Advances in miniaturized biomedical microsystems, ranging from in vitro microphysiological systems (MPS) to implantable devices, are enabling new modes of continuous, autonomous preclinical studies. This thesis presents a set of interconnected research contributions on millimeter-scale fluorescence-sensing and ultrasonic energy-harvesting microsystems, collectively advancing the development of integrated and miniaturized biomedical instrumentation.

The first part introduces an integrated microoptical system for fluorescence sensing in MPS, incorporating custom micro-optics and miniaturized excitation and detection units with tailored optical filters. This platform enables real-time, continuous fluorescence monitoring of microtissues under physiologically relevant conditions, strengthening the analytical capabilities of MPS for long-duration studies of drug delivery and cellular behavior.

The second part translates these sensing concepts to fully implantable microsystems capable of autonomous, long-term in vivo fluorescence recording. A compact 5 × 5 × 5 mm³ implant integrates a miniaturized optical module and low-power electronics to track fluorescence dynamics within living tissue. Validated across phantom, in vitro, ex vivo, and in vivo studies, the system demonstrates two-week continuous tracking of tumor-associated fluorescence, establishing its suitability for preclinical studies.

The final part focuses on ultrasonic energy harvesting to enable the autonomous operation of implantable devices. A MEMS-based piezoelectric ultrasonic energy harvester (PUEH) fabricated using a low-temperature bonding process allows integration of high-performance bulk PZT-5H, demonstrating the potential of MEMS architectures for efficient ultrasonic power transfer. An integrated energy-harvesting node, also in a 5 × 5 × 5 mm³ form factor, combines the MEMS-based PUEH with power management and storage to support autonomous operation of millimetric implants.

Together, these contributions advance miniaturized fluorescence sensing and ultrasonic energy transfer, enabling versatile microsystems for biomedical applications.

Framsteg inom miniatyriserade biomedicinska mikrosystem, allt från in vitro-mikrofysiologiska system (MPS) till implanterbara enheter, möjliggör nya former av kontinuerliga, autonoma prekliniska studier. Denna avhandling presenterar en uppsättning sammankopplade forskningsbidrag om millimeterskaliga fluorescensavkännande och ultraljudsenergiupptagnings-mikrosystem, som tillsammans främjar utvecklingen av integrerade och miniatyriserade biomedicinska instrument.

Den första delen introducerar ett integrerat mikrooptiskt system för fluorescensavkänning i MPS, som innehåller anpassad mikrooptik och miniatyriserade excitations- och detektionsenheter med skräddarsydda optiska filter. Denna plattform möjliggör kontinuerlig fluorescensövervakning i realtid av mikrovävnader under fysiologiskt relevanta förhållanden, vilket stärker MPS analytiska kapacitet för långvariga studier av läkemedelsleverans och cellulärt beteende. Den andra delen översätter dessa avkänningskoncept till helt implanterbara mikrosystem som kan utföra autonom, långsiktig in vivo-fluorescensregistrering. Ett kompakt 5 × 5 × 5 mm³-implantat integrerar en miniatyriserad optisk modul och lågeffektselektronik för att spåra fluorescensdynamik i levande vävnad. Systemet har validerats i fantom-, in vitro-, ex vivo- och in vivo-studier och demonstrerar två veckors kontinuerlig övervakning av tumörassocierad fluorescens, vilket fastställer dess lämplighet för prekliniska studier. Den sista delen fokuserar på ultraljudsenergiupp-samling för att möjliggöra autonom implantatdrift. En MEMS-baserad piezoelektrisk ultraljudsenergiuppsamlingsenhet (PUEH) tillverkad med en lågtemperaturbindningsprocess möjliggör integration av högpresterande bulk-PZT-5H, vilket demonstrerar potentialen hos MEMS-arkitekturer för effektiv ultraljudsenergiöverföring. En integrerad energiuppsamlingsnod, också i en formfaktor på 5 × 5 × 5 mm³, kombinerar MEMS PUEH med energihantering och lagring för att stödja autonom drift av millimetriska implantat.

Tillsammans främjar dessa bidrag miniatyriserad fluorescensavkänning och ultraljudsenergiöverföring, vilket möjliggör mångsidiga mikrosystem för biomedicinska tillämpningar.

Microphysiological systems (MPS) are advanced in vitro platforms engineered to replicate in vivo conditions for studying human biology, disease mechanisms, and drug responses with greater physiological relevance. Fluorescence sensing is widely used as a functional readout in MPS due to its high sensitivity, selectivity, and stability. However, conventional fluorescence sensing systems often rely on bulky instrumentation with limited integration, which restricts continuous in situ monitoring, scalable high-throughput analysis, and spatially resolved investigation in multi-organ-on-a-chip models. To address these limitations, we present a highly miniaturized, fully integrated optical system with a 1 mm² footprint, enabling continuous in situ fluorescence monitoring of three-dimensional microtissues in close proximity. The system integrates microscale illumination and sensing units for fluorescence excitation and selective detection, an optical element for guided light propagation, and a microcage for mechanical confinement of microtissues. To demonstrate its capabilities, we integrated the miniaturized optical system with an MPS-relevant platform to monitor fluorescence signals in transgenic mouse pancreatic islets expressing genetically encoded calcium indicators. The integrated platform enables real-time, continuous monitoring of islet responses to potassium chloride stimulation and tracking of calcium oscillations for over two hours, providing valuable information about the functional status of the pancreatic islets. Our work enhances the analytical capabilities of MPS through the integration of miniaturized on-chip quantitative assessment tools, enabling precise, in situ, and continuous monitoring of biological activities in close proximity.

In vivo fluorescence sensing devices have recently gained considerable attention owing to their capabilities and potential in advancing biomedical research, clinical diagnostics, and therapeutic applications. In this work, we present a highly miniaturized, fully implantable device capable of excitation, detection, and recording of fluorescence signals, enabling continuous measurements of biological processes in vivo. The device was engineered to be minimally invasive, with a compact 5×5×5mm³ form factor. It incorporates an optical system integrating micro illumination and sensing units with a sub-mm2 footprint, achieving selective detection of fluorescence signals in close proximity. Additionally, the device features low-power on-board electronics and a customized bi-stable magnetic switch for remote activation, resulting in a device lifetime of over a month once the device is powered on. The device successfully recorded the infusion of green fluorescence protein (GFP) solution at a low concentration of 100 μg/mL delivered at a rate of 4 μL/h for a 24-hour period, as well as the diffusion of a 150 μL GFP bolus with a concentration of 200 μg/mL over a 40-hour period, in a tissue-like phantom model made of gelatin. Further, the device was implanted into a living mouse for subcutaneous in vivo GFP recording as a proof of concept, and the fluorescence signal was successfully detected and recorded in the living animal.

Cracking-assisted nanofabrication techniques have gained widespread applications across diverse engineering fields for the creation of nanoscale features, valued for their simplicity, cost-effectiveness, and high resolution. However, conventional methods often struggle to control the density, shape, and uniformity of nanocracks due to random stress concentrations caused by material defects and uncontrolled mechanical stress distribution during nanocrack formation. To address these limitations, we developed a highly reliable and reproducible nanocrack patterning method capable of creating large-scale, customizable nanocrack patterns on flexible substrates via the compressive-shear stress coupling effect. Our approach utilizes photolithography-based microphotoresist structures and simultaneous bending and pressing to induce highly localized stresses at the corners of the structures, facilitating the formation of nanocracks. This method enables precise spatial and shape control of nanocrack patterns in functional materials on flexible substrates. For example, in platinum films on polymer substrates, we achieved a uniform and consistent average nanocrack spacing of 40 μm with a standard deviation as low as 0.1 μm across 100 parallel nanocracks. The technique is versatile and can be applied to various functional materials, such as copper and indium tin oxide. We further showed the creation of diverse curved and closed-shape nanocracks, including zigzag, wave, square, circle, parallelogram, and cross shapes, in copper thin films. Finally, we applied this method to various engineering fields to demonstrate its efficacy, including strain sensors with gauge factors of approximately 380, a three-dimensional pressure sensor array capable of reliably measuring pressures below 0.1 N, and nanowire patterning with highly uniform spacing (40 ± 0.5 μm) on polymer substrates that offered both flexibility and transparency.

MEMS-based piezoelectric ultrasonic energy harvesters (PUEH) have become one of the most promising options for replacing or transferring energy to batteries in medical implants, where device miniaturization and power optimization are needed. Among the most commonly used piezoelectric materials in PUEH, lead zirconate titanate (PZT) is widely acknowledged for its excellent piezoelectric properties, good stability, and low cost. However, the performance of PZT degrades when the processing temperature approaches and exceeds half of its Curie temperature Tc, limiting its application. Here, we demonstrate a highly miniaturized, low-temperature fabricated MEMS-based PUEH with an effective ultrasound harvesting area of 0.79 mm2 and an effective device volume of 0.35 mm3. The low-temperature adhesive epoxy bonding ensures the temperature throughout the entire fabrication process remains below 85°C, which preserves the properties of the integrated piezoelectric material to the greatest extent. This allows the use of bulk PZT-5H, a material that possesses superior piezoelectric properties, but has a relatively low Tc, to enhance device performance. Our device outputs a root-mean-square (RMS) voltage of 0.62 V and an RMS power of 0.19 mW on a 2 kΩ resistive load at an optimum operating frequency of 200 kHz, with a reception distance of 20 mm in water and input acoustic power intensity of 178 mW/cm2. The proposed design and fabrication technique enable our device to achieve the smallest effective size among the reported MEMS-based PUEH while still being capable of powering up numerous implantable medical devices and being compatible with various commercially available power management units. [2024-0081]

We demonstrate a low-temperature fabricated MEMS-based piezoelectric ultrasonic energy harvester with enhanced device performance. Compared to state-of-the-art, our work uses a low-temperature bonding method, which ensures the integrated piezoelectric material undergoes prominently lower temperatures (≤ 85 °C) throughout the whole fabrication process. Due to this, bulk PZT-5H, a material with superior piezoelectric properties, could be used in this type of application for the first time. The method guarantees the device fabrication temperature well below the PZT-5H Curie temperature (225 °C) and preserves its piezoelectricity to the greatest extent. As a result, devices fabricated using the proposed method achieve higher performance than the devices prepared by the MEMS fabrication method using BCB bonding. The root-mean-square voltage and the average power outputs at the frequency (170 kHz) where maximum voltage and power outputs were observed were improved by 38 % and 92 %, respectively.

Recently, copper oxide (CuO) has drawn much attention as a promising material in visible light photodetection with its advantages in ease of nanofabrication. CuO allows a variety of nanostructures to be explored to enhance the optoelectrical performance such as photogenerated carriers scattering and bandgap engineering. However, previous researches neglect in-depth analysis of CuO's light interaction effects, restrictively using random orientation such as randomly arranged nanowires, single nanowires, and dispersed nanoparticles. Here, we demonstrate an ultra-high performance CuO visible light photodetector utilizing perfectly-aligned nanowire array structures. CuO nanowires with 300 nm-width critical dimension suppressed carrier transport in the dark state and enhanced the conversion of photons to carriers; additionally, the aligned arrangement of the nanowires with designed geometry improved the light absorption by means of the constructive interference effect. The proposed nanostructures provide advantages in terms of dark current, photocurrent, and response time, showing unprecedentedly high (state-of-the-art) optoelectronic performance, including high values of sensitivity (S = 172.21%), photo-responsivity (R = 16.03 A/W, lambda = 535 nm), photo-detectivity (D* = 7.78 x 10(11) Jones), rise/decay time (tau(r)/tau(d) = 0.31 s/1.21 s).