Where Integrated Electronics Meets Bio/Micro-Technology: From Synthetic Microstructures to Living Cells On-Chip

The always more predominant synergy between the biological and engineering worlds, is leading to an extremely fruitful mutual cooperation in which biology can benefit of engineering innovations and, vice versa. In this framework, unknown biological processes and complex bio-chemical dynamics can finally be unveiled, tremendously contributing to improve the current health-care and diagnostic paradigm. To reach this ambitious aim, it is fundamental to understand how these two worlds, apparently so distant, can efficiently and mutually integrate. My Ph.D. thesis was focused, specifically, on the interaction between electronics and cardiac cells, due to the intrinsic electrical activity of the latter. Due to the micrometer dimensional scale of the cells, it is advantageous to also use micrometer-scale electrodes, capable to interface with the living entities at their natural and functional dimensions where the most relevant processes happen. For this reason, I analyzed in depth also the use of electrical platforms, embedding micro-electrodes, both passive or with CMOS circuits directly underneath. Due to the complex nature of the problem of the cells viability on-chip, at first synthetic microstructures were used to test and optimize the sensing capabilities of the developed platforms. Specifically, zinc oxide (ZnO) micro-wires were at first deposited across the nanometric-spaced gap induced by exploiting the electromigration phenomenon on a micrometric gold metal wire. Thanks to the physical/electrical properties of ZnO microwires, the main goal was to create a multi-sensor capable to simultaneously detect variations of pH, temperature and UV-visible light, all important parameters to monitor in cell cultures. To improve the robustness of the system against electrical noise, the same microstructures were deposited across couples of micrometer electrodes, but this time fabricated on the surface of a CMOS chip. In this way, the electronic read-out of the variation of the electrical properties of the microstructure, according to the variation of the external parameters selected, was performed directly underneath the electrodes surface, hence reducing noise and parasitics. Specifically, 24 couples of aluminum electrodes, were designed so to allow multiple measurements on the same chip. To improve the quality of the electrical contact between the microstructure and the aluminum electrode, easily oxidizing, a tailored electroless gold plating process was optimized to modify the electrodes surface to gold. The CMOS chip with deposited ZnO microwires was then used to investigate the UV-visible light sensing capabilities of the microstructure. To understand the complex and multiple requirements of performing, instead, measurements of living cardiac cells on chip, a visiting period of 6 months was spent at the Kademhosseini laboratory in Boston (USA), part of the Harvard-MIT health science and technology division. During this time, the needs of primary neonatal rats cardiomyocytes were investigated by developing and electrically modulated bio-hybrid actuator, triggered by the beating activity of cardiac cells, and fabricated using bio-compatible hydrogels. After this extremely important intermediate step, preliminary experiments were done, at the end of the Ph.D. activity by measuring the electrical signals of cardiac cells directly on the surface of CMOS multi-electrodes arrays platforms. Some tests were performed also functionalizing the surface of the CMOS chips with the hydrogel developed in Boston for the bio-hybrid actuator. This activity was performed at the Italian Institute of Technology of Genova (Italy). The main focus of this activity was trying to evoke the firing of an electrical cardiac signal, commonly known as cardiac action potential, by applying an electrical stimulation. At the same time, the biologically-produced electrical signals were also recorded in real-time. Although the performed activity represented only an initial proof-of-concept, it provided an important insight to the challenges to be faced when living entities are deposited on electronic chips. At the same time, the preliminary experiments revealed the huge potentiality of active micro-electronic platforms for the monitoring, study and excitation of living cardiac cells. Thanks to these extremely multi-disciplinary studies it will be possible to significantly impact the current health-care and drug-development paradigms due to the possibility to investigate, previously unknown or not well characterized, biological processes, directly at their proper dimensional scale, with state-of-the-art integrated and hybrid electronic platforms.