Yu-Chong Tai - US grants

This award provides funds to help with the establishment and initial operation of a microfabrication facility that will produce semi-conductor devices to be used in neuroscience, microelectronics and related areas of microdevice research. The neuroscience devices will be used for both in vitro and in vivo experimentation aimed at the simultaneous monitoring of the activity of an array of nerve cells. Other types of devices to be fabricated include micro-robots, -sensors, -antennas and pumps. An important role of the he facility is expected to be the training of students and advanced investigators who have need of these devices in the techniques used for microfabrication. The remarkable progress in the miniaturization of electronic circuit boards has lead to the realization that a variety of other types of micrometer-sized devices can be made. these include both mechanical and electronic devices. In particular, the ability to fabricate microchip-like multi-well cell culture dishes, where each well is the size of a single cell, has opened up the possibility of simultaneous recording of the activity of each of many interconnected nerve cells growing in culture. This type of experimentation could lead to significant advances in understanding the operation of networks of nerve cells, an area which has, in recent years, been the subject of much theoretical interest. Similar devices, which could be implanted directly in the brain, should allow measurement of the activity of many cells in a single region of the brain. Such experimentation has enormous potential for clarifying our understanding of the functional organization of the brain and of how brain cells integrate and differentiate sensory input.

Specific technical objectives of this research are to: o Evaluate the current understanding of material properties (primarily for silicon, bulk and thin films), as a basis for good spring design. These properties will not only include the tensile and shear moduli, but also the yield strength, fracture, and fatigue properties. o Determine a set of commonly required spring configurations (cantilevers, spirals, bridges, etc). o Analyze (utilizing micro-finite element analysis) spring configurations for their compliance, resistance to manufacturing errors and tolerances, resistance to stress concentrations, fatigue, etc. o Analyze spring configurations for their micro- dynamic responses, resonant frequencies, etc. o From the above, extract a set of rules for designing standard springs. The rule-set will depend upon: material; stiffness (or natural frequency) required; space and orientation required; preferred technology, and other aspects. o Integrate the rule-set into a computer-aided micro-mechanical spring/oscillator design system.

0421543
Scherer
This proposed instrumentation acquisition is that of a dual-beam focused ion beam scanning electron microscope (FIB/SEM) system, with which the involved research team intends to investigate electromagnetic phenomena at the nanometer scale. The involved research 'team' includes three collaborative elements. CalTech will take the lead, JPL will provide supplemental input, and the FIB/SEM vendor (i.e., FEI Inc.) will not only furnish the basic hardware but will interactively assist CalTech students and faculty in their efforts with software optimization.

ABSTRACT

Proposal Number: 1247526
P.I.: Emami-Neyestanka, Azita

This proposal explores a new class of microelectrode arrays, Instead of having one large chip that gets connected to the electrode array via a dense cable, many tiny low-cost chips that form a complete system are distributed over a foldable substrate along with the electrodes. The location of the chips and the electrodes will be optimized through the design of the origami structure. The electronic chips will have efficient capacitive sensors that not only can determine the proximity of the chips, but also help to reconfigure the chips/sensors to establish optimum communication links between the chips. The origami structures will have a number of important properties, they: 1) can be folded (e.g. rolled into a cylindrical shape) for insertion into the human body through minimally invasive procedures; 2) will self-deploy when they are released within the human body; 3) will take up unique curved shapes that precisely match the organs to be stimulated.

1353006
Emami-Neyestanak

This project will focus on mechanically and electrically adaptive and modular designs that conform to the tissue. Instead of having one large chip connected to a dense electrode array via a cable, many tiny low-cost chips that form a complete system are distributed over a foldable substrate. Specified regions of the substrate willt be arranged to establish relations in the final folded form. New patterns will be developed that can be tiled into pixel arrays and provide 3D positioning of the components mounted upon the substrate. The reconfigurable chips will have novel proximity sensors and communication circuits to form a complete system suitable for the origami structure and deployment. Micromechanical latches will be used for fixation and tuning of the structure. Different module "types" will be developed that can be elegantly tiled into arrays and result in 3D shapes that match the contour of the tissue. The reconfigurable chips will have novel proximity sensors, communication and power delivery circuits to form a complete system with the proposed modular structure.

ABSTRACT The California Institute of Technology (Caltech) and the University of California at Los Angeles (UCLA) have partnered to integrate advanced imaging and sensing coupled with computing needed to translate technological innovation to address the global cardiometabolic disease. The UCLA/Caltech integrated Theranostic Engineering to Advance Metabolic Medicine (iTEAM) Program represents a new paradigm that will be formalized into a 2-year, structured curriculum with an emphasis on recruiting the under-represented post-doctoral engineers or physical scientists into leadership roles in academia and industry. The convergence of the fundamental strengths of Caltech and clinical strengths of UCLA is conducive to individualize training in 1) advanced sensing or 2) imaging coupled with computing to address 3) cardiometabolic disease. The iTEAM program is partnering with industry leaders (Amgen, Johnson & Johnson, Medtronic, and Edwards Lifesciences) for internship, mentorship, and leadership programs. Both the Caltech Diversity Center and UCLA Faculty Diversity & Development Office have supported workshops on Science Technology Engineering & Mathematics (STEM) for women and underrepresented minorities. To implement this UCLA/Caltech iTEAM program, we have developed a mentoring and self-evaluating structure in the inclusion of 21 primary and co-mentors, 13 consulting mentors, and 10 industry leaders (42% female). Each iTEAM scholar will have co-mentorships: a primary mentor from enabling technologies and a secondary from cardiometabolic medicine and/or industry. In Year 1, iTEAM scholars will: 1) Participate in an initial two- day workshop including mentors, program leaders, clinicians, physician-scientists, and industry leaders to explore projects, expectations, mentorship, and goals; 2) Meet one-to-one with the Program Director(s) to finalize a primary (imaging or sensing) and a co-mentor (cardiometabolic disease or industry); 3) Develop an Individualized Development Plans (IDP) with the Advising & Training Committee to finalize the project; and 4) Strengthen fundamental knowledge in advanced imaging, sensors, or computation and didactic training for ethics in biomedical research and publications. In Year 2, iTEAM scholars will be afforded 1) the opportunity to present work-in-progress and provide feedback in quarterly meetings with a primary mentor and with a co- mentor, 2) an option to participate in a certificate in Pathways in Clinical and Translational Research from the UCLA Clinical Translational Science Institute (CTSI) or Law and Technology for FDA regulatory science (BE188/299); and/or 3) to participate in UCLA CTSI-sponsored professional development in preparation for an academic or industry career. Both Caltech and UCLA Deans have committed matching funds for each iTEAM scholar. UCLA Vice Provost for Graduate Education and has also committed supplemental trainee support to enhance the diversity of trainees. Overall, this program infuses the scientific workforce with the next generation of theranostic bioengineers prepared to solve the worldwide threat of cardiometabolic disease.

PROJECT SUMMARY/ABSTRACT This Phase I/II STTR Fast Track proposal responds to the call from the 2018/2019 NCATS SBIR/STTR Research Priorities to develop technologies so that ?new treatments and cures for disease can be delivered to patients more quickly?. The production of life-altering gene editing vectors, cancer killing viruses, and life- saving vaccines currently depends on traditional cell culture techniques. A number of virus-based and cell- based therapies have become clinical treatments for cancer, for genetically-related blindness, for immunodeficiency, and for inborn errors of metabolism. In this exciting field, many therapies being developed are on waitlists to be tested. However, current cell culture-based production is costly and slow to attend the existing demand. For instance, a clinical trial for AAV-based gene editing requires 1016-17 viral particles, a quantity currently requiring a year for production and costing 1-2 million dollars. Thus, the cost of $400,000 to $1,400,000 per patient for recently approved gene medicines is not surprising. These price tags simply are not sustainable for society. In the event of a pandemic, it would take years to generate sufficient doses of vaccines to protect the 7 billion world population by current production methods. Thus, increasing the efficiency and speed of culture of production cell lines are common goals for manufacturing of gene editing vectors, oncolytic viruses, and vaccines. Our joint research efforts at XDemics Corporation, the California Institute of Technology, and the City of Hope National Medical Center, have resulted in an improved method of cell culture. Based on a known fact that oxygen delivery is the most rate-limiting process for increasing cell density, viability, and virus production we created a novel high density cell respirator (HDCR) (US Patent no. 10,053,660) from highly oxygen permeable material that can be inexpensively molded into large sheets, with integrated cell retention architecture, for efficient membrane oxygenation of adherent or suspension cells. Our hypothesis is that elimination of shear stress and the low flow media delivery through the HDCR, enabled by the decoupling of gas exchange via membrane oxygenation of cells, will allow for improved yield, decreased cost, and increased speed of production of therapeutic viral vectors and viruses. We have preliminary data confirming this hypothesis and have produced prototypes for optimization. Herein we propose Phase I studies to optimize the design of the HDCR for cell growth and demonstrate virus production. Proposed Phase II studies will consist of research and development of production processes for multiple viral vectors, including AAV and immuno- oncolytic poxvirus/vaccine. We expect that the HDCR will disrupt the field of vector and virus production, by allowing >10 times greater efficiency and >2-10 times greater speed of production. Our long-term goal is to speed up production of clinically-relevant quantities of viral medicines and vaccines from years down to months. Decreasing the cost of gene therapy vectors, cell-based immunotherapies, and vaccines will accelerate development of novel therapies for treating cancers, gene defects, and infectious diseases.

Abstract Despite recent advances in implantable biomedical devices, the utilization of wireless power delivery continues to be a challenge due to anatomical size constraints that limit sufficient power transfer. In addition to pacemakers, implantable stimulators, including neuromodulation devices used for spinal cord, deep brain, and peripheral nerve stimulation, are confined by the same lead-based architecture. Thus, developing wireless power transfer for implantable devices, including the pacemaker, has the potential to mitigate a host of device- related complications. A primary challenge in inductively powered biomedical devices remains in developing a micro-scale receiver antenna with sufficient power output while minimizing transmitter power consumption over an anatomically and wirelessly feasible range. Eliminating the pacing leads, bulky batteries, fixation-associated mechanical burden, and repeated procedures for battery replacement and device retraction remains an unmet clinical need. In this context, we seek to advance a long-range inductively powered wireless and batteryless micro (µ)-system with sufficient power for pacing functionality. Our encouraging preliminary results support the feasibility of a pacing system with a subcutaneous unit and micro-scale pacer unit to induce sufficient power transfer for ex vivo pacing to a porcine heart. We hereby address the fundamental constraints of in vivo long- range pacing using an intravascular micro-pacing system. Our objective is to integrate advanced antenna and circuit design into a pacer system to enable intravascular deployment of wirelessly powered µ-pacer to the anterior cardiac vein (ACV) for pacing. Our goal is to eliminate the device fixation- and lead-related mechanical complications for optimal power transfer efficiency. To deliver our objective, we have three aims. In Aim 1, we will demonstrate the fundamental µ-antenna design and fabrication to enhance power transfer efficiency. In Aim 2, we will integrate CMOS technology and the novel parylene-on-oil encapsulation to enable intravascular deployment. In Aim 3, we will demonstrate the µ-pacer for real-time intravascular pacing in our pre-clinical model. Successful deployment of this wireless power transmission system provides the theoretical and experimental framework to overcome the anatomical size constraints that limit sufficient power transfer with translational implications for both cardiac and non-cardiac stimulation.

ABSTRACT This T32 program represents a new paradigm for training biophysical scientists and engineers to traverse cardiovascular medicine. The convergence of engineering with medicine is transforming clinical and patient care via advances in flexible electronics for sensing and imaging, coupled with machine learning, which has introduced new innovations to confront the rising endemic of cardiometabolic disorders. The University of California at Los Angeles (UCLA) and the California Institute of Technology (Caltech) are partnering to develop the UCLA/Caltech integrated Cardiovascular Medicine for Bioengineers (iCMB) Program, that will be formalized into a 2-year, structured curriculum with an emphasis on recruiting the under-represented post- doctoral engineers or biophysical scientists into leadership roles in academia and industry. The approach is to strengthen individualized training in 1) advanced sensing or 2) imaging coupled with machine learning to address 3) cardiometabolic disease. The iCMB program will be built upon two successful Caltech and UCLA joint training programs: the Medical Scientist Training Program (MSTP) for MD-PhD students and the unique Subspecialty Training and Advanced Research Program (STAR) for fellowship-level physicians to obtain a PhD. The partnerships with the industry leaders from Amgen, Johnson & Johnson, Medtronic, and Edwards Lifesciences have enriched our internship, mentorship, and leadership programs. Both the Caltech Diversity Center and UCLA Faculty Diversity & Development Office have supported workshops on Science Technology Engineering & Mathematics (STEM) for women and under-represented minorities. To implement this iCMB Program, we have developed a novel mentoring and self-evaluating structure in the inclusion of 24 seasoned mentors, 4 emerging faculty, 22 Clinical Faculty (42% female), and 10 industry leaders. Each iCMB scholar will have co-mentorships: a primary mentor from cardiometabolic medicine and a secondary from enabling technologies or industry. In Year 1, iCMB scholars will develop fundamental knowledge in advanced imaging, sensors, or computation and didactic training for ethics in biomedical research and publications. In Year 2, iCMB scholar will have an option 1) to participate in a certificate in Pathways in Clinical and Translational Research from the UCLA Clinical Translational Science Institute (CTSI) or Law and Technology for FDA regulatory science (BE188/299); and/or 2) to participate in UCLA CTSI-sponsored professional development in preparation for an academic or industry career. Both Caltech and UCLA Deans have committed matching funds for each iCMB scholar. Our Vice Provost for UCLA Graduate Education has also committed supplemental trainee support to enhance the diversity of trainees. Therefore, the complementary and synergistic strengths of the Caltech/UCLA iCMB Program provide a new infusion of workforce prepared to solve the worldwide endemic of cardiometabolic disease.