Test Structures for Developing Packaging for Implantable Sensors

With their capacity for real time monitoring and spatial mapping, implantable sensors are becoming an increasingly important aspect of next generation precision healthcare. Microfabricated sensor systems are a popular choice, owing to their capacity for miniaturisation, repeatable mass manufacture, and numerous pre-existing sensor archetypes. Despite the drive for development, packaging these sensors for the environment within the body, as well as the implantation process itself, presents a significant challenge. This paper presents microelectronic test structures, which can be used to assess, compare, and optimise implantable packaging solutions in a standardised manner. The proposed structures are used to investigate: (i) the capacity of the material to be patterned, (ii) the permeability of the insulation material, (iii) adhesion of the encapsulant to the die, and (iv) the physical robustness of the package to implantation through a needle. They are used to characterise an example packaging strategy, using biocompatible epoxy-resin. In addition, a method of optimising the packaging performance using the test structures is presented

Post-operative monitoring of intestinal tissue oxygenation using an implantable microfabricated oxygen sensor

Anastomotic leakage (AL) is a common and dangerous post-operative complication following intestinal resection, causing substantial morbidity and mortality. Ischaemia in the tissue surrounding the anastomosis is a major risk-factor for AL development. Continuous tissue oxygenation monitoring during the post-operative recovery period would provide early and accurate early identification of AL risk. We describe the construction and testing of a miniature implantable electrochemical oxygen sensor that addresses this need. It consisted of an array of platinum microelectrodes, microfabricated on a silicon substrate, with a poly(2-hydroxyethyl methacrylate) hydrogel membrane to protect the sensor surface. The sensor was encapsulated in a biocompatible package with a wired connection to external instrumentation. It gave a sensitive and highly linear response to variations in oxygen partial pressure in vitro, although over time its sensitivity was partially decreased by protein biofouling. Using a pre-clinical in vivo pig model, acute intestinal ischaemia was robustly and accurately detected by the sensor. Graded changes in tissue oxygenation were also measurable, with relative differences detected more accurately than absolute differences. Finally, we demonstrated its suitability for continuous monitoring of tissue oxygenation at a colorectal anastomosis over a period of at least 45 h. This study provides evidence to support the development and use of implantable electrochemical oxygen sensors for post-operative monitoring of anastomosis oxygenation

A Low Cost Patternable Packaging Technology for Biosensors

This paper demonstrates a simple and low cost technology to reliably and accurately package integrated chips. Microchannels and cavities of minimum feature size of 500 μm can be reliably reproduced. In addition, the curing depth in relation to the exposure time was investigated. A simple microfluidic device, consisting of a 500 μm channel and 2 mm ports, was manufactured to demonstrate the possibilities of this technology. Extensive electrochemical experiments showed that the packaging material is a good insulator and leaves no residue on the chip

Synaptophysin sustains presynaptic performance by preserving vesicular synaptobrevin-II levels

The two most abundant molecules on synaptic vesicles (SVs) are synaptophysin and synaptobrevin-II (sybII). SybII is essential for SV fusion, whereas synaptophysin is proposed to control the trafficking of sybII after SV fusion and its retrieval during endocytosis. Despite controlling key aspects of sybII packaging into SVs, the absence of synaptophysin results in negligible effects on neurotransmission. We hypothesised that this apparent absence of effect may be because of the abundance of sybII on SVs, with the impact of inefficient sybII retrieval only revealed during periods of repeated SV turnover. To test this hypothesis, we subjected primary cultures of synaptophysin knockout neurons to repeated trains of neuronal activity, while monitoring SV fusion events and levels of vesicular sybII. We identified a significant decrease in both the number of SV fusion events (monitored using the genetically encoded reporter vesicular glutamate transporter-pHluorin) and vesicular sybII levels (via both immunofluorescence and Western blotting) using this protocol. This revealed that synaptophysin is essential to sustain both parameters during periods of repetitive SV turnover. This was confirmed by the rescue of presynaptic performance by the expression of exogenous synaptophysin. Importantly, the expression of exogenous sybII also fully restored SV fusion events in synaptophysin knockout neurons. The ability of additional copies of sybII to fully rescue presynaptic performance in these knockout neurons suggests that the principal role of synaptophysin is to mediate the efficient retrieval of sybII to sustain neurotransmitter release

Comparison of Conventional and Maskless Lithographic Techniques for More than Moore Post-processing of Foundry CMOS Chips

This article details and compares the technology options for post-processing foundry produced CMOS at chip-scale to enable More than Moore functionality. In many cases there are attractions in using chip-based processing through the Multi-Project Wafer route that is frequently employed in research, early-stage development and low-volume production. This article identifies that spray-based photoresist deposition combined with optical maskless lithography demonstrates sufficient performance combined with low cost and operational convenience to offer an attractive alternative to conventional optical lithography, where spin-coated photoresist is exposed through a patterned photomask. [2020-0249

Optimization of Nafion Polymer Electrolyte Membrane Design and Microfabrication

Nafion is a solid electrolyte polymer that can be used as a sensor membrane in microfabricated electrochemical oxygen sensors. It allows ions to be transported between the sensor electrodes and removes the need for a liquid electrolyte. Here we used a series of small square Nafion test structures, fabricated on a variety of materials using standard thin-film patterning techniques, to optimize the design and processing of Nafion membranes. Measurements showed that the choice of photoresist developer is critical. Use of diluted MF-26A developer provided the most effective and manufacturable process. The underlying material also had an influence on robustness, with silicon dioxide and platinum giving the longest membrane lifetime under simulated conditions of use. Membrane size had no clear effect on lifetime, and under optimal processing conditions there were minimal failures even under continuous mechanical agitation for up to six weeks. We also developed test electrodes covered by Nafion, and showed that they were effective at supporting electrochemical oxygen detection

Test structures for the characterisation of sensor packaging technology

This paper presents three test structures targeted at characterising sensor packaging materials for liquid environments. The test structures enable the evaluation of: 1) the successful removal of packaging material on sensing areas, 2) the permeability of the packaging material to its environment, 3) electrical continuity through the packaging process, and 4) the ingress of the liquid environment between the packaging material and the chip surface. The paper presents an example of the evaluation of a UV curable resin as packaging process for a biomedical sensor