One of the many applications of organ-on-a-chip (OOC) technology is the study of biological processes in human induced pluripotent stem cells (iPSCs) during pharmacological drug screening. It is of paramount importance to construct OOCs equipped with highly compact in situ sensors that can accurately monitor, in real time, the extracellular fluid environment and anticipate any vital physiological changes of the culture. In this paper, we report the co-fabrication of a CMOS smart sensor on the same substrate as our silicon-based OOC for real-time in situ temperature measurement of the cell culture. The proposed CMOS circuit is developed to provide the first monolithically integrated in situ smart temperature-sensing system on a micromachined silicon-based OOC device. Measurement results on wafer reveal a resolution of less than ±0.2 °C and a nonlinearity error of less than 0.05% across a temperature range from 30 to 40 °C. The sensor's time response is more than 10 times faster than the time constant of the convection-cooling mechanism found for a medium containing 0.4 ml of PBS solution. All in all, this work is the first step towards realizing OOCs with seamless integrated CMOS-based sensors capable to measure, in real time, multiple physical quantities found in cell culture experiments. It is expected that the use of commercial foundry CMOS processes may enable OOCs with very large scale of multi-sensing integration and actuation in a closed-loop system manner.

We present the first Organ-on-Chip equipped with a low-impedance Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) MicroElectrode Array (MEA). The novel device allows simultaneous mechanical stimulation with a stretchable PDMS membrane and electrical monitoring via the PEDOT:PSS MEA of multiple in vitro cell cultures. The surface area enhancement and the morphology of the PEDOT:PSS allows an increase of the charge injection per unit area at the electrode-electrolyte interface, resulting in significantly lower electrochemical impedance of the electrodes. In particular, at 1 kHz the fabricated PEDOT-MEA electrodes show a reduction of the overall impedance up to 99.4 and 93.3 % in comparison with benchmark TiN and Pt electrodes. The superior performance of PEDOT:PSS were also confirmed via Cyclic Voltammetry measurement, in which PEDOT:PSS showed a very large capacitive current, compared with the benchmark electrodes both in the forward and the reverse scans. The obtained results confirm the effectiveness of the proposed PEDOT:PSS coating, and introduce this material in the OOC field. Moreover, the quality and morphology of the fabricated PEDOT:PSS based electrodes were assessed via SEM imaging and Raman spectroscopy.

Organ-on-chip (OOC) is becoming the alternative tool to conventional in vitro screening. Heart-on-chip devices including microstructures for mechanical and electrical stimulation have been demonstrated to be advantageous to study structural organization and maturation of heart cells. This paper presents the development of metal and polymeric strain gauges for in situ monitoring of mechanical strain in the Cytostretch platform for heart-on-chip application. Specifically, the optimization of the fabrication process of metal titanium (Ti) strain gauges and the investigation on an alternative material to improve the robustness and performance of the devices are presented. The transduction behavior and functionality of the devices are successfully proven using a custom-made set-up. The devices showed resistance changes for the pressure range (0-3 kPa) used to stretch the membranes on which heart cells can be cultured. Relative resistance changes of approximately 0.008% and 1.2% for titanium and polymeric strain gauges are respectively reported for membrane deformations up to 5%. The results demonstrate that both conventional IC metals and polymeric materials can be implemented for sensing mechanical strain using robust microfabricated organ-on-chip devices.

This work presents the first multi-well plate that allows for simultaneous mechanical stimulation and electrical monitoring of multiple in-vitro cell cultures in parallel. Each well of the plate is equipped with an Organ-on-Chip (OOC) device consisting of a stretchable micro-electrode array (MEA). For the first time, a film assisted molding (FAM) process was employed to embed an OOC into a multi well plate format packaging. The functionality of the MEA in the device was assessed with electrochemical impedance spectroscopy. Moreover, the biocompatibility of the plate was demonstrated with cardiomyocytes derived from human induced pluripotent stem cells (iPSC) cultured in the wells.

We present a novel and highly reproducible process to fabricate transferable porous PDMS membranes for PDMS-based Organs-on-Chips (OOCs) using microelectromechanical systems (MEMS) fabrication technologies. Porous PDMS membranes with pore sizes down to 2.0 μm in diameter and a wide porosity range (2–65%) can be fabricated. To overcome issues normally faced when using replica moulding and extend the applicability to most OOCs and improve their scalability and reproducibility, the process includes a sacrificial layer to easily transfer the membranes from a silicon carrier to any PDMS-based OOC. The highly reliable fabrication and transfer method does not need of manual handling to define the pore features (size, distribution), allowing very thin (<10 μm) functional membranes to be transferred at chip level with a high success rate (85%). The viability of cell culturing on the porous membranes was assessed by culturing two different cell types on transferred membranes in two different OOCs. Human umbilical endothelial cells (HUVEC) and MDA-MB-231 (MDA) cells were successfully cultured confirming the viability of cell culturing and the biocompatibility of the membranes. The results demonstrate the potential of controlling the porous membrane features to study cell mechanisms such as transmigrations, monolayer formation, and barrier function. The high control over the membrane characteristics might consequently allow to intentionally trigger or prevent certain cellular responses or mechanisms when studying human physiology and pathology using OOCs.

We present a novel method to easily and reliably transfer highly porous, large area, thin microfabricated Polydimethylsiloxane (PDMS) porous membranes on Lab-on-Chip (LOC) and Organ-on-Chip (OOC) devices. The use of silicon as carrier substrate and a water-soluble sacrificial layer allows a simple and reproducible transfer of the membranes to any PDMS-based OOC and LOC device. The use of IC and MEMS compatible techniques reduces significantly the fabrication time and the need of manual handling. Our method is suitable for automatic assembling systems, such as pick-and-place, crucial to significantly increase the throughput of OOC and LOC devices assembling. Membranes with 8 μm pore size and as thin as 4 μm are successfully transferred. The viability and biocompatibility of the transfer was assessed by culturing two different cell lines on an OOC with transferred porous PDMS membranes.

Polymeric (PEDOT:PSS) strain gauges embedded in PDMS membranes fabricated using a full wafer-scale fabrication process capable of realizing reproducible small features, are reported. The devices are characterized using a customized setup, which provides mechanical stretch while dynamically reading the electrical resistance. Measurements show relative resistance changes of approximately 11% for applied pressure up to 4 kPa. The process described is tailored to fabricate pressure sensors and microelectrodes for a flexible substrate-based Organ-on-Chip platform.

Sensing and stimulating microstructures are necessary to develop more specialized and highly accurate Organ-on-Chip (OOC) platforms. In this paper, we present the integration of a conductive polymer, poly (3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), on a stretchable membrane, core element of an Heart-on-Chip. The electrical conductivity along with its biocompatibility, high transparency (≈88%) and mechanical elasticity (≈1.2 GPa) make this material a candidate to develop novel microstructures for electrical monitoring and stimulation of cells in flexible-substrate based OOCs. Microstructures with different shapes and geometries of PEDOT:PSS embedded in a 9 μm-thick Polydimethylsiloxane (PDMS) membrane are developed following a wafer-level fabrication approach. PEDOT:PSS layers between 120 nm and 300 nm are obtained by varying the deposition conditions. The layers are successfully patterned and microstructures with lateral dimensions down to 2 μm. The obtained results indicate that this polymer is a suitable material for microfabrication of sensing and stimulating elements in OOC platforms.