Advancements in healthcare technology are driving innovation through the decentralization and personalization of medicine. The convergence of Pharma, MedTech, and ECS industries has led to new medical domains, including bioelectronic medicines and personalized ultrasound. Ultrasound, particularly through Micromachined Ultrasonic Transducers (MUTs), is a key technology in these fields. MUTs, which include CMUTs (Capacitive Micromachined Ultrasonic Transducers) and PMUTs (Piezoelectric Micromachined Ultrasonic Transducers), offer benefits over traditional PZT transducers, such as lower costs and the absence of toxic materials.
This thesis focuses on pre-charged collapse-mode CMUTs, which operate without a DC bias voltage, making them suitable for in-body applications. This is achieved by embedding a charge storage layer in their dielectric. The research involved designing and testing a first and second generation of CMUTs with different charge storage layers. The second generation showed improved performance and comparable results to standard externally biased CMUTs.
The primary application explored was using pre-charged CMUTs as ultrasonic power receivers for implantable devices. The impact of lateral and angular misalignment on power efficiency was studied, with angular misalignment being most detrimental. Solutions proposed included decreasing the frequency, partitioning the receiving transducer, and using a beamforming algorithm.
Experimental evaluations showed power conversion efficiencies up to 80% with optimal load and about 50% with a resistive load at 2.5 MHz. These efficiencies are comparable to those achieved with PZT transducers but with better biocompatibility.
Finally, the thesis demonstrated the functionality of the first ultrasonically powered implantable device using pre-charged CMUTs for battery charging. The device achieved a total system efficiency of 21%, significantly better than other implantable devices using PMUT or PZT transducers.
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Objective: This work focuses on the feasibility of using Electrical Impedance Spectroscopy (EIS) to differentiate between cancerous and healthy tissues in real-time alongside the GI tract. This is to see whether it is possible to support surgeons when taking biopsies, or to see if it is possible to make biopsies obsolete with EIS. Methods: The study is limited to three tissue types representing the GI tract. These tissues are the esophagus, ileum, and colon tissue. Impedance measurements are taken with a 4-electrode probe on a Hewlett Packard 4192A LF HP Impedance Analyzer. All measurements are taken over a frequency range of 1 kHz to 7 MHz in 300 steps. Seven patients are included: three esophagus, two
leum, and two colon. Forty-eight ex vivo measurements are taken; 32 are on healthy tissue and 16 on cancerous tissue. Almost all measurements are verified by histological assessment (golden standard). In this work, a combination of parameterization with a classification method is made to create a classification strategy. These can be listed as the Cole impedance model, the two-pole Cole impedance model, the two-pole Cole impedance model in combination with a
Constant Phase Element (CPE), and PCA. The Cole impedance models are combined with thresholding, and the PCA is combined with a SVM. Results: The thresholding algorithm is created in combination with the α2 parameter (P < 0.05) from the two-pole Cole impedance model in combination with a CPE. The thresholding value is determined in a LOOCV approach via ROC curves created to search for the threshold that gives the most significant summation of sensitivity and specificity. In the combination of PCA and SVM, the PCA uses three principal components (containing 96.37% of the total variance), and the SVM applies an Radial Basis Function (RBF) kernel. For the 2-pole Cole impedance model with CPE
in combination with thresholding, we find an accuracy 0.5208, sensitivity 0.4375, specificity 0.5625, Positive Predictive Value (PPV) 0.3333, Negative Predictive Value (NPV) 0.6666, and Mathews Correlation Coefficient (MCC) 0.0000. For the PCA in combination with the SVM, we find an accuracy of 0.4167, a sensitivity of 0.0000, specificity of 0.6250, PPV of 0.0000, NPV of 0.5556, and MCC -0.4082. Conclusion: It is concluded that we cannot create an algorithm that either supports surgeons or replaces a biopsy in the GI tract with the current setup. This is highly likely due to the extremely low amount of data that is included to train
the algorithm.

Drug efficacy and side effects are significantly impacted by the first-pass metabolism, a sequence of events that occurs in the stomach and the liver after oral ingestion. Accurate prediction of this mechanism is crucial for a faster and more cost-efficient drug development process. Replicating the first-pass metabolism in vitro using standard cell culture techniques is challenging due to its complexity involving simultaneous transport and organ-organ interactions in both the gut and liver tissue. A more precise in vitro to in vivo translation of drug distribution, efficacy, and toxicity may be provided by organ-on-a-chip (OoC) models, thereby creating the ability to partially replace currently-used animal models. More specifically, gut-liver-on-a-chip models can aid with in vitro predictions of oral drug administration and the first-pass metabolism. Therefore, the aim of this thesis was to develop an OoC system that could accommodate both intestinal and hepatic cell sources. A hollow fiber membrane (HFM) as a cell scaffold was a critical component of the chip design in order to more accurately reproduce the three-dimensional native environment of the cells. Additionally, the system would need to exhibit the ability to be interconnected quickly and easily, thereby creating the possibility to develop a MOoC system in a plug-and-play manner in a later stage of development, enabling the ultimate realization of organ-organ interactions.

With today’s aging population and the prevalence of chronic illnesses, healthcare systems worldwide are struggling to accommodate the increasing number of patients. This projected growth and rising demand underscore the importance of advancing wearable devices. In the realm of diagnostic healthcare, the pursuit of non-invasive and safe techniques is paramount. Until now, body patches have predominantly focused on monitoring surface-level body parameters such as temperature, humidity, pH, oxygen saturation, and electric potentials. The introduction of ultrasound patches extends the realm of possibilities, enabling a deeper exploration of physiological processes within the body. Additionally, ultrasound serves as a non-invasive diagnostic technique. To facilitate medical ultrasound imaging, an acoustic interface is indispensable for the unimpeded transmission of waves through the skin and tissue. This interface must maintain proper hydration and adhere to the skin to ensure a conforming acoustic connection. Initially, this MSc. thesis research aimed to conduct lifetime performance tests on promising ultrasound acoustic interface materials. These tests were conducted by placing wearable ultrasound patches with the acoustic interface materials in place on an ultrasound phantom. With the ultrasound transducer, ultrasound images were made over a fixed period. This experiment was done to see to which extent the image quality would degrade over time for the different interface materials. The available ultrasound phantoms did not meet the requirements of skin-mimicking properties, on which the lifetime of the acoustic materials would be tested. Consequently, this research opted to simulate specific skin conditions: temperature, moisture, and acoustic properties like human tissue. Different iterations were made and evaluated during the development of the final ultrasound phantom model. In this thesis, five different models were evaluated, and eventually, the final model was presented: A three-layer model. The phantom model consists of a gel wax filled with scattering objects, visible with ultrasound, at specific depths inside the filling. To mimic the water loss rate of the skin, a hydrating layer of agar was placed on top of the gel wax filling. A PET foil was deployed with a specific number of holes to let water through from the agar layer to regulate the amount of water evaporation over time. To mimic skin temperature, the phantom model was placed in an oven at T = 34 °C. With this final model, the lifetime experiments were conducted with six potential interface materials: AquaFlex (solid hydrogel), HydroAid (solid hydrogel), Ecoflex (silicone), Axelgaard (ECG solid hydrogel), HH5023 (ECG solid hydrogel), and HH5450 (ECG solid hydrogel). The duration of this experiment was eight days, after which the agar layer started to degrade and shrink. The filling and scattering objects of the phantom model are reusable, while the hydration layer has to be replaced or disposed of after five days. Further, acoustic properties, like materials-specific attenuation coefficient, of potential acoustic interface materials and materials used in the phantom were measured using a though-transmission setup. Also, a validation assessment of skin compatibility of the potential interface materials for a long duration of time was conducted. This was done with the consultation of experts in medical devices, medical professionals and literature. With these three different subjects of this MSc. the attenuation coefficient of six different acoustic interface materials are characterized and validated to be compatible with human skin for longer periods. The phantom model developed satisfies the requirements set and, most importantly, mimics skin temperature and water loss rate. One round lifetime (eight days) performance experiments of acoustic interface materials using the phantom model. It is difficult to conclude to which extend the image quality degraded over time for the different interface materials due to the agar layer dehydration after eight days and that the experiment was only conducted once. For future recommendations, it is suggested that the lifetime experiments be repeated using the phantom model for these six different interface materials. It could also be an option to renew the hydration layer every seven days to prevent the agar layer from dehydrating over the acceptable limit if the experiment requires longer periods.

Cardiorenal Syndrome (CRS) is a multi-organ disease characterized by a reciprocal pathological interaction between the heart and kidneys during acute or chronic injury. Yet, a complete understanding of the underlying bi-directional pathophysiological mechanisms is lacking, hence obscuring effective diagnostic strategies, patient stratification and adequate administering of intervention therapies. Thus far, CRS has only been modelled in in vivo animal models, which are inherently limited in terms of experimental control and translatability of results to humans physiology. This underlines the need to develop more advanced in vitro models that accurately recapitulate the complex inter-organ cross talk responsible for the onset and progression of CRS. However, to date no such disease model system has been reported.

This project set out to design, develop and validate a microfluidic set-up, which would then enable the investigation of CRS in a three-dimensional environment. To that end, a theoretical framework covering all aspects related to Multi-Organ-On-Chip (MOoC) design was developed. This framework then formed the foundation for an extensive list of requirements to establish an ideal microfluidic set-up for a heart-kidney disease model. Various conceptual circuit designs were proposed and evaluated on the basis of the set requirements and their associated priority.

By executing feasibility studies, simulating computational fluid dynamics, designing specific organoid inserts and eventually setting-up the proposed microfluidic circuits, a better understanding of the technological and biological challenges to be addressed was obtained. Proof-of-principle experiments were promising, but more experimental iterations with a focus on in-depth biological tissue characterization are required to further evolve and fully validate the
proposed cardiorenal model. Pressing issues entail establishing physiologically relevant scaling ratios, reducing required medium volume and identifying the exact disease models to incorporate once the physiological organoid system is functional and has been validated.

Biomedical micro-electromechanical systems or BioMEMS are microdevices with actuation or sensory function in biomedical applications. In this process, polymers are widely used as material layers. Polymers have significant advantages for applications in BioMEMS, such as low cost and ease of fabrication.
The problem at the moment is the lack of information needed to compare polymers with each other in order to identify their characteristics and properties. These characteristics are particularly important for the biocompatibility of the BioMEMS. Therefore, the optical characteristics, surface characteristics, adhesion etching, and cytotoxicity are investigated. For the optical characteristics, the polymers were examined for fluorescence and transmission of light. For the surface characteristics, hermeticity (non-permeable) and wettability (hydrophilic or hydrophobic surfaces) were examined. Furthermore, adhesion and etching were studied for their (chemical) resistance. Finally, the polymers were examined for their toxicity to cells (cytotoxic).
Through these tests, more information about the polymers and their characteristics has been obtained through these tests.
The results of these different tests cannot be combined into a single polymer showing the best results from all tests. The fluorescence test showed that the layers of the final device are important as they can be responsible for different intensities of fluorescence. Furthermore, it was found that perminex is the most hydrophilic but may fracture in saline solution.
It was noteworthy that the polymers, which are already widely used in BioMEMS applications (SU-8 and parylene-C), appeared to be the only ones to exhibit negative effects on cells (toxicity and cell growth inhibition). The other polymers tended to do significantly better there. Even though a number of properties that are important for biocompatibility were evaluated here, to ensure that the polymers and BioMEMS devices are fully compliant, testing will be required to meet the ISO standard 10993.

Organs-on-Chips (OoCs) are micro-engineered devices in which small samples of human-organ tissue are cultured on the substrate. A chip is designed in such a way that it can emulate the in-vivo physiological environment for disease modeling and drug screening. OoC technology can be incorporated into the drug development process from early drug discovery to pre-clinical drug screening. This cutting-edge technology can reduce the use of laboratory animals as animal models do not accurately recapitulate the in-vivo physiology and pathology of the human body. Current microfabrication techniques integrate features like microfluidics and micropumps into OoC devices to provide the necessary perfusion. Additionally, it is possible to monitor the behavior of cells or tissue by incorporating sensors into the platform.
Cardiovascular diseases are a leading cause of death worldwide, which calls for an ideal in-vitro screening model for cardiotoxicity. The MUSbit™ device, an OoC developed by Bi/ond, incorporates a 3D muscle microtissue anchored to two pillars designed to align the tissue. The device consists of a microfluidic channel to offer the necessary perfusion to mimic the blood flow through the heart. Bi/ond aims to electrically pace the cardiovascular bundle via the two pillars and record the electrical activity of the cardiac cells. This is achieved by combining an electrode and the pillar. Thus, a 3D electrode in integrated into the platform. Compared to 2-D microelectrode arrays (MEAs), 3D electrodes have a larger surface area, lowering the electrode impedance and increasing the signal-to-noise ratio (SNR).
The existing method of Bi/ond incorporates the electrode underneath the pillar via a cavity ( also known as the basement) in silicon fabricated using Deep Reactive Ion Etching (DRIE). This thesis focused on combining the electrode underneath the pillar by optimizing the critical steps in the fabrication process. The basement provides a form of adhesion for the pillars towards the later stages of the process. Due to the limitations concerning the step coverage of the different layers deposited over the current profile of the cavity, the design was modified. In this project, two main goals were defined and achieved. Firstly, the basement design was optimized by wet etching the silicon using potassium hydroxide (KOH) to obtain a cavity with a slanted sidewall. The photolithography on the layers and the step coverage of the deposited layers on the cavity were investigated. Experiments were performed to observe the effect of the modified basement design on the pillars (without the electrode). Secondly, the feasibility of integrating the electrode underneath the pillar without a basement was assessed. The photomask of the essential layers (except the metal) was designed accordingly. Finally, the influence of the alternative designs on the pillars was tested to verify their viability. Both approaches showed that it is practical to implement the techniques which can be compatible with the process of Bi/ond. The several microfabrication tests presented in this work set a foundation to incorporate the electrodes into the platform, making ground for future studies.

Implantable Medical Devices (IMDs) offer a wide range of applications including but not limited to blood pressure monitoring, bladder pressure sensing, glucose level monitoring, neurostimulation etc. For such applications, it is often desired that an IMD is as small as possible while meeting the required objective. Consequently, using a battery as a power source for this miniaturized IMD is inhibited as it occupies huge space. A good alternative for the battery as the power source is the Wireless Power Transfer (WPT) method. Among the WPT techniques, ultrasound (US) has seen increasing popularity in the past decade owing to its unique advantages such as better resolution, lower propagation attenuation, better health benefits etc. Ultrasound WPT methods involve an ultrasound transducer that converts ultrasonic energy into electrical energy to power the IMD. One such transducer is the Capacitive Micromachined Ultrasound Transducer (CMUT). As the name suggests it is a capacitive ultrasound transducer that is micromachined on silicon substrates. Accordingly, this technology offers advantages such as the ability to integrate with CMOS technology, larger bandwidth and the ability to fabricate large arrays of these transducers. Previous research in CMUTs has proven that the CMUTs can be used to efficiently harvest US energy at depths of more than 100 mm. Consequently, this paves the foundation for miniaturized US-based implants that can be placed deep inside the human body, using CMUT technology. Building on this foundation, this thesis work explores the next steps in realizing a CMUT based implant. Two research questions are the main focus of this work: 1. How can we locate such small sized deep implants in order to transfer power efficiently? 2. How can we communicate with this device using ultrasound waves? Addressing the first issue, a Time Reversal beamforming based tracking algorithm is developed that is able to track CMUTs occupying a surface area of about 6.3 mm2 moving at speeds up to 1.25 mm/s in water. Addressing the second issue, a communication protocol is formulated to establish ultrasound communication. This protocol makes use of the focused US beam achieved during tracking to communicate while offering simultaneous power transfer. A data rate of 2 kb/s is achieved using this protocol when the transmitter (TX) and the receiver (RX) are separated by a distance of 130 mm with a phantom filling up the gap. US based IMDs can be built to occupy only a few mm2 of area, especially when using micromachined transducers such as CMUTs. This work, the tracking algorithm and the communication protocol further provide proof of concept for reliable localization of CMUTs and low power data communication, hence providing good prospects for CMUT applications in the field of Implantable Medical Devices.

Elongated mechanical ventilation is associated with ventilator-induced lung injury (VILI), diaphragmatic muscle atrophy, patient discomfort, increased mortality rates and higher healthcare costs. However, hospitals are lacking in user-friendly, affordable and accurate methods to measure the decline the respiratory condition. Computed tomography (CT) is often used for visualization of the thorax, but it is expensive, time-consuming and uses unsafe ionizing radiation. Healthcare staff from the LUMC has expressed their need for a monitoring device using user-friendly, safe, affordable and accurate technology.
Current developments in ultrasound technology are resulting in smaller, cheaper and higher quality ultrasound devices. Micro-electro-mechanical (MEMS) ultrasound also allows for wearable solutions, such as patches attached to the skin. Besides, ultrasound does not use ionizing radiation and is therefore safer to use than CT.
Since ultrasound patches are already in development for other applications, for instance hemodynamic and bladder monitoring, the possibility of using it for respiratory monitoring for mechanically ventilated patients is investigated. In this report, the possibilities of using ultrasound patches for continuous respiratory monitoring for mechanically ventilated patients are explored. The focus points are usability and workflow design.
The design of a placing system is proposed, which allows the user to properly place the patches on the right location. This system is based on using an existing ultrasound transducer, in this case the Philips Lumify L12-4, to generate a full image. Then, the patch can be placed. This system allows for the use of both imaging and non-imaging patches. The electronics are reusable. The other parts can be adapted for the use with different transducers and applications, beyond respiratory monitoring.

Particle sorting is an important step in many biological and biomedical techniques. One sorting technique that has received a lot of attention is based on acoustophoresis. Manipulating cells with acoustic forces allows for a sorting method based on physical properties in a non-invasive, label-free, and biocompatible manner. To date, acoustic sorting devices have been developed using either an interdigitated transducer (IDT) or a lead zirconate titanate (PZT) as an acoustic source. IDTs generate surface acoustic waves (SAW) that can sort particles with high precision, however only low throughput is possible. PZT, on the other hand, generates bulk acoustic waves (BAW) that allows for a simple device architecture with high throughput. Nevertheless, the current research done on BAW sorting devices also shows the disadvantage of frequency restrictions.

An attractive alternative to PZT in acoustic sorting devices that has yet to be researched, are the capacitive Micromachined Ultrasonic Transducers (CMUT). CMUTs are well-known for their broad bandwidth, batch production and the possibility for complex designs and integration with electronic circuits.
In this work, we present proof-of-concept devices to examine that CMUTs can be used as an acoustic source for particle sorting. Two different acoustic-microfluidic device interfaces were considered, namely the sidewall and the top area of the CMUT. Additionally, the presence of an acoustic pressure within the silicon substrate of the CMUT's die was investigated.

Experiments show that CMUTs generate an acoustic pressure within the silicon substrate of the CMUT's die. This acoustic pressure increased 6.4 times when a phase alignment approach was used compared to when no phase alignment approach was used. Following these findings, acoustic-based sorting devices were assembled to perform particle alignment experiments. It was shown that continuous particle sorting could be demonstrated efficiently for both interfaces by using a pressure field based on standing waves. Additionally, structures integrated into the microfluidic devices, such as a vacuum horn, have the potential to amplify the acoustic signal. These findings indicate that CMUT-based microfluidic devices could provide a promising method for sheathless particle sorting.

Active implantable devices are conventionally powered with batteries. The miniaturisation of implants necessitates the need to find an efficient way to transfer power wirelessly. Ultrasound energy transfer with its short wavelength, small receiving transducer size, beamforming capability makes deep tissue penetration possible making it a good alternative for powering deep implants. There is also the advantage of using the reflected energy (ultrasound echo) from the implants to perform passive uplink data telemetry. The ultrasound power transfer efficiency depends on how well the energy is focused on the implant. So, the implant needs to be located first and then an initial contact needs to be established that can then be used to fine-tune beam forming attributes such as focus depth and steering angle.
In this work, a simple low power uplink data telemetry circuit to establish the 'first contact' that sends information on the implant's energy status to the transmitter is designed. The telemetry uses load impedance modulation to passively transmit back information. This principle is tested using an experimental setup with a 4 MHz burst frequency and different resistive loads varied from 0 Ω to 2000 Ω. Next, an algorithm was developed that automatically finds the optimal focus and steering angle settings so that the maximum amount of power is transferred to the ultrasound energy scavenger. This algorithm works based on the information sent from the uplink data telemetry circuit.
The results show that load impedance modulation can effectively be used for backscatter communication. A reflected energy change of up to 40% is observed between matched and mismatched load conditions. This load modulation was implemented in the uplink data telemetry circuit. A simple low power circuit that consumes less than 0.5 μW was designed for this. The uplink telemetry protocol uses pulse width modulation to send the storage capacitor voltage which powers the implant, and an almost linear correlation was found between the pulse width and the supply voltage. The algorithm produces a heat plot showing the maximum power transferred at the location where CMUT was placed and gives the optimal value of focus and steering angle.

The lack of reliable disease models hampers the development of safe and effective drugs for humansas they fail to precisely identify the cardiotoxicity profile of drug compounds. Recent technological advancements have led to the development of the"Organ-On-Chip"(OOC) technology. OOCs are miniaturized micro-engineered devices which aim to accurately recapitulate the physiological conditions of different organs. In order to develop a Heart-On-Chip (HOC) device as an in-vitro screening platform for cardiotoxicity, it is essential to integrate micro-electrodes (MEAs) in a flexible polymeric substrate that can be manufactured with standard micro-fabrication techniques. Besides electrical stimulation and recording, the device should be capable of accommodating the different cellular structures of the human heart along with its vasculature, which is in continual exposure to perfusion with fluid. In this manner, a platform that is cleanroom-compatible, scalable and physiologically representative of the human heart can be developed.The OOC device of Bi/ond provides an ideal platform in which MEAs can be successfully integrated. The device also offers microfluidic channels that supply the cardiac co-culture with the necessary perfusion to mimic the blood flow through the heart. In order to integrate TiN MEAs in the Bi/ond platform,several technological challenges need to be tackled. In previous work, polymers were often utilized as the insulation layer for the metal interconnects. Processing of polymers in a silicon-based cleanroom environment requires additional dedicated equipment. Therefore, it is necessary to investigate the feasibility of alternative dielectric, cleanroom-compatible materials, such as silicon nitride. Secondly, the metal lines experience considerable amounts of stress at the interface of the flexible membrane and the rigid silicon frame during the fabrication and post-fabrication process. By customizing the mechanical design of the PDMS membrane as well as the metal interconnects, the stress developed at the interface can be reduced, which can ultimately improve the yield of the devices due to the formation of fewer cracks in the metal lines.In this thesis, three goals were defined and achieved in order to develop a proof-of-concept for a HOC device with silicon nitride encapsulated TiN MEA in a thick PDMS layer, which can be further integrated in a microfluidic device. First, a study of the compatibility and characterization of SiNx insulation layers with PDMS membranes was performed. The adhesion between the nitride and PDMS membrane was improved by sandwiching a thin silicon oxide layer in-between the nitride and the PDMS. Additionally, the optimum deposition techniques for the nitride layers were demonstrated. Secondly, the yield of the devices was improved by optimizing the designs of the interconnects and the shape of the PDMS membranes. A novel turtle shaped design for the membrane was developed which helped to redistribute the stress at the interface. This novel design resulted in a yield higher than 75%.Thirdly, a silicon-based cleanroom compatible fabrication protocol was optimized and defined for processing a HOC device with a TiN MEA encapsulated by SiNx in a 200μm thick PDMS membrane.Moreover, based on the techniques developed by Bi/ond, this device module was successfully integrated in a microfluidic device. Finally, Electrochemical Impedance Spectroscopy (EIS) measurements were carried out to confirm the functionality of the electrodes. The average impedance value at 1 kHz of three working electrodes was measured to be in the order of 800 kΩ, proving that an electrical connection was successfully established between the embedded TiN electrodes and the bondpads on the silicon frame.

Diagnostic imaging is a fundamental requirement for the effective treatment of about 25 % of patients globally. Ultrasound imaging is considered the safest, least expensive and most convenient diagnostic imaging modality. Its widespread adoption has been in the area of 2D imaging. However, the accuracy of diagnosis with 2D ultrasound imaging is highly dependent on the experience and expertise of the sonographer because the sonographer has to mentally create a 3D impression from multiple 2D images of the region of interest and this could lead to erroneous diagnosis. 3D ultrasound imaging addresses this concern, however, it drives up the cost of ultrasound imaging. Also, disadvantages such as difficulty in taking quality images, prolonged time in learning how to effectively take these images and human distress during the acquisition of these images have been reported. By leveraging the high level of precision, accuracy and maneuverability provided by robotic systems in conjunction with low-end ultrasound imaging platforms, 3D ultrasound images can be captured, the problem of human distress alleviated and subsequently reducing the cost of 3D ultrasound imaging. This project sought to explore the feasibility of designing a low-cost 3D ultrasound robotic system. The design followed a distributed system approach using ROS (Robotic Operating System) where the data acquisition decoupled from the processing and visualization unit. The performance of the design was tested by constructing 3D ultrasound images of custom made phantoms. These results were compared with 3D ultrasound images of the phantoms acquired using the Philips EPIQ 7 - a high-tier ultrasound machine. The results obtained with this design had a low resolution in comparison with those obtained with the Philips EPIQ 7 however, a 3D point cloud representation of the object embedded in the phantom can be seen. Also, a full 3D image of the phantom could not be acquired due the transducer movement limitations of the design. This design successfully demonstrates the feasibility of integrating low-end electronics with robotic systems to acquire 3D ultrasound images.

Isolation of specific biological phenomena in vitro is critical to understanding living systems, due to cells’ innate capacity to integrate and respond to a wide range of signals simultaneously. Concomitantly, advances in micromanufacturing techniques overlap with progress in tissue engineering to produce microenvironments that better mimic in vivo systems. The convergence of these fields has given rise to microfluidic 3D culture platforms which have resulted in a large shift in the understanding of how many biological processes unfold due the platform’s ability to highly control microarchitectures, biochemical gradients, co-culture conditions, and mechanical stimuli. So-called Organ on Chip’s (OOCs) have been instrumental in shifting the paradigm in which cell culturing is carried out and in which ways scientists think about testing potential drug therapeutics.
The microfluidic OOC platform, inCHIPitTM, by BIOND Solutions, B.V. is a versatile tool designed for co-culture with a variety of macroscopic tissue types, such as organoids, explants, spheroids, and microtissues. It is a silicone (a.k.a. PDMS) and silicon-based platform that has the capacity for pneumatically controlled flexions and monitoring bioelectrical potentials. The inCHIPitTM model has already be implemented to model various organs, including midbrain organoids and induced pluripotent stem cells (iPSCs). The purpose of this study, however, is to further characterize the laboratory tool itself rather than the potential biological applications. Here, optical coherence tomography (OCT) is used to interrogate the OOC device’s construction and culture capability by making use of properties of interfering waves and backscattering light. Furthermore, the microfluidic fluid flows and diffusion events in an OOC were characterized with OCT for the first time. And, as proof of concept, organoid-like bodies (OLBs) and their impact on flows in culture were examined.
inCHIPitTM consists of two microcompartments – a straight microfluidic channel and a culture well separated by a microporous PDMS membrane – which are supported by a series of interlocking plates and a culture lid, all composed of different materials. In terms of imaging quality, the plate material choice and lid optical traits played a key role by limiting background noise, yet, for instance, the culture lid qualities would prove inhibiting to OCT measurements during actual cell culture experiments. Moreover, the fluid velocity profiles within in inCHIPitTM microfluidics were observed and were demonstrated to exhibit characteristic velocity profiles. It was also shown that mass transport phenomenon across the porous membrane in the cell culture well occur and follow typical diffusive mechanisms. Further, initial observations as to the effects of OLBs on fluid flow characteristics in the inCHIPitTM platform were reported. The compilation of OCT and OLB measurements and observations make a strong argument for the potential of inCHIPitTM system as a staple of biomedical applications.

Cardiac mapping techniques, in which an electrode-array is placed directly on the surface of the heart, were developed to gain a better insight in the underlying electropathology of cardiac arrhythmias. This procedure is performed in patients undergoing cardiac surgery, but here not all relevant cardiac structures and conduction inquiries can be tested due to possible complications. Hence, to fulfill this gap, an ex vivo Langendorff perfused heart model was designed in this study. Porcine hearts were collected at an abattoir and resuscitated on this setup, after which cardiac mapping was performed. The presented method is the first to perform epicardial mapping on an isolated beating porcine slaughterhouse heart and can be used for a large variety of electrophysiology studies.

Implantable medical devices (IMDs) such as cardiac pacemakers, cochlear implants, and neurostimulators improve millions of people’s lives every day. Over the years, IMDs have significantly improved in function, increased in lifetime, and decreased in size. However, further miniaturisation is limited by the batteries used to power these devices, and therefore methods to power them wirelessly are gaining in popularity. The technique most used to wirelessly power IMDs is electromagnetic energy transfer. However, at low frequencies, this method is limited to shallow implants due to its low directivity, while at high frequencies it is limited by attenuation in the human body. Therefore, ultrasound energy may be the future of wirelessly powering implants. Its high directivity and low attenuation in the human body opens up the possibility to wirelessly power deep implants without any harmful side effects. An ultrasound energy transfer set-up was established in this work to demonstrate that Philips’ capacitive micromachined ultrasound transducers (CMUTs) can be used as ultrasound energy harvesters. Normally, CMUTs need a bias voltage to function as an energy harvester. However, the CMUTs in this work are chargeable and therefore eliminate the need for this bias voltage. The results show that charged CMUTs can indeed be used as efficient energy harvesters of ultrasound and that information can be sent back to the ultrasound probe using echo modulation. The charged CMUTs showed to be able to harvest sufficient energy to stimulate a nerve and power a Bluetooth module, even when ultrasound sent through 90mm of biological (pork) tissue. The maximum power harvested during the ultrasound energy transfer experiments was 250mW over a transferring distance of 75mm.

The application of implantable medical devices (IMDs) is increasing rapidly due to the many health benefits they provide in diagnosing and treating diseases. However, these devices have to be able to survive harsh body conditions to ensure their reliability and functionality. Bodily fluids initiate chemical degradation and corrosion in the devices especially in the metal interconnects. Therefore, the devices are encapsulated by various forms of hermetic and non-hermetic packaging. The current standard hermetic packaging is not suitable for miniature microelectronics. As a result, conformal encapsulation is currently being developed. Multiple inorganic and organic layers of materials or a combination of different layers are used to achieve corrosion protection. Polyimide (PI) is a type of polymer that is used as encapsulation material in bioelectronic devices. Recently, there has been an increasing interest in using thin inorganic layers such as SiC and SiO₂ between the polyimide layers in order to improve the PI to PI adhesion. In this thesis, first, the corrosion phenomenon in bioelectronics and the available packaging methods are explained. Next, test structures that contain polyimide encapsulation with and without the SiC and SiO₂ ceramic layers are microfabricated. In order to provide accelerated aging conditions to the samples, a lifetime measurement set-up is modeled and built. Finally, the test structures are tested in the lifetime set-up to evaluate their reliability performances in accelerated aging conditions. The leakage currents of the test structures are measured as a function of the soaking time. Samples with SiC and SiO₂ thin layers exhibit a high leakage current value and fail relatively fast. In addition, samples are analyzed by electrochemical impedance spectroscopy (EIS) measurements and the samples without the ceramic layers demonstrate a capacitive behavior in lower frequencies.

During the past decade, Implantable biomedical devices have emerged as an efficient treatment for neurological disorders. Among them, low-intensity focused ultrasound (LIFU) has recently gained interest due to its focusing ability, depth of penetration and reversible effects. Although the exact biophysical mechanism that leads to the interaction between ultrasound and neurons is not clear yet, many successful applications have been reported both in vitro and in vivo in animals, raising prospects for clinical applications. Nevertheless, treatments were mainly delivered transcranially due to the lack of implantable technologies, constraining the frequency range to below 1 MHz. Thanks to the development of biocompatible capacitive micromachined ultrasound transducers (CMUTs), ultrasound has become implantable, opening the way for high frequency ultrasound neuromodulation. In addition, implantable biomedical devices are becoming smaller and smaller, requiring their power supply to follow this trend. Batteries can be a limiting factor for their miniaturisation and other powering methods have been investigated. Among them, ultrasound as a means to wirelessly transfer power represents the best trade-off between the amount of available power, implanted receiver size, and depth of penetration. Also in this case, biocompatible CMUTs could be used as transducers to power an implanted device. Yet they require a DC bias source in the order of tens of volts which is not practical for an implanted device. In this thesis the application of ultrasound for implantable biomedical devices is investigated. First, the modulation of the excitability of in vitro mice hippocampal brain slices (normal and epileptic) using high frequency sonication protocols is explored. Secondly, wireless power transfer using CMUT devices with charges trapped in the dielectric which do not require a DC bias voltage is investigated. The results indicate that high frequency ultrasound clearly affects the excitability of neurons, having an excitatory effect when delivered using a 5 MHz continuous wave sonication protocol, while it inhibits the neurons when they are exposed to pulsed wave ultrasound at 13 MHz. The intensities used were in line or much lower compared to values used by other groups of researchers. In addition, ultrasound power transfer with an efficiency higher than 48% was achieved using CMUT devices with charges permanently trapped in their Al2O3 layer. This efficiency was in line with values obtained by other groups using piezoelectric transducers.
Based on these results, it is clear that ultrasound, specifically using implantable CMUT devices, has a great potential to be used in bioelectronic medicine applications for both the treatment of neurological disorders as well as a means of power transfer.

Heart disease - already a leading cause of death in industrialized societies - is becoming more and more prevalent as society ages. With this increase, improvements in diagnosis and monitoring of heart disease are necessary. Current state-of-theart cardiac assessment techniques are invasive and too strenuous for heart disease patients. Therefore, there is a need for a noninvasive, fast, and mobile cardiac evaluation method. We propose the use of personalized lumped parameter models to simulate the circulatory system, so that left ventricular pressure can be estimated from left ventricular volume as acquired with 3D ultrasound imaging. Subsequently, the estimated pressure and the imaged left ventricular volume can be used to reconstruct pressure-volume loops, which are significantly indicative of cardiac health. As ultrasound is fast, not strenuous, and can be applied from the bedside, this method is suitable for critical care patients.

The Flex-to-Rigid (F2R) technology platform is an interconnect platform to integrate heterogeneous electronic systems and devices onto a partially flexible chip for minimally invasive medical instruments. This technology platform allows for the integration of micro electro-mechanical systems (MEMS) and integrated circuits (IC) on a chip in a planar plane, which can later be folded into any arbitrary shape. Downscaling of the technology and the increasing number of integrated components in the F2R platform have a high impact on the power distribution and consequently on the signal integrity. It is widely accepted that one of the most powerful strategies to encounter signal integrity problems is to use decoupling capacitors. However, there is an inherent trade-off between the capacitance and size of a capacitor. This thesis is focused on the development on high density capacitors for the integration in the F2R technology platform. One of the objectives was to increase the capacitance density. Because there is limited space available on the F2R chip, additional area to increase the capacitance is found in the depth of the silicon. By etching multiple trenches into the silicon, a capacitance density increase by a factor of 10 is obtained. To even further increase the capacitance, the use of a silicon dioxide – silicon nitride – silicon dioxide multilayer (ONO) dielectric is reviewed. Moreover, a first step has been made in the fabrication of high breakdown voltage and low breakdown voltage parts in this dielectric layer. A second objective was to deliver the capacitors as a ‘’building block’’ that can be implemented in the F2R process flow. Therefore, the process needs to be compatible with the standard IC and MEMS technologies that are available in the Philips Innovation Service cleanroom. The steps of the fabrication process are verified and where needed optimized, and a dedicated mask set is designed for the fabrication of the capacitors. With this mask set, the so called trench capacitors have been made. These test devices are characterized in terms of breakdown voltage and capacitance. It is found that the capacitance density can be increased by an order of magnitude with the introduction of trenches to the test devices. In addition, the advantage of a multilayer dielectric compared to a single layer dielectric is shown.