated, cylindrical (in vivo-like) shape (average contact angle was 84.73o). The cylindrical shape and a significantly (p <0.05) denser microtubule structure in cells on thick films possibly suggest a more mature cardiomyocyte. However, there was no significant effect on the Ca2+ physiology between the two groups. The micro-patterning technology was able to deliver free-standing Parylene C thin films (2-10 μm) to study the effect of substrate elasticity and flexibility on the Ca2+ physiology of NRVM. Preliminary results showed that fluorescent amplitude and time to peak were improved in structured NRVM cultures on stand-alone Parylene films compared to rigid Parylene-coated glass surfaces. However, no such trend was present in Ca2+ release parameters (T50, T90). The flexibility of the culture substrate was also manipulated by employing free-standing micro-patterned Parylene C films of distinct thicknesses (2-10 μm), but did not affect the cellular Ca2+ physiology. Further biological validation is needed with a larger sample size to draw a certain conclusion. The cell patterning technology was transferred to commercially available planar Multi-Electrode arrays (MEAs) to demonstrate integrability of this method with existing monitoring tools. The micro-patterned MEAs induced anisotropic cardiomyocyte cultures, as they substantially increased the longitudinal-to-transverse velocity anisotropy ratios (1.09, n=4 to 1.69, n=2), promoting action potential propagation profiles that closer resembled native cardiac tissue. Furthermore, the micro-engineered MEAs were proven to be reusable, yielding a versatile and low-cost approach that is compatible with state-of-art recording equipment and can be employed as a more reliable, off-the-shelf tool for drug screening studies. Selective hydrophilic modification of Parylene C was also employed to activate locally the H+ sensing capacity of such films, implementing extended-gate pH sensors. The ability of Parylene C to act in a dual way - as an encapsulation material and as an active pH sensing membrane - was demonstrated. The material exhibited a distinguishable sensitivity dependent on the oxygen plasma recipe, relatively low drift rates and excellent encapsulation quality. Based on these principles, flexible Parylene-based high-density miniaturised electrode arrays were fabricated, employing Parylene as a flexible structure material and as a H+ sensing membrane for local detection of pH. The presented Parylene-based technology has the potential to deliver integrated lab-on-chip implementations for growing cells in vitro with controlled microtopography while monitoring the extracellular electrical and pH gradients across the culture in a non-invasive way, with application in drug screening and disease modelling.Open Acces

A novel approach for micro-antenna fabrication on ZrO2 substrate assisted by laser printing for smart implants

The use of Yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) in medicine has rapidly expanded over the past decade, driven by its advantageous properties, showing potential to overcome titanium alloy in implant fabrication. The release of metal ions and the aesthetic problems of titanium alloy implants are the main reasons for this trend. In addition to meeting expectations regarding its properties, an implant must possess intrinsic capacities such as auto-diagnostic and auto-treatment. Thus, based on the concept of smart implants, this work proposes a hybrid approach for printing a part of the communication system of a zirconia implant by resorting to laser technology, aiming to endow the implant with intrinsic capacities. Therefore, the antenna was designed and then printed on the zirconia surface. The laser was applied as a versatile tool, whether for preparing the surface of the material in a subtractive way, by creating the micro-cavity, or for printing the silver-based antenna in an additive way through laser technology. The silver powder was used as the conductor material of the antenna. The results revealed that the antenna is capable of communicating from inside the body with the outside world without needing to have an exterior antenna attached to the skin.This work has been supported by the FCT (Fundação para a Ciência e Tecnologia -Portugal) in the scope of the projects UID/EEA/04436/2019; Magsense_POCI-01-0247-FEDER-033783, Add.Additive_Manufacturing to Portuguese Industry_POCI-01-0247-FEDER-024533, grant SFRH/BD/ 116554/2016 and the CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) for the grant 205791/2014-

Next-Generation Diamond Electrodes for Neurochemical Sensing: Challenges and Opportunities

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. Carbon-based electrodes combined with fast-scan cyclic voltammetry (FSCV) enable neurochemical sensing with high spatiotemporal resolution and sensitivity. While their attractive electrochemical and conductive properties have established a long history of use in the detection of neurotransmitters both in vitro and in vivo, carbon fiber microelectrodes (CFMEs) also have limitations in their fabrication, flexibility, and chronic stability. Diamond is a form of carbon with a more rigid bonding structure (sp3-hybridized) which can become conductive when boron-doped. Boron-doped diamond (BDD) is characterized by an extremely wide potential window, low background current, and good biocompatibility. Additionally, methods for processing and patterning diamond allow for high-throughput batch fabrication and customization of electrode arrays with unique architectures. While tradeoffs in sensitivity can undermine the advantages of BDD as a neurochemical sensor, there are numerous untapped opportunities to further improve performance, including anodic pretreatment, or optimization of the FSCV waveform, instrumentation, sp2 /sp3 character, doping, surface characteristics, and signal processing. Here, we review the state-of-the-art in diamond electrodes for neurochemical sensing and discuss potential opportunities for future advancements of the technology. We highlight our team’s progress with the development of an all-diamond fiber ultramicroelectrode as a novel approach to advance the performance and applications of diamond-based neurochemical sensors

High-resolution 3D printing enabled, minimally invasive fibre optic sensing and imaging probes

Minimally invasive surgical procedures have become more favourable to their traditional surgical counterparts due to their reduced risks, faster recovery times and decreased trauma. Despite this, there are still some limitations involved with these procedures, such as the spatial confinement of operating through small incisions and the intrinsic lack of visual or tactile feedback. Specialised tools and imaging equipment are required to overcome these issues. Providing better feedback to surgeons is a key area of research to enhance the outcomes and safety profiles of minimally invasive procedures. This thesis is centred on the development of new microfabrication methods to create novel fibre optic imaging and sensing probes that could ultimately be used for improving the guidance of minimally invasive surgeries. Several themes emerged in this process. The first theme involved the use and optimisation of high-resolution 3D injection of polymers as sacrificial layers onto which parylene-C was deposited. One outcome from this theme was a series of miniaturised parylene-C based membranes to create fibre optic pressure sensors for physiological pressure measurements and for ultrasound reception. The pressure sensor sensitivity was found to vary from 0.02 to 0.14 radians/mmHg, as the thickness of parylene was decreased from 2 to 0.5 μm. The ultrasound receivers were characterised and exhibited a noise equivalent pressure (NEP) value of ~100 Pa (an order of magnitude improvement compared to similarly sized piezoelectric hydrophones). A second theme employed high-resolution 3D printing to create microstructures of polydimethylsiloxane (PDMS) and subsequently formed nanocomposites, to create microscale acoustic hologram structures. This theme included the development of innovative manufacturing processes such as printing directly onto optical fibres, micro moulding and precise deposition which enabled the creation of such devices. These microstructures were investigated for reducing the divergence of photoacoustically-generated ultrasound beams. Taken together, the developments in this thesis pave the way for 3D microfabricated polymer-based fibre optic sensors that could find broad clinical utility in minimally invasive procedures

Integrated Electronics for Wireless Imaging Microsystems with CMUT Arrays

Integration of transducer arrays with interface electronics in the form of single-chip CMUT-on-CMOS has emerged into the field of medical ultrasound imaging and is transforming this field. It has already been used in several commercial products such as handheld full-body imagers and it is being implemented by commercial and academic groups for Intravascular Ultrasound and Intracardiac Echocardiography. However, large attenuation of ultrasonic waves transmitted through the skull has prevented ultrasound imaging of the brain. This research is a prime step toward implantable wireless microsystems that use ultrasound to image the brain by bypassing the skull. These microsystems offer autonomous scanning (beam steering and focusing) of the brain and transferring data out of the brain for further processing and image reconstruction. The objective of the presented research is to develop building blocks of an integrated electronics architecture for CMUT based wireless ultrasound imaging systems while providing a fundamental study on interfacing CMUT arrays with their associated integrated electronics in terms of electrical power transfer and acoustic reflection which would potentially lead to more efficient and high-performance systems. A fully wireless architecture for ultrasound imaging is demonstrated for the first time. An on-chip programmable transmit (TX) beamformer enables phased array focusing and steering of ultrasound waves in the transmit mode while its on-chip bandpass noise shaping digitizer followed by an ultra-wideband (UWB) uplink transmitter minimizes the effect of path loss on the transmitted image data out of the brain. A single-chip application-specific integrated circuit (ASIC) is de- signed to realize the wireless architecture and interface with array elements, each of which includes a transceiver (TRX) front-end with a high-voltage (HV) pulser, a high-voltage T/R switch, and a low-noise amplifier (LNA). Novel design techniques are implemented in the system to enhance the performance of its building blocks. Apart from imaging capability, the implantable wireless microsystems can include a pressure sensing readout to measure intracranial pressure. To do so, a power-efficient readout for pressure sensing is presented. It uses pseudo-pseudo differential readout topology to cut down the static power consumption of the sensor for further power savings in wireless microsystems. In addition, the effect of matching and electrical termination on CMUT array elements is explored leading to new interface structures to improve bandwidth and sensitivity of CMUT arrays in different operation regions. Comprehensive analysis, modeling, and simulation methodologies are presented for further investigation.Ph.D

Fibre optic pressure sensors in healthcare applications

This PhD thesis provides an extensive description of the development of two fibre optic pressure sensors for applications in health care: (i) a miniature fibre optic Fabry–Perot pressure sensor for fluid pressure measurements in invasive blood pressure monitoring and; (ii) a highly sensitive fibre Bragg grating sensor for contact/interface pressure measurement. The fibre optic Fabry-Perot pressure sensor has a diameter of 125 μm and is created by forming a cavity at the tip of a single-mode optical fibre. Parylene films were used as the pressure-sensitive diaphragm. The performance of three sensors with different aspect ratios has been investigated. The pressure sensing range of ~10 kPa (diastolic pressure)- ~15 kPa (systolic pressure) was targeted; sensor with the cavity of 70 μm in diameter and cavity length of 87 μm is able to sense within a range of 0- 18 kPa with an average sensitivity of 0.12 nm/kPa and response time of 3 seconds. The temperature sensitivity of 0.084 nm/°C was observed. Hysteresis and wavelength drift were observed for the sensors, which may be due to the permeability of the Parylene film to the air. Solutions for reducing hysteresis, wavelength drift and temperature cross-sensitivity are discussed in detail. Fibre Bragg grating (FBG) sensor technology is an ideal candidate for contact pressure measurement in compression therapy, pressure ulcer or prosthetics due to its many advantages such as conforming to body parts, small size, biocompatibility and multiplexing capabilities. A successful mathematical model for an FBG contact pressure sensor for healthcare applications has been presented and experimentally validated. The model has been compared with previous studies reported in the literature and takes into account birefringence. The highest sensitivity was achieved for the disc shape with a sensitivity of 0.8719 nm/MPa for a diameter of 5.5 mm, thickness of 1 mm and Young’s modulus of 20 MPa. This sensor was comprised of a 3 mm long FBG 6 centrally located in the patch. This is a pressure sensitivity of ~270 times increase when compared with a bare FBG reported in the literature. Birefringence effect was observed for the disk patch for pressures larger than 2.6 MPa. Even though FBGs provide high sensitivity in contact pressure sensing in healthcare, the potential applications are limited by the size and cost of commercially available FBG interrogators. A successful first attempt towards the development of a single channel compact FBG interrogation was accomplished. The system consists of a three-section distributed Bragg Reflector (DBR) tuneable laser, microcontroller unit, precision 5 channel current driver IC, photodiode circuit and a temperature controller IC. The tuneable laser was calibrated within 1535-1544 nm wavelength range to produce three current–wavelength lookup tables for wavelength resolution of 1 nm, 0.1 nm, 0.01 nm which is dependent on the current resolution. Futureworkincludesaddingpowercircuitry, a photodiode circuit and a feedback circuit to minimize power fluctuations. The system was tested compared to the commercial Smartscope FBG interrogator