Innovative drug screening platforms should improve the discovery of novel and personalized cancer treatment. Common models such as animals and 2D cell cultures lack the proper recapitulation of organ structure and environment. Thus, a new generation of platforms must consist of cell models that accurately mimic the cells' microenvironment, along with flexibly prototyped cell handling structures that represent the human environment. Here, we adapted the 3D-bioprinting technology to develop multiple all-inclusive high throughputs and customized organ-on-a-chip-like platforms along with printed 3D-cell structures. Such platforms are potentially capable of performing 3D cell model analysis and cell-therapeutic response studies. We illustrated spherical and rectangular geometries of bio-printed 3D human colon cancer cell constructs. We also demonstrated the utility of directly 3D-bioprinting and rapidly prototyping of PDMS-based microfluidic cell handling arrays in different geometries. Besides, we successfully monitored the post-viability of the 3D-cell constructs for seven days. Furthermore, to mimic the human environment more closely, we integrated a 3D-bioprinted perfused drug screening microfluidics platform. Platform's channels subject cell constructs to physiological fluid flow, while its concave well array hold and perfused 3D-cell constructs. The bioapplicability of PDMS-based arrays was also demonstrated by performing cancer cell-therapeutic response studies. Traditionally, biomedical research has relied on animal models or two-dimensional (2D) cell cultures. Animal models, though one of the most commonly used systematic models, provide a limited understanding of humanspecific biology of different tissues. This is due to several reasons, such as fundamental differences between humans and animals 1 , low throughput studies, in addition to the ethical concerns 2. Animal testing is not costeffective, considering the cost to provide care, food, and shelter for the animals. Moreover, it is still possible that animal models can show promising results for drug treatments that can be harmful when tested on human subjects 3. On the other hand, despite the broad applications of 2D-cell cultures, these models only interact with their microenvironment in two dimensions, which in most cases cannot properly represent physiological conditions 4. Several studies have shown that 2D-cell constructs possessed altered cell polarity, mechanical cues, biochemical signals, and cell-cell interactions 5. Recently, there has been an emergence of three-dimensional (3D) cell models that better capture the complex cellular microenvironment than the conventional 2D models. 3D-models have shown improvement and relevance in vivo cell structure and function, where features such as the cell type, cell morphology, cell propagation, as well as, differentiation are more precisely represented 6-13. Furthermore, one should note that each year, billions of dollars are wasted because of preclinical 2D cell culture failure in predicting drug safety ...

An impedance-based interdigitated biochemical sensor is presented in this work that is designed and fabricated using a standard polycrystalline silicon process. The sensor provides a near real-time, non-invasive, label free and rapid detection technique to quantify chemicals and biomarkers in aqueous solutions. The combination of sensor structure and aqueous solution creates an equivalent electrical circuit comprised of constant and variable capacitive and resistive elements such as solution resistance and double-layer capacitance formed at the interface of the electrodes surface and the solution. The equivalent circuit and its elements are used to quantify the concentration of chemicals in an aqueous solution using the impedance of the system. Diethylhexyl phthalate (DEHP) solution is utilized to characterize and analyze the sensor's response via electrochemical impedance spectroscopy. Finite element analysis and experimental data are used to determine the components of the equivalent circuit. The experimental results show that the sensor is able to detect the concentration of DEHP as low as 0.02 ppm. Using the circuit model and experimental data, the change of doublelayer capacitance and solution resistance of the system for different solution concentrations are obtained. The results show that the double-layer capacitance increases with solution concentration, while the solution resistance decreases. The experimental results also verify the electrical circuit model used for the sensing system.

Three-dimensional biomimetic biosensors for food safety applications are presented. The sensors mimic the porous media of fresh produce and can detect the presence of pathogens in low concentration, monitor their internalization, and also determine potential formation of biofilm. The sensors use capacitive/impedance measurement for detection and have 3-dimensional structures allowing microorganisms to occupy the space between electrodes and the substrate. Interdigitated sensors with suspended electrodes and a parallel-plate sensor are studied using finite element analysis, and their performance is compared to that of a 2-imensional planar sensor. The simulation results show that under similar circumstances, all 3D sensors provide better sensitivities for detection of microorganisms and biofilm formation compared to the 2D sensor. 3D interdigitated and parallel-plate sensors display 16% and 30% higher sensitivity in detection of microorganisms, and 44% and 48% higher sensitivity for detection of biofilm formation, respectively. Furthermore, a biomimetic device with stack of electrodes is presented that can monitor the internalization of pathogens in real time. The device forms layers of multiple sensors resembling the actual fresh produce and can track the penetration of microorganisms inside the device. This novel structure allows us to understand how long it takes for microorganisms to penetrate in a produce and how environmental parameters such as temperature variation or the presence of nutrients or sanitizers affect their behavior, providing invaluable data to improve food safety and optimize the sanitization processes.

Internalization of pathogens inside pores and channels of fresh produce and formation of polymeric biofilm around their colonies are important phenomena in food safety due to complications they create for removal and inactivation of pathogens. The practical challenges does not allow for monitoring the pathogen-produce interaction in real time and under different ambient conditions. The present work introduces a biomimetic biosensing platform that simulates the actual produce and can detect the presence, growth and internalization of microorganisms and also potential formation of biofilm. The system consists of layers of capacitive electrodes made of polycrystalline silicon which are designed based on a standard foundry process (PolyMUMPs). The electrodes form multiple impedance-based biosensors and can simulate porous medium of the produce surface. As the cells reside on the surface of the top layer or penetrate inside the system, the capacitance value of each electrode pair changes. Monitoring the capacitance change of each biosensor allows us to determine where the microorganisms are and also whether their population is increasing. To demonstrate the applicability of our proposed biosensing system, a comprehensive FEM simulation is performed using ANSYS® APDL. The simulation results show that each pair of electrodes displays a specific pattern of capacitance change when cells reside on the system’s surface, move inside, grow or produce polymeric biofilm, because the electrostatic properties of cells and biofilm polymers are different from those of the solution. Analyzing the capacitance patterns allows us to determine that cells are at which stage of growth or internalization, and how far they have moved inside the system.

In this work, the development of three-dimensional impedance-based biochemical sensors for detection of chemicals and biological agents in aqueous solutions is presented. The sensors are made of a stack of suspended electrodes that allow the solution to occupy the space between them and create a larger interface area between the aqueous solution and the electrodes. Increasing the solution-electrode interface area drastically changes the impedance of the sensor-solution resulting in a better sensitivity. Low concentrations of di-ethylhexyl phthalate (DEHP) in deionized water are used as the target chemical to demonstrate the advantage of new design over conventional planar interdigitated sensors. Experimental measurements are carried out to characterize the response of the planar and 3D sensors and their Nyquist plots are compared, displaying significant sensitivity improvement in 3D sensors. An electrical model for the sensors is developed that considers different physical phenomena such as doublelayer capacitance, solution resistance, Warburg effect and parasitic parameters. Nonlinear interpolations of the experimental data show that the equivalent electrical circuit is in good agreement with the Nyquist plots obtained from test data. The curve fitting of the tested data to the equivalent electrical circuit displays good agreement between the model and the tested data.