Megan T. Valentine, Ph.D. - US grants

This three year REU Site program is a continuation of a highly successful program at the University of California, Santa Barbara (UCSB), which brings community college students from across California to engage in interdisciplinary research. This program, entitled "Internships in Nanosystems Science, Engineering and Technology"(INSET), will expand opportunities for community college students, promoting their future academic and career success in science and engineering through multi-tiered mentorship. The INSET program will be hosted by the California NanoSystems Institute (CNSI), where research explores the richness of opportunities in forming new materials and complex systems by integrating nanoscale building blocks from both biological and electronic materials. Interns performing research within the CNSI will gain hands-on experience in the development of cutting-edge technologies that fall outside the traditional boundaries of science and engineering disciplines. Additionally, the INSET program will collaborate with the Center for Nanotechnology in Society, which will engage students in discussions and research projects on the societal impacts of new nanotechnologies. This collaboration will foster students' and researchers' abilities to enable broadly multi-disciplinary research, engaging not only the natural sciences and engineering, but also social sciences and mathematics.

INSET recruitment efforts will build on established relationships with California community colleges that have sizable underrepresented and disadvantaged populations. INSET will have extensive impact on the greater UCSB community. The program will also enhance the role of mentorship and the professional development of graduate student mentors through training workshops and networking. Additionally, program staff will take a leadership role in coordinating activities with several other UCSB undergraduate research programs during the
summer, including a campus-wide undergraduate research colloquium.

Nationally, this program will enhance the capacity of other institutions to support community college transfer students by raising the profile of high-achieving community college student researchers, promoting successful university/community college partnership models, and disseminating INSET evaluation findings through publications and professional conferences.

The research objective of this Faculty Early Career Development (CAREER) award is to use a suite of custom imaging and microscale manipulation tools to investigate the interdependence of motility, adhesion and transport in neurons. Neurons are specialized cells, with highly elongated geometries, that form mechanically connected networks to enable transmission of signals in the nervous system. The development of healthy neural networks depends on the action of filamentous cytoskeletal structures: actin guides neuron growth and adhesion, while microtubules serve as the tracks for the long-distance intracellular transport of proteins and organelles that is required to maintain the extended cell protrusions. Studies conducted under this award will determine the extent and nature of the coordination between the actin and microtubule structures by measuring how errors in long-distance transport affect cell adhesion and motility, and how chemically- and mechanically-engineered scaffolds that modulate adhesion affect transport. The effects of sudden impact injury on single neuron mechanics, adhesion and transport will also be determined.
If successful, this research will provide a new paradigm for the experimental investigation of neurons (-). One that integrates distinct features such as adhesion or transport into one comprehensive model of neuron function. Ultimately, the results will lead to the design of improved neural devices and implantation materials, and novel treatment strategies for a wide range of neurological disorders and traumatic brain injuries (TBI). The educational goals are to include undergraduate students in all aspects of research, and to develop new teaching material on the emerging field of neuron mechanics. A new internship program, Veteran-student Internships in Biomechanics Research and NeuroTechnology (VIBRANT) will be developed to bring veteran students from local community colleges to campus to pursue independent research. One-on-one mentoring and professional development opportunities will be provided to encourage and empower veteran students to pursue science and engineering degrees.

Cell survival depends on the efficient transport and sorting of protein and chemical species into different functional compartments. Nanoscale motor proteins that grasp membrane-bound cargos and move them along polymer filaments enable this transport. The resultant cargo motion is thought to arise from the cooperative action of multiple motor proteins, but the extent of cooperation and the molecular mechanisms that enable it are poorly understood. One possible mechanism for cooperation lies in the ability of multiple motors to share the load necessary to move the cargo. Such load splitting is expected to depend strongly on the mechanical properties of the cargo surface, but the detailed relationship between load splitting, transport efficiency, and cargo mechanics is unknown. The objective of this research project is to determine how membrane mechanics influences the ability of motor proteins to cooperatively transport cargos. To this end, biomimetic cargos with well-controlled interfacial chemistry and mechanical properties will be generated and coupled to motor proteins in vitro. The mechanical properties of the cargo surfaces will be varied from purely rigid surfaces with immobile motor attachment sites to purely fluid surfaces made of lipids that can rearrange their positions. The fluid cargos, which are thought to better mimic the properties of cargos in living cells, would allow motor binding sites to easily move on the cargo surface as the motor proteins move. The impact of these interfacial lipid rearrangements on cargo motion will be assessed using precision biophysical tools. Specifically, the ability of motors to cooperatively move fluid and rigid cargos against an external force will be determined and quantitatively compared. Computer simulations and analytical theory will be developed to understand the experimental data and generate testable predictions for the effects of membrane mechanics on cargo transport in cells.

If successful, this research will provide important new insight into the fundamental mechanisms and regulation of intracellular transport, while creating outreach and training activities at the interface of biology, physics, and engineering. In particular, community college and undergraduate students will participate in hands-on research, and this work will form the thesis project of one graduate student, who will develop expertise in experiments, computation and analytical theory. The outcomes of this project will be incorporated into interdisciplinary biophysics/biomechanics courses at UCSB and the Santa Barbara Advanced School for Quantitative Biology, and will be disseminated broadly in publications and conferences.

Non-technical Abstract:
This project will determine the optimal design parameters for strong, resilient polymeric materials to improve their use in a wide range of applications including as smart structural materials that can heal after failure, as tissue replacements for damaged joints, and as scaffolds for the large-scale manufacture of stem cell cultures. Our study takes advantage of the unique features of protein-based polymers to create materials with enhanced toughness and resiliency. Our results will provide not only optimization criteria, but will establish the relationships between molecular structure and bulk, macroscopic material response. Building such connections between length scales is very important, and will enable other academic and industrial engineers to leverage our work to solve numerous problems in materials science. This study will engage graduate, undergraduate and community college students in materials research, while providing hands on training in state-of-the-art experimental and computational methods. The students and the PI will participate in community outreach events and visits to local elementary schools to advance a public understanding of cutting edge materials science.


Technical Abstract:
This project will enable the improved design of strong, resilient polymeric materials by establishing the relationships between structure and mechanics in adhesive rigid rod polymer networks. We use a model system made of filamentous cellular proteins called microtubules with chemical and mechanical properties we can tightly control. Experimentally, we apply local forces to such networks using focused electromagnetic fields to manipulate microscale particles and we relate particle displacement to understand the local mechanical properties of the gels. Unlike most synthetic systems, protein-based networks are very rigid allowing them to retain an intrinsic memory of their initial, unloaded state. Moreover, protein-based crosslinkers are labile: their bonds break under force but can reform when the force is removed. These unique features increase biomaterial toughness and resiliency, and allow such materials to 'heal', even when they are locally loaded to failure. Through experimentation and simulation, our work will establish the microscopic origins of material response, and will guide the development of bio-inspired materials that are durable, adaptive, and self-healing. Such materials could be used as artificial tissues or as smart structural materials where shock absorption under loading is required. This work will engage graduate, undergraduate and community college students in materials research. The students and the PI will participate in community outreach events at local elementary schools to advance a public understanding of cutting edge materials science and will share our results broadly through publications, conferences, and in-person visits to local schools.

An award is made to the University of California, Santa Barbara (UCSB) to acquire a high-resolution, fast, laser-scanning confocal microscope. This award will allow critical problems in biophysics, neuroscience, and bioengineering to be addressed, while substantially increasing the research and training capacity of the campus. In particular, this new instrumentation will provide scientists at UCSB with unprecedented abilities to measure the dynamic motions of microscale structures in biological and bioinspired materials. Undergraduate and graduate students will gain expertise in cutting edge technologies, imparting new scientific knowledge, developing new materials, and understanding human health. A partnership with the Wolf Museum of Exploration + Innovation (MOXI) will bring the discoveries enabled by this award to the public.

The fast-scanning, high-resolution confocal microscope with spectral detection capabilities (Leica TCS SP8x) will substantially modernize the Neuroscience Research Institute (NRI)/Molecular Cellular and Developmental Biology Microscopy Facility. The new instrument will transform the institutional research capabilities for collecting quantitative, high spatial and temporal resolution images in order to carry out NSF-funded research addressing diverse and critical research questions in developmental biology, quantitative biophysics, bio-inspired materials research, and neuroscience. These include investigations of: (1) intra- and inter-cellular interactions and the dynamics of morphogenesis and tissue remodeling; (2) human brain development using stem cell-derived cerebral organoids; (3)"smart" materials in which the mechanical properties can be dynamically controlled through responsive molecular architecture; (4) the dynamics of surface diffusion, convection and adhesion; and, (5) the molecular and biophysical mechanisms driving tunable iridescence. In addition to the immediate gains in speed and sensitivity, this project will provide for minor modifications to customize the new microscope and make it compatible with a wide range of customized biophysical tools, including a miniaturized surface forces apparatus (SFA), high-force magnetic tweezers devices, and a scanning probe microscopy system that combines imaging and multielectrode array technologies to map and manipulate neural tissues in culture. Additionally, the proposed instrumentation will be used in a variety of classroom, training, and outreach activities that will significantly enhance the education and mentorship of graduate and undergraduate students, and will bring diverse cohorts of students and experts to UCSB to perform research. A new partnership between the UCSB NRI and the Wolf Museum of Exploration + Innovation (MOXI) will engage the public in active learning about optics, light and imaging, while sharing the important discoveries and applications of the research enabled by this award. These activities will substantially expand the impact of this project beyond our campus, and will further strengthen UCSB's position as a leading institute in quantitative biology, neuroscience, biomaterials and bioengineering research and education.

CBET - 1631656
Turner, Kimberly

The brain is a highly plastic organ, capable of learning, remembering and adapting. However, it is also a plastic material with mechanical properties of strength, hardness, and impact resistance. A major challenge in neuroengineering is to understand the biophysical properties of the brain and how these differ between individuals. In particular, how do differences in the mechanical properties of the brain alter the experience of force and the consequences of impact? A major limitation in the systematic study of force on the brain has been the inability to reliably apply impacts or pressure to individual cells. The uHammer project aims to develop just such a highly engineered tool for the application of force to individual neural cells. These single cell studies will allow us to compare individual differences in neural responses to force, including changes in cell mechanics, structure, viability, and gene expression. This project, a collaboration between industry and multi-faceted academic team, will support the Ph.D. work of two graduate students, hold a workshop to bring together top researchers interested in this important societal problem, and train undergraduate research interns, while attempting to unlock some of the mysteries surrounding the brain today.

The focus of this work is to probe the mechanical properties of neural tissue and the subsequent effects on function. To examine the consequences of force on neurons, a device must apply precise forces to single cells over a few microseconds. No existing devices provide these force and temporal responses, and developing such a device would enable broad, new classes of cellular measurements. The development of a MEMS based device (the uHammer) that uses time gated magnetic actuation to deliver milliNewton impact forces to single cells in a high throughput fashion, will enable these measurements. The device, capitalizing on recent advances in micro and nanoscale transduction, microfluidics, and analytical techniques, will allow cells to be monitored in real-time and collected after impact for analysis. The uHammer will enable entirely new classes of experiments, in which the biological consequences of impact loading can be recorded and monitored as a function of force amplitude, direction, duration, and time after loading. The focus is to develop a significantly improved understanding of the role of impact and pressure loading on individual neurons, neural progenitors, and brain tissue. The technical goals are to Design, fabricate and test a tool (the uHammer) able to apply physiologically relevant loads to single cell, optimize the device for high-throughput manipulation of neural stem cells, and quantify the effect of impact on single cell mechanics, structure, viability, colony formation and gene expression. The uHammer team of engineers, neuroscientists, biologists and industry leaders is able to tackle these challenging questions, while also providing a unique learning environment for undergraduates and graduate students. The multidisciplinary uHammer team has the ability to design new technology with the end user in mind, enable new scientific discovery, and transform it into therapies and treatments. The proposed technology will enable experiments that are not presently possible, and the link to and commitment from industrial partner Owl Biomedical, will enable rapid commercial developments. With these partnerships and goals in hand, UCSB is poised to make game-changing breakthroughs on problems including traumatic brain injury (TBI) and Alzheimers disease

This project will advance the control of continuum soft robots in complementary areas of representation and implementation. First, it will explore the use of data-driven modeling techniques that are especially well-suited to high-dimensional nonlinear systems. Continuum systems are high dimensional because they may be formed into many distinct, independent shapes, while soft structures frequently exhibit nonlinear dynamics due to their characteristically large deformations. Second, it will explore sensing and actuation using materials that change their mechanical properties in response to light. Light may be steered to various parts of the robot through waveguides made from compliant materials in a variety of geometries, chosen to naturally match the compliance and geometry of the robot. Multiple commands or measurements may be combined on a single waveguide by using different colors of light for different signals. This helps address the large number of sensors and actuators needed to fully monitor and control these high-dimensional systems. The results of this work will be a new class of optically controllable, continuum, compliant, and configurable robots, or C4 optorobots for short. The capabilities of C4 optorobots will be valuable in numerous applications, including inspection of hard-to-reach areas and minimally invasive surgery. This project will include validation experiments, such as a representative engine inspection task, simulated tissue ablation in the heart, and simulated blood clot removal in the brain. Outreach activities of this project will focus on training of graduate and undergraduate students from underrepresented groups, including community college students, in emerging areas of soft robotics.

This project will combine two key innovations - Koopman Operator Theory (KOT) and light-modulated materials design. KOT uses a data-driven approach to identify the eigenmodes of a complex, nonlinear system, thus enabling optimization of control inputs for greatest impact. KOT can produce a linear dynamical model that matches the system behavior, suitable for use in a model-based control. Light combined with photoresponsive materials can provide such control inputs because wavelength, intensity, pulse duration, and spatial distribution can be precisely and nearly instantaneously controlled. Accordingly, this project will accomplish the following goals: 1) Use KOT to extract and formulate linear, dynamic models of C3 robotic sub-systems and implement model-based control schemes using finite control inputs; 2) Develop transduction mechanisms, through engineered light delivery, novel chemical synthesis, and integration into light-responsive materials, to actuate C3 robotic sub-systems; 3) Integrate light-activated robotic sub-systems and model-based linear control schemes to realize controllable, continuum, compliant, and configurable robots -- C4 optorobots.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Cells generate significant forces that are critical to growth, wound healing and many tissue functions, but measuring these forces within living tissues remains a significant challenge. One promising approach is to embed, within the tissue, microscopic sensors that can be stretched, compressed and deformed by cell-generated forces. By recording these sensor shape changes with microscopy, the cell-generated forces can be measured over time. One barrier to developing this technology is the lack of robust, non-toxic, polymeric materials for use as sensors. This project aims to address this challenge by developing a fundamental understanding of how polymer composition and processing control the structural and mechanical properties of hydrogels. The results of this work will enable the design and manufacturing of hydrogel-based materials for specific sensing applications, and will establish predictive relationships between sensor shape and applied force. The knowledge and materials developed through this award will promote their use in tissue engineering and reconstruction, bioengineering devices, and medical diagnostics. This project will provide important opportunities for education and outreach. Diverse cohorts of graduate and undergraduate students will be recruited and trained in biomaterial science and engineering. Elementary school students will be given opportunities to experiment with polymers and learn about the relationships between shape, mechanics and force. Course materials and informational videos will be generated and distributed to provide teachers and the public with resources to understand and appreciate the importance of biomaterials science in biology, engineering and medicine.


PART 2: TECHNICAL SUMMARY

This project combines theory and experiment to develop and optimize non-toxic hydrogel microspheres for use as sensors of cell-generated forces in multicellular aggregates and tissues. The study will establish the material design criteria that enable programming of the mechanical properties of polymeric hydrogels, including single and multi-phase materials that exhibit linear and nonlinear mechanical responses, respectively. The results of this work will establish how polymer length, network architecture, crosslinking density, and hydrophobic content influence the material?s shear elasticity and compressibility. Experimental manufacturing methods will be optimized and theoretical models will be developed to understand and program the material mechanics for cell sensing applications. Sensor performance will be validated in biological assays. These results will provide the foundational knowledge needed to develop new classes of biocompatible hydrogel materials for cell force sensing, cell encapsulation and soft tissue regeneration and replacement.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).

NON-TECHNICAL SUMMARY

A team of five physicists, biologists, and engineers aim to design and create a new class of self-directed, programmable, and reconfigurable materials inspired by cells and capable of producing force and motion. This approach will capitalize on two important design principles of living organisms: (1) cells are composite in nature to meet numerous functional demands, and (2) decision-making and timing are achieved through biomolecular circuitry. This effort will couple synthetic hydrogels to living layers of active polymer composites infused with cellular timing circuits to produce next-generation materials that self-actuate programmable cycles of work and motion. The proof-of-concept design will be a gap-closing micro-actuator that closes upon exposure to light and then autonomously re-opens at times and locations programmed into the embedded cell circuits. The material development aims, customized high-throughput characterization, and publicly shared property-formulation libraries will empower the broader Materials Genome Initiative (MGI) community to manufacture and deploy such disruptive materials of the future.

The effort will provide opportunities to a diverse set of undergraduate, post-baccalaureate, graduate student, and postdoctoral researchers to broaden the STEM-trained workforce pool. Specifically, the effort will build a new undergraduate research and professional development program with students pursuing interdisciplinary materials research across the five campuses. By developing a fundamental understanding of how to manufacture and control such materials, this project will enable exciting future applications for self-healing infrastructure, self-regulating delivery vehicles, self-propulsive materials, micro-robotics, and programmable dynamic prosthetics.

TECHNICAL SUMMARY

The overarching goal of this research is to develop the foundational technologies, predictive models, and formulation libraries needed to pioneer a new class of autonomous reconfigurable materials with self-generated spatiotemporal control. The project will engineer active biotic-abiotic materials that uniquely emulate living organisms–performing robust autonomous programs without intervention–in contrast to current active matter systems that are labile in nature and require external triggers or contrived conditions to enable activity. Leveraging advances in synthetic biology and active matter physics, and guided by multi-scale mechanistic modeling, the effort will functionalize layers of abiotic hydrogels and active cytoskeleton composites with cellular circuitry for in situ bioproduction of material-modifying proteins to impart temporal control of mechanics, structure and activity. This will allow the research to spatiotemporally program restructuring, work, and motion with an autonomous gap-closing actuator built from abiotic-biotic layers programmed to produce cytoskeleton-modifying proteins on a user-defined schedule. In this way, iterative design-build-test-learn cycles will be utilized to accelerate discovery–linking theory, fabrication, computation, and characterization to establish a broad phase space of structure-mechanics-function relationships. The modular material platform, multi-scale mechanistic modeling, mechanical and structural characterization, and publicly disseminated formulation-property database will contribute to the overarching goals of the MGI to harness autonomous, biomolecular systems and create next-generation programmable living materials.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.