Biomedical integrated circuit design for an electro-therapy device : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Electronics and Computer Engineering (Bioelectronics) at School of Engineering and Advanced Technology, Massey University, Albany Campus, New Zealand

Journal articles in Appendix A removed for copyright reasons. Chapters 3, 4 and 5 published respectively as:
Abbas Al-Darkazly, Ibtisam A., & Hasan, S. M. Rezaul. (2016). A waveform generator circuit for extra low‐frequency CMOS micro‐power applications, International Journal of Circuit Theory and Applications, 44, 266-279.  https://doi-org.ezproxy.massey.ac.nz/10.1002/cta.2074
Abbas Al-Darkazly, Ibtisam A., & Hasan, S. M. Rezaul. (2016). Dual-band waveform generator with ultra-wide low-frequency tuning-range,  IEEE Access, 4, 3169-3181. DOI: 10.1109/ACCESS.2016.2557843
Abbas Al-Darkazly, Ibtisam A., & Hasan, S. M. Rezaul. (2017). Optimized low-power CMOS active-electrode-pair for low-frequency multi-channel biomedical stimulation, Microelectronics Journal, 66, 18-24. https://doi-org.ezproxy.massey.ac.nz/10.1016/j.mejo.2017.05.014A biomedical integrated circuit design (IC) is utilized for the development of a novel non-invasive electro-therapy device, for low frequency multi-channel biomedical stimulation to transform immune activity and induce anti-viral state. Biomedical integrated circuit design is an important branch of modern electronic engineering that uses the application of electronic engineering principles for biomedical disciplines, to develop bioelectronics devices that are implanted within the body and for non-invasive
devices to improve patient’s lives. These devices use the application of an electric field to stimulate reactions to restore normal cell functions and activate the cells to treat a variety of disorders or disease conditions. Bioelectronics devices can be designed for use as alternative treatments to overcome the deficiencies of several conventional medical treatments. It could potentially assist as drug-free relief when therapeutic drugs become ineffective, costly, with serious side effects and cannot be replaced, loss of future treatment options, and hence, life threatening, as for drug resistant Human immunodeficiency virus (HIV-1) patients. Since the underlying mechanisms of the biological system and disease state is dominated by electrostatic interactions, specifically, the interaction between HIV-1 and the host cell that is predominantly by electrostatic interactions (protein charge-charge interaction) has an important role in its life cycle replication. At given pulses, the charge distribution and polarization of the electro-active protein molecules takes place, inducing conformation change which can enhance immune activity and inhibit the interaction of HIV-1 and host cells, disturbing its life cycle, leading to the mechanisms of the inactivation signal-induced virus death. These electrically induced protein transformations is used in this research as blood-cell treatment and as anti-HIV-1
electrotherapy. Advances in bioelectronics technology, which involve new CMOS IC design, and in bio-electrochemistry science, which include cellular function, electro-active biomolecules and their responses, have contributed to this project to develop the
concept of a novel electro-therapy device, for biomedical treatment applications. This involves understanding of the underlying mechanisms of the biological system and disease condition from an electronic engineer’s point of view as well as the interface between the electronic signal and the biological cells, and how electronic devices and circuitry directly communicate with the electro-active body tissue and blood cells. This research project addresses the design and development of a novel energy efficient miniature biomedical device using a new CMOS technology. It can generate, deliver and control an appropriate periodical low frequency electrical pulses, through the low-resistance skin surface to a patient’s blood. The notable feature of such a smart device is its cellular specificity: the parameters of the generated electrical pulse which are designed and selected in order to stimulate only one particular type of tissue (blood) leaving the others unaffected. The device comprises a mixed-signal low power dualband waveform generator (WFG) chip along with a novel two band tuning system. It was fabricated using Global Foundries (GF) 8RF-DM 130-nm CMOS process with a supply voltage of ±1V for the analog circuit and +1V for logic circuits. The WFG core (band I) can be tuned in the range 6.44 kHz - 1003 kHz through bias current adjustment, while a lower frequency (band II) in the range 0.1 Hz to 502 kHz can be provided digitally. Two WFG approaches, that comprise relaxation oscillators with different relaxation timing networks, have been developed for comparison. Since the aim of this work is to transfer electrical signal in a specifically controlled fashion through the tissue, a novel low power active electrode-pair signal
delivery system, compatible with human skin with high signal integrity, is developed. The circuit was fabricated in a 130-nm CMOS process using a low supply-voltage of +1.2V to deliver bi-phase square waveform signals from 16 selectable low-frequency channels. The individual active electrode can also be used to deliver mono-phase square/triangular waveform output signals. Accuracy, safety, low power, light-weight, miniature and low-cost characteristics are the main concerns. Being a miniature bioelectronics component with low power consumption, the proposed device is suitable both as a non-invasive and as an implantable biomedical device, in which WFG and electrodes circuitry can communicate with the electro-active biomolecule, strongly stimulating certain events in a complex biological system. A theoretical analysis, experiment design and performance are carried out in invitro environments to examine the effect of the designed signal on human blood cellular proteins. Proteins that display a heterogeneous structure have various conductivities and permittivity (determining the interaction with the electrical field) and possess dielectric properties with a large conformation change, undergoing structural rearrangements in response to cellular signals. The frequency-dependent dielectric present in proteins involves the redistribution and alignment of the proteins charged molecule and its polar molecule in response to an applied external electrical field can also induce conformation change. Interference polarization within proteins could interrupt the interaction between both sides of predominantly host cell proteins and of the HIV-1 infective envelope and its protein particles. This could disturb the signalling proteins for cell activation, and, hence, the virus cannot conjugate with the target cells and control the host cell protein activity. Since the virus is unable to reproduce out of a host cell, hence the virus cannot mutate and develop resistance easily, and use alternative binding and entry mechanisms as in the pharmacological approaches. After carefully studying the interaction of the
HIV-1 virus and the host cell, with respect to signal transfer, CD4 receptor, co-receptors CCR5 and nuclear transport factor nucleoporins FGNup153 proteins of the lymphatic system, which are essential targets for HIV-1 infection and its life cycle replication represent an attractive target to investigate in this research project. The activities of the underlying mechanism of the target cell are then examined utilizing immunofluorescence microscopy technique with specific fluorescent labelled antibodies, and accurate results are obtained with relatively low cost. The results demonstrated that the low frequency electrical pulse could inhibit virus attachment and fusion. It is also could provide a permeability barrier, that prevents the import and export of large macromolecule virus particles through the nuclear pore complex. These effects could induce an antiviral state for a period of time, and stope HIV-1 virus replication, with no potential risks and harm to the host cells, compared to the common
drugs. This is promising for the conception of HIV-1 treatment in vivo. Although further investigations are required in order to fully use the application of electrical stimulation in vivo for treatment, the result is provides the necessary impetus for the
applications of low frequency electrical stimulation on human immune response. This might offer important antiviral therapy against the most devastating pathogens in human history. This doctoral research is not only of academic interest but also highly relevant to medical applications. It is considered potentially beneficial in the development of knowledge in advanced technology for electro-medical treatment devices, their design, structure and applications to extend life, and for future growth in the biotechnology industry, therefore beneficial for the patients, physicians and for humanity