Microphysiological systems (MPSs) are cellular models that replicate aspects of organ and tissue functions in vitro. In contrast with conventional cell cultures, MPSs often provide physiological mechanical cues to cells, include fluid flow and can be interlinked (hence, they are often referred to as microfluidic tissue chips or organs-on-chips). Here, by means of examples of MPSs of the vascular system, intestine, brain and heart, we advocate for the development of standards that allow for comparisons of quantitative physiological features in MPSs and humans. Such standards should ensure that the in vivo relevance and predictive value of MPSs can be properly assessed as fit-for-purpose in specific applications, such as the assessment of drug toxicity, the identification of therapeutics or the understanding of human physiology or disease. Specifically, we distinguish designed features, which can be controlled via the design of the MPS, from emergent features, which describe cellular function, and propose methods for improving MPSs with readouts and sensors for the quantitative monitoring of complex physiology towards enabling wider end-user adoption and regulatory acceptance.@en

An organ-on-chip (OoC) is a microelectromechanical (MEMS) device that aims to recapitulate in-vitro the physiology of the smallest functional unit of an organ in order to perform drug analysis or study disease models. OoCs are very complex systems that require actuation and sensing capabilities within controlled and delicate environment. The research presented in this thesis focuses on a transductive material that offers promising properties for organ-on-chip. The objective of the thesis is to demonstrate the potential of using ion-based electroactive materials to tackle current OoC limitations. An ionic electroactive material, called ionic polymer metal composite (IPMC) is proposed, characterized and developed in order to increase the ease of use, integrability, and scalability of OoC. The IPMC consists of a soft polymer, doped with ions naturally present in standard culture media, flanked by platinum electrodes on opposite sides. This biocompatible material shows good actuation and sensing capabilities, requires low driving voltage and has been herein investigated as a potential transducer for several organ-on-chip applications. A first version of the IPMC with a thickness of 180 𝜇m (called thick IPMC) showing good actuation capabilities has been adopted to implement a micropump and a tissue stretcher. The cells strecher could exhibit biologically relevant strain (0.1 %) while showing no toxicity, and the micropump achieved biologically relevant wall shear stress (0.008 Pa) through liquid flow within microchannels. Furthermore, in this thesis, this moisture-sensitive material has been investigated in the context of wafer-level process flow using state-of-the-art microfabrication tools to demonstrate its compatibility with silicon-based technology. A second version of the IPMC has been developed based on a thinner polymer (50 𝜇m, called thin IPMC), as well as an adjusted manufacturing recipe in order to explore the material potential as a sensor for OoC. A comparative study has been performed between the manufacturing of thick and thin IPMC, evidencing different dynamics of the electroless deposition reaction depending on the thickness of the polymer used. The developed thin IPMC shows superior sensing capabilities by virtue of lower flexural rigidity and higher electrodes conductivity. The applications explored with the thin IPMC are microfluidics flow sensing and strain sensing. The microfluidic flow sensor exhibits good sensing capabilities with a sensitivity of 4.78 mV/(uL/s) and a linear behavior in the studied range. In addition, soft lithography and patterning of hydrogel have been investigated on top of the thin IPMC, to further assess the material as a smart substrate for tissue engineering. The present thesis anticipates a potentially significant impact of smart materials as a new tool to engineer multi-functional culture substrates for OoC as well as develop electronically-controllable flexible membranes for micro pumping.@en

Ionic polymer metal composites (IPMCs) are a class of materials with a rising appeal in biological micro-electromechanical systems (bio-MEMS) due to their unique properties (low voltage output, bio-compatibility, affinity with ionic medium). While tailoring and improving actuation capabilities of IPMCs is a key motivator in almost all IPMC manufacturing reports, very little efforts have been dedicated to sensing using IPMC thinner than 100 µm. Most reports on IPMC manufacturing and utilization rely on 180 µm-thick Nafion with platinum electrodes, too stiff for bio-MEMS applications. The same fabrication process on thinner membranes does yield in very poor electrodes and performance, and needs to be studied to increase flexibility and sensitivity in the microscale range. This study demonstrates an electroless Pt deposition method for fabricating bio-MEMS-suitable 50 µm-thick IPMC samples. First, we perform a comparative study on the platinum distribution within the Nafion backbone as well as on the surface for the standard electroless deposition recipe for thin (50 µm) and thick (180 µm) Nafion. We report strong differences in platinum distribution for thick and thin IPMC that experienced the same manufacturing process. By varying chemical concentrations from the standard recipe we obtain convenient platinum distribution on thin Nafion, with platinum mainly localized in proximity of surface, as well as electrodes with lower sheet resistance. We could measure the flexural rigidity as 3.43 × 10 − 8 N·m², 46 times lower than standard 180 µm-thick IPMC. The calculated sensitivity is 0.476 ± 0.02 mV mm⁻¹ and the limit of detection for our sensor is 500 ± 20 µm. This procedure sets a milestone for manufacturing 50 µm-thick IPMC for transducers and sensors in bio-MEMS applications.

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Organ-on-a-chip (OoC) and microfluidic devices are conventionally produced using microfabrication procedures that require cleanrooms, silicon wafers, and photomasks. The prototyping stage often requires multiple iterations of design steps. A simplified prototyping process could therefore offer major advantages. Here, we describe a rapid and cleanroom-free microfabrication method using maskless photolithography. The approach utilizes a commercial digital micromirror device (DMD)-based setup using 375 nm UV light for backside exposure of an epoxy-based negative photoresist (SU-8) on glass coverslips. We show that microstructures of various geometries and dimensions, microgrooves, and microchannels of different heights can be fabricated. New SU-8 molds and soft lithography-based polydimethylsiloxane (PDMS) chips can thus be produced within hours. We further show that backside UV exposure and grayscale photolithography allow structures of different heights or structures with height gradients to be developed using a single-step fabrication process. Using this approach: (1) digital photomasks can be designed, projected, and quickly adjusted if needed; and (2) SU-8 molds can be fabricated without cleanroom availability, which in turn (3) reduces microfabrication time and costs and (4) expedites prototyping of new OoC devices@en

Sensing flow rates in structured microenvironments like lab-on-chip (LOC) and organ-on-chip (OoC) is crucial to assess important parameters such as transport of media and molecules of interest. So far, these micro-electromechanical systems for biology (bio-MEMS) mostly rely on flow sensing systems based on thermal sensors. However, thermal flow sensing has limitations, since the measurement principle, which is based on generation of heat, can negatively affect the biological system by increasing the fluid temperature above physiological conditions. To overcome this issue, we propose a novel electro-mechanical flow sensor centered around the deformation of a cantilever made of a thin and biocompatible ionic electroactive polymer. The polymer, called ionic polymer metal composite (IPMC), is doped with ions naturally present in most cell media for LOC and OoC devices. Unlike already existing cantilever-based systems which rely on piezo sensitive materials, our IPMC-based flow sensor shows durability in wet environment. We were able to successfully measure pulsatile flow induced by pipetting with flowrate gradually increasing from 10μL/s to 40μL/s. The proposed flow sensor shows good sensing capabilities (4.78 mV/(μL/s)) with a linear behavior in the studied range. This work sets a milestone for using flexible, electroactive materials for sensing applications in delicate biological microenvironments.

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Stemming from the convergence of tissue engineering and microfluidics, organ-on-chip (OoC) technology can reproduce in vivo-like dynamic microphysiological environments for tissues in vitro. The possibility afforded by OoC devices of realistic recapitulation of tissue and organ (patho)physiology may hold the key to bridge the current translational gap in drug development, and possibly foster personalized medicine. Here we underline the biotechnological convergence at the root of OoC technology, and outline research tracks under development in our group at TU Delft along two main directions: fabrication of innovative microelectromechanical OoC devices, integrating stimulation and sensing of tissue activity, and their embedding within advanced platforms for pre-clinical research. We conclude with remarks on the role of open technology platforms for the broader establishment of OoC technology in pre-clinical research and drug development.@en

Organ-on-chip (OoC) devices are in rising demand for high-throughput and low-cost development and toxico-logical screening of chemicals and pharmaceuticals, as they accurately mimic in vitro physiological conditions as in the human body. In particular, OoCs are urgently needed for screening cardiovascular drug toxicity. Physiological relevance of cardiovascular cell cultures requires moving substrates. To date cell culture substrates have been commonly actuated by pneumatic systems, which are bulky, expensive and non-user-friendly, and may thus limit the adoption of OoCs by researchers and industry. In this paper we propose the first actuating and sensing smart material-based OoC device and demonstrate its functionality by culturing human vascular smooth muscle cells (vSMC). Our device utilizes a single ionic polymer metal composite (IPMC)-based transducer to provide both actuation and sensing. The soft IPMC substrate allows to intermittently apply cyclic loading to tissues and to sense their spontaneous contractions. We integrated the transducer within a compact, easy-to-operate, economically affordable and scalable OoC prototype, which achieves an actuation range of 0.2 mm and 0.72 V/mm sensing resolution. The 0.1 % strain induced by actuation on cells accurately corresponds to in vitro strains for vSMCs. We successfully grew vSMCs on the IPMC substrate, and actuated them for 150 min at 1 Hz. Fluorescent staining showed no evidence of adverse effects. These results are a major step towards versatile OoCs for a wide variety of biological modelling of human tissues.@en

•Actuation has been succesfully performed for 2h30 with no side effects nor
delimination of the human tissue
•0.1 % strain has been achieved during the actutaion mode, close to the
strain experienced in vivo by vSMCs
•0.72 V/mm sensitivity has been shown on the sensing mode
•Batch fabrication and downscaling will be targetted in the near future
•Actual sensing of the cells’ contraction will be reserved for further work @en