David Erickson - US grants

Proposal Number: 0529045
Principal Investigator: David C. Erickson
Affiliation: Cornell University
Collaborative Research - SST: Integration of Spectroscopic Sensors and Electroactive Nanowell Arrays with Microfluidic Chips Based on Thermocapillary Actuation

Microfluidic devices for liquid dosing, transport and mixing are driving innovation in genomic and pharmaceutical research as well as rapid commercialization of portable kits for home, industrial or military use. Such devices, predicted to revolutionize portable chemical detection and analysis, are expected to generate over 2 billion dollars in income by 2010. The newest open format devices, based on actuation of free surface flows, i.e. liquid-liquid or gas-liquid interfaces, provide an especially attractive platform for highly sensitive detection of adsorbed species. Essential to the operation and control of these devices is development and integration of sensing arrays for high resolution, autonomous identification of sample position, volume, temperature, speed, composition and molecular species. This research program targets the development and integration of miniaturized optical, spectroscopic and electroactive sensors with thermofluidic chips. The three-part program includes (a) integration of thin film waveguides with open fluidic devices for evanescent sensing of stationary or moving samples, (b) development of a novel liquid-core waveguide based on thermocapillary actuation of microscale rivulets and (c) development of electroactive nanowell traps for electrostatic confinement and concentration of biomolecules. The waveguide sensors will be used to monitor droplet location, composition, rate constants for chromogenic reactions, and binding to functionalized quantum dots in a liquid suspension. Additional signal enhancement will be explored through evanescent coupling to micro-ring or micro-disc resonators fabricated on the chip surface. The electroactive nanowell sensor arrays positioned beneath stationary or moving droplets will allow development of an electrical impedance spectroscopic technique for use as an environmental sensor of aqueous borne bacterial pathogens. Sensor development and optimization will proceed through experiment, theoretical modeling and numerical simulations. The broader impacts of this grant are as follows: The interdisciplinary nature of the research will allow development of a novel fluidic chip with integrated sensing arrays and provide students with unique training at the crossroad of microscale transport phenomena and photonics, two high growth areas with numerous applications to bio- and nanotechnology. Undergraduates will be recruited through the NSF REU programs at Cornell and Princeton to aid with chip and nanowell fabrication, assembly of simple prototypes and data analysis. Students will be trained in the physical and engineering principles governing advanced optical and electrokinetic sensing platforms; they will also develop demonstration units for undergraduate lab courses and K-12 education. The Princeton PI will expand a current course on microfluidic phenomena to include a 2nd semester on sensing principles for miniaturized devices. She will also be leveraging this study toward establishment of a new Princeton Center on Advanced Fluidic Technologies, a large scale pilot program currently under consideration by the New Jersey Commission on Jobs Growth and Economic Development The Cornell PI will design a new course geared toward modern engineering and fabrication techniques of optical and spectroscopic sensors for lab-on-a-chip technologies. The PIs will jointly organize sessions on optofluidics and sensing at the IEEE Tranducers and SPIE Optical Information Systems meetings.

A major challenge in using stochastic self-assembly as a manufacturing paradigm is to deterministically assemble complex structures comprising large numbers of particles in specified, non-regular geometries. Our goal in this grant is to exploit dynamic microfluidic effects both to accelerate and to control self-assembly of micro-scale tiles (microtiles). The approach we are using is based on a hierarchical, dynamically-programmable fluidic self-assembly of components. Once in place, each component can further control local flow to attract or repel additional microtiles and thus explicitly direct and accelerate the 'growth' of the target structure or recover from assembly errors. Our objective is to demonstrate the formation of groups of microtiles into specified millimeter-scale assemblies.

If successful, the results of this research will open the door to future low-cost, scalable fabrication of three-dimensional micro-scale devices, required in numerous applications. Results from this research will also be used to develop educational software for demonstrating and experiencing the challenges and opportunities involved in manufacturing based on self-assembly concepts.

0708599
Erickson, David C.

This NSF-NIRT award is centered around the active integration of nanophotonics, nanofluidics, nanomaterials and single molecule physics into a new field, refered herein as ''Nanophotofluidics''. The assembled team consists of researchers from Cornell University and the University of Rochester bringing distinct individual expertise to form the integrated, multidisciplinary research program to exploit the extremely high optical intensities achievable in our newly developed 50nm wide exposed mode ?slot waveguides? to perform optofluidic tweezing and propulsion (by exploiting polarization and scattering/adsorption forces) and demonstrate a series of new active nanoscopic single molecule and multi-particle analytical tools.

Intellectual Merit

This program is divided into three focused research areas: 1) develop a better fundamental understanding of the coupling of electromagnetics and hydrodynamics on the nanoscale to demonstrate the core elements of a broader nanophotofluidic transport architecture, 2) demonstrate the most resolute separation mechanism developed to date, and 3) develop a new mechanism for investigating single protein folding dynamics in solution.

Broader Impacts

Integrating photonic elements as active components in micro- and nano-fluidic devices represents a largely unexplored area that could have significant impact that could be extended into a broad new class of photonically driven microfluidic devices where rapid, network based particle manipulation is performed using the high-speed components already developed by the telecommunications industry. Such platforms may find application in emerging fields such as nano-assembly (offering all the advantages of optical tweezing but more rapidly and with sub-wavelength precision). A fundamental part of this program is an outreach and education strategy consisting of: 1) The development of a series of integrated educational units distributed to K-12 classrooms nationwide through the Cornell Main Street Science program and 2) An interdisciplinary nanoscience and engineering seminar series for the upstate New York area. This seminar series will attract attendees from both universities as well as undergraduate institutions in upstate New York. The talks will also be posted on a dedicated website for download. Students from the target institutions will also be given the opportunity to post questions on a dedicated website which will be answered directly by the speaker or the PIs.

This research is well aligned with both NSF Active Nanostructures and Nanoscale Devices and System Architecture research themes.

[unreadable] DESCRIPTION (provided by applicant): The need to rapidly diagnose emerging viral threats along with the potential for associating individual or multiple point polymorphisms with disease states and pharmacological responses has lead to a recent interest in the development of new high-throughput nucleic acid biosensors. In this application, R21 support is requested for the development of "Nanoscale Optofluidic Sensor Arrays" which represent a new paradigm in high fidelity, high throughput, and unlabeled biosensing. The technique relies on shrinking the fluidic system down to the same scale as the wavelength of light and using the properties of a unique silicon nanophotonic structure to gain access to the evanescent field and to provide spatial localization of the reaction site. As is demonstrated this technique: (1) has attogram level detection sensitivity without the need for target labeling, (2) enables independent functionalization of individual nano-sensing sites with sub-micron spacing (3) ensures each solution phase nucleic acid target has multiple opportunities to hybridize with its surface immobilized complement (4) allows for inherent two dimensional multiplexing and (5) enforces reaction specificity through a unique electrokinetic stringency technique. Though broadly applicable to a wide range of nucleic acid applications, here we propose to demonstrate the platform through the specific detection of viral pathogens (focusing on the four serotypes of Dengue virus which has been identified by the Center of Disease Control and Prevention as one of the emerging diseases of our century) multiplexed simultaneously against a series of independent samples. This exploratory work builds on the PI's and Co-PI's background in integrated microfluidic devices, nanoscale optofluidic integration, high-throughput nucleic acid screening and RNA based viral pathogen biosensors. In this work we will focus on the experimental development of the sensor platform in preparation for an R01 application in which the device will be applied to clinical diagnostics and will incorporate sample preparation steps such as immunomagnetic separation, RNA extraction and pre- concentration prior to sensor analysis. Dengue virus is a major public health concern in tropical and subtropical areas. It causes an estimated 50 million illnesses annually, including 250,000-500,000 cases of Dengue Hemorrhagic Fever with 5-10% of mortality. Development of the Nanoscale Optofluidic Sensor Array could provide a technique by which viral pathogens like, but not limited to Dengue, can be detected at very low quantities in a highly parallel format. The near term major application will be as an early stage detection platform. [unreadable] [unreadable] [unreadable]

0846489
Erickson

To develop a research area called "Optofluidics", the PI will perform both theoretical and experimental investigations into the fusion of microfluidics and optics. While the idea of fluid-optical devices can be traced back as far as the liquid mirror telescopes of the 18th century, microfluidics presents a unique opportunity for creating microscale analogues of these early devices. A series of fundamental studies will develop a new form of microfluidic transport exploiting the electromagnetic energy in photonic devices to capture, transport and separate particles. Additionally, the PI will create a new class of reconfigurable photonic system of microfluidic devices to transport, switch and modify light. These efforts require numerical/analytical modeling examining the coupling between hydrodynamics and electromagnetics, an experimental aspect to verify these models, and an implementation focus aimed at providing a "proof-of-concept" demonstration of a practical technology.

Optical force transport has several advantages over other microscale techniques (e.g. electrophoresis, dielectrophoresis, and pressure) including opposite transport scaling laws, significantly higher separation resolutions and insensitivity to surface/solution conditions. By exploiting waveguides to deliver the electromagnetic energy, the PI shows that the fundamental limitation preventing widespread adoption of optical transport in microfluidic devices can be solved. A technology development thrust will also be pursued for a waveguide-based separation device for viral identification. This second thrust will develop a largely new application area for microfluidics and a new approach to reconfigurable photonics based on transport of electromagnetic energy within microfluidic streams, exploiting the same handling techniques developed for transporting chemical samples on-chip to shuttle light around.

The PI plans development of a web-deployed "FluidicsWiki" organized around the central theme of micro and nanofluidics to allow user-edited content and thus the site can dynamically evolve with the field. The overall goal is to synchronously disseminate both summaries of recent research and educational tutorial content from and to the entire community. A planned series of academic and community outreach activities include organizing a biennial conference on optofluidics, conducting seminars on microfluidic technology for K-12 teachers, and explaining the benefits of nanotechnology to the public at the New York State Fair.

The research objective of this Interdisciplanary Research (IDR) project is to develop self-reliant, self-powered microsystems for autonomous biophysical monitoring. These systems will be applied to the understanding of avian flight biology through the development of a "Lab-on-a-Bird." The approach taken will be to intertwine a number of micro- and nanotechnologies (including biosensors, microfluidics, drug delivery, energy harvesters) with the living animal and will enable on-line monitoring of blood metabolites. The interdisciplinary project combines expertise from the Engineering and Ecology departments at Cornell University with the avian experts at the Cornell Laboratory of Ornithology.

If successful, the benefits of this research will be two-fold. The first will be from the development of the individual nanotechnology based components and the engineering behind integrating them into a single self-reliant system. It is expected that these systems would have impact well beyond the specific platform here, potentially leading to devices that can provide continuous human health monitoring or become nodes for networks of environmental sensors. The second area of impact will be in the development of an entirely new way of studying avian behavior. For example, these systems could enable us to track physiological changes in a single moving bird thereby yielding priceless information on its internal state and enable an unprecedented understanding of the movement decision-making. Eventually the technologies developed here could be eventually used to provide early warning of viral mutations and outbreaks and to better understand the health of the local ecosystems. A series of targeted curriculum and web-based experiences will also be developed that will engage both high school and adult audiences in learning about bird migration, related physiology, and the technological advances that are making possible new discoveries in these fields.

The project is an Interdisciplinary Research (IDR) Project jointly funded by ENG/CMMI and BIO/IOS.

DESCRIPTION (provided by applicant): In this work, we propose a joint project between the Erickson and Chen labs at Cornell University to demonstrate an entirely new approach to the study of weak protein-protein interactions through the development of a single molecule nanophotonic optical trapping and florescence resonant energy transfer (FRET) technique. The molecular system we apply the technique to here is the human copper transport pathway from the intracellular copper chaperone Hah1 to the copper transporting ATPase Wilson disease protein (WDP). Abnormal function of this transport pathway can lead to diseases such as Wilson disease and familial amyotrophic lateral sclerosis. Despite its importance, very limited quantitative information is available on how Hah1 and WDP interact. A major difficulty in obtaining this information is the lack of a single molecule analysis tool which can simultaneously: (1) capture and suspend small molecules in free solution for an indefinite period time (2) effectively "concentrate" the set of molecules of interest to a point where weak protein-protein interactions can be studied and (3) allow rapid modulation of the external environmental conditions (e.g. background ion concentration). The core technological advancement we propose to exploit here in order to meet these requirements is our recently demonstrated optically resonant nanotweezers. The advantage of optical confinement techniques, like optical tweezers, in single molecule analysis is that they can suspend and concentrate targets in dynamically changing background solutions. Fundamentally however, existing optical confinement techniques are limited by diffraction which places a lower bound on the size of dielectric target which can be trapped to about 100nm. We demonstrate here that our planar optically resonant nanotweezers allow us to concentrate the optical energy in such a way that this force can be enhanced so as to trap molecules as small as a few nanometers, bringing us down into the range to make single protein measurements possible. In this work we propose to initially develop the system by trapping a series of larger test proteins (6-8nm) building on our previous work in trapping nucleic acids. After initial development we will conduct a series of single molecule trapping-FRET studies on the Hah1-WDP complex examining how binding interactions respond to changes in Cu1+ ion background concentration. PUBLIC HEALTH RELEVANCE: Metal ions, for example iron and copper, are essential nutrients that can also be toxic if their concentration exceeds the physiological limit. Abnormal function of metal transport molecules can lead to diseases such as Wilson disease, Menkes disease and familial amyotrophic lateral sclerosis. In this work we propose to develop a fundamentally new approach to optically based single molecule analysis and apply it to understanding the function of a series of proteins which control intracellular copper transport.

DESCRIPTION (provided by applicant): Antimicrobial chemokines (AMCs) are understudied members of the family of host defense peptides, which together play an essential role in protecting a wide variety of organisms from bacterial infection. Understanding how AMCs recognize and bind to bacterial targets is key to understanding the basic mechanisms of the innate immune system, as well as designing new antimicrobial therapies that build on millions of years of co-evolution between pathogens and the innate immune system. This application tests the hypothesis that different bacteria are not uniformly affected by AMCs, and identifying bacterial proteins that modulate AMC susceptibility will uncover processes that could provide novel targets for antimicrobial therapy. Since differences in binding to AMCs could be a critical determinant of bacterial susceptibility, we have developed a flow cytometry based assay to measure AMC binding to bacterial cells. Aim 1 involves utilizing this assay to screen thousands of Yersinia transposon mutants to identify those with high AMC binding phenotypes compared to wild type bacteria. Genes associated with lipopolysaccharide biosynthesis appear to play a major role in AMC avoidance and resistance, and Aim 2 involves a detailed characterization of the contributions of these genes to AMC avoidance in both Y. pseudotuberculosis and Y. pestis. Aim 3 tests whether increases in AMC binding due to specific mutations correlate with increased sensitivity to killing by AMCs, as well as by other host defense peptides. Understanding how AMCs and other host defense peptides recognize and bind bacteria, as well as how bacteria evade the antimicrobial activity of host defense peptides, could lead to novel drug targets that enhance the innate immune system. The therapeutic use of AMCs to fight infections may be significantly enhanced by simultaneously targeting processes such as lipopolysaccharide biosynthesis that are required for resistance to these peptides. PUBLIC HEALTH RELEVANCE: This project involves determining how bacterial pathogens resist the body's innate immune defenses. These defenses include a family of peptides called antimicrobial chemokines. These peptides can kill bacteria directly, in addition to their other roles in the immune system. New treatments that interfere with bacterial defense mechanisms could render pathogens less able to cause disease.

Through the Learning Assistants Become Teachers (LABT) project, the University of Montana (UM) in partnership with the Missoula County Public Schools is recruiting thirty individuals to complete baccalaureate degrees in mathematics, chemistry, biology, geosciences, environmental science, computer science, or physics and providing them up to three years of scholarship support to complete their STEM degree and earn secondary teacher licensure.

The LABT project is designed to transform the culture of mathematics and science teacher preparation on the UM campus through the recruitment of STEM undergraduates to become assistants in large section mathematics and science courses. The students work in pairs, and with faculty and graduate assistants, to engage other undergraduates as peer tutors and this provides them with experiences as facilitators of learning in anticipation of becoming teachers in middle and high school classrooms. Additionally, the Learning Assistant model is being extended into elementary and secondary schools where the Noyce Scholars assist master teachers in high-need school districts. Noyce Scholars are being prepared to work in western Montana communities, which are rural and represent a diversity of cultures, including different Native American tribes.

The goals of the LABT project are to:
1. design a recruitment and Noyce Scholarship award strategy that increases the number of middle/high school mathematics and science teachers entering the profession prepared to teach effectively in rural and frontier areas;
2. improve the quality of education for Noyce scholars by instituting a summer field science workshop and an academic year pedagogy seminar;
3. improve the quality of education for both Noyce scholars and undergraduate students in targeted mathematics and science courses by using Noyce scholars as Learning Assistants (peer mentors using supportive teaching strategies); and
4. establish a culture at UM that engages faculty, graduate students, and undergraduates in the learning of mathematics and science content through research-based teaching.

The LABT is characterized by freshmen and sophomore summer internships, modifications to courses in which Learning Assistants work, pedagogy seminars, mentoring by master teachers, and online wiki and Moodle mentoring of Noyce Scholars as they transition into the early years of their teaching careers. Freshmen and sophomore summer internships in ecological field placements serve as a first exposure to teaching, while serving as one recruitment mechanism for Noyce Scholars. Semester-long pedagogy seminars for all Learning Assistants, graduate teaching assistants, and faculty interested in the model or teaching within the targeted courses will be provided. STEM courses in which Learning Assistants are used are being customized to include greater use of small-group work and questioning techniques that encourage mathematical and scientific discourse, including challenging assumptions, revealing contradictions and constructing new understandings. Participating faculty recruit Learning Assistants from the best and brightest former students so that subsequent course offerings become transformed through the use of these Noyce Scholars.

Increasing the number, quality, and diversity of mathematics and science teachers with majors in STEM disciplines ensures a depth of content knowledge which, when linked to the skill set developed as Learning Assistants, provides novice teachers with a solid foundation for success in the teaching profession. As the LABT project focuses specifically on preparing future mathematics and science teachers for success in rural/frontier areas of the west, and high-need reservation areas, persistent patterns in which these areas are educationally underserved are being thwarted.

DESCRIPTION (provided by applicant): In this work we propose a joint project between the Erickson and Chen labs at Cornell University to develop a new approach to study the weak protein-protein interactions that govern intracellular metal and metal co-factor transport at the single molecule level. The approach involves the use of Optically Resonant NanoTweezers which we demonstrated during preceding exploratory R21 grant are capable of trapping proteins as small as a few nanometers, breaking through a long established barrier in optical physics. In addition to developing comprehensive information on the protein interaction dynamics for copper ion and vitamin B12 trafficking, through this program we will develop two general NanoTweezer based protocols for a quantitative single molecule florescence quenching assay (smFQ) and a single molecule florescence resonant energy transfer assay (smFRET) that can be applied to numerous other biophysical problems. Safe trafficking of metal ions and metal-containing cofactors inside cells to avoid toxicity is mediated by metallochaperones which deliver these reactive species to their target destinations while protecting them from adventitious reactions. Abnormal function of this transport pathway can lead to diseases such as Wilson disease, Menkes disease, and familial amyotrophic lateral sclerosis. Despite its importance, very limited quantitative information is available on the biophysical mechanisms that enable this safe transfer or cause it to break down. A major difficulty in obtaining this information is the lak of a single molecule analysis tool which can simultaneously: (1) capture and suspend small molecules in free solution for an indefinite period time (2) effectively concentrate the set of molecules of interest to a point where weak protein-protein interactions can be studied and (3) allow rapid modulation of the external environmental conditions. One potential method by which the above goals could be achieved is through the use of optical tweezers. Fundamentally however, existing optical confinement techniques are limited by diffraction which places a lower bound on the size of dielectric target which can be trapped to about 100nm. With the optically resonant nanotweezer technology we have shown that this force can be enhanced 1000's of times so as to trap proteins (including the Wilson disease proteins used here) as small as a few nanometers. In this proposal, we show how we can adapt this technology to (1) non-invasively capture and suspend individual macromolecules in free solution (2) guide additional molecules to the capture region so that interactions can be observed and (3) maintain captured particles in position while the suspending solution is changed. When applied to intracellular metal transport these capabilities can speed up the process for discovering how metalochaperones respond to different environmental conditions and ultimately what leads to the pathologies listed above.

DESCRIPTION (provided by applicant): In this project we propose to develop solar-thermal microfluidics for point-of-care diagnostics of tropical disease infections. Using this technique we believe it possible to extract and detect purified, concentrated, cholera toxin from a complex biosample, like vomit, using nothing more than creative manipulation of the ambient sunlight. A clear need exists for easy-to-use diagnostic tests that can rapidly screen complex samples, like stool or vomit, for a broad swath of bacteria and viruses associated with tropical diseases. Traditionally this has been done using simple easy to use diagnostics, such dipstick assays. These are popular because they require only the insertion of the sample and the fluid transport, sample processing, and detection reaction all occur autonomously without further input from the user or external power. While extremely successful for performing simple detection assays on simple samples (e.g. hCG in urine), when applied to the detection of rarer targets in more complex sample matrices they tend to exhibit very poor clinical sensitivity/specificity. Most of th attempts to close the gap between performance and clinical requirements have involved the incorporation of more complex microfluidics, to better process/concentrate the sample, and ultrasensitive nanobiosensors, to detect the target at lower levels. While these approaches do have better clinical performance, the added complexity, cost, and loss of autonomy stand in direct contrast with what makes the simple assays popular. Here we propose that solar-thermal microfluidics can facilitate complex sample processing in a way that is quasi-autonomous, easy to operate, and does not require any external energy input beyond ambient sunlight. Put simply, the technique involves a simple shadow mask placed between a microfluidic chip and the incident sunlight that induces a well-defined thermal pattern on the chip. We show that by creative arrangement of these thermal patterns complex sample processing operations can be achieved including: (1) thermo-phoretic sample filtration, (2) thermo-wetting triggered microfluidic transport, and (3) thermal-release following molecularly specific concentration. A user switches between different stages in the assay simply by clicking the shadow mask into a new position. Our goal in this proposal is to develop the fundamental science behind solar-thermal microfluidic sample processing and demonstrate that it can be used to extract and concentrate cholera toxin B from a synthetic vomit sample.

PI: Erickson, David
Proposal: 1343058
Title: INSPIRE Track 2: Public Health, Nanotechnology, and Mobility (PHeNoM)

This INSPIRE award brings together research areas traditionally supported by: the Biophotonics and Nanobiosensing Programs in the Chemical, Bioengineering, Environmental, and Transport Systems Division (CBET) of the Engineering Directorate (ENG); the Communications, Circuits and Sensing Systems Program in the Electrical, Communications and Cyber Systems Division (ECCS) of the ENG Directorate; the Science, Technology and Society Program in the Social and Economical Sciences Division of the Social, Behavioral and Economic Sciences Directorate (SBE); and the Smart Health and Wellbeing Program in the Information and Intelligent Systems Division (IIS) of the Computer & Information Science Engineering Directorate (CISE).

Significance
The science and technology enabled by the Public Health, Nanotechnology and Mobility (PHeNoM) project may ultimately lead to widespread access to health information obtainable from lab-on-chip technology. This research project could alter the domestic healthcare landscape by enabling earlier-stage detection of disease, reducing the cost of public healthcare delivery, and allowing individuals to take better control of their own well-being. Such advances require the integration of the social and technical contexts of health care device deployment. This integration is accomplished by gathering feedback on early versions of the technology and modifying future designs based on that initial feedback. Iterations between feedback and design are facilitated by research efforts that interpret the feedback and guide the development process. The ultimate transfer of the technology to the marketplace is enabled by a new education effort that involves a unique combination of coursework, business plan development, pre-seed grant workshops, and collaborations with existing start-ups in the mobile health space.

Technical Description
Advancements in nanotechnology and microfluidics have enabled the development of lab-on-chip devices that can detect and quantify protein, genetic, and other biochemical markers of diseases with precision. Currently-available personalized diagnostic devices are limited to conditions that require either frequent monitoring (e.g. glucose for diabetics) or "binary" results (e.g. pregnancy). The goals of the PHeNoM program are to demonstrate that deployment of lab-on-chip technology can be fundamentally altered by taking advantage of ubiquitous smartphone technology and show that the fusion of physical sensing and molecular assays on mobile platforms enable healthcare diagnostics that are more informative than either technology alone.

To meet these aims, the investigators are focusing their efforts on developing and deploying three systems that may have an immediate impact on advancing personalized healthcare in the United States: a Stress-Phone for long term stress management, a Nutri-Phone for bloodwork-enabled nutritional awareness, and a Hema-Phone for monitoring viral loading in HIV+ patients. Beyond the immediate merits of these technologies, the broader merit of this project is the demonstration of new "bioinfo-mobile" diagnostics that intertwine the advantages of mobility, computation, physical sensing, and biomolecular assays.

Abstract The goal of this project is to develop a complete sample-in-answer-out solution to the diagnosis of Kaposi's sarcoma (KS) in limited resource settings through the development of our KS-Detect system. Kaposi's sarcoma is the leading cancer in men and the second leading cancer in women in sub-Saharan Africa. KS is difficult to distinguish from other angioproliferative diseases, particularly in Africa where access to trained pathologists is limited to few hospitals and immunohistochemistry is practically non-existent. Multiple studies have shown that PCR based nucleic acid identification of Kaposi's sarcoma herpesvirus (KSHV) in skin biopsies represents the best method of performing an unambiguous diagnosis in the absence of immunohistochemistry. The KS-Detect system combines our (1) lab-on-a-syringe technology for biopsy extraction and sample processing, (2) solar-thermal PCR for extremely low-power nucleic acid amplification, and (3) a nanoparticle based colorimetric smartphone assay for the quantification of the results. The system is designed to be used by a field nurse and addresses a number of challenges with low resource setting diagnosis of Kaposi's sarcoma including: the ability to take and process a biopsy samples in the field, providing at least a 10-fold increase in the number of diagnostic reactions that can be performed on a single battery charge by using sunlight to drive the thermal cycling process, and elimination of the reliance on specialized instrumentation requiring only a smartphone and a lens thereby enabling the system to be fixed in the field by the operator. We have already demonstrated each of the three technologies used in the KS-Detect system. The aims of this R21 effort are to optimize each of the technologies while integrating them into the workflow, and to perform a series of system level validation experiments using human samples. This pre-clinical optimization is critical prior to clinical implementation.

This Partnerships for Innovation: Building Innovation Capacity (PFI:BIC) project from Cornell University aims to develop a simple, cost-effective technology to obtain personal micronutritional status using a smartphone. This system would provide this information allowing users to accurately track their nutritional status directly rather than relying on guesses based on diet. The "NutriPhone" system is comprised of a hardware accessory that attaches to a smartphone, custom test strips that accept a blood sample and conduct a detection assay, and a software app. The app operates the smartphone, interprets the test strip results, displays the results to the user in an intuitive fashion, and provides therapeutic suggestions, if needed. The personalized self-report and automated data streams are expected to yield greater awareness and self-management of health and diet.

Vitamin and micronutrient deficiencies are responsible for a multitude of adverse health conditions, including anemia, rickets, scurvy, adverse pregnancy outcomes, infant growth inhibition, osteoporosis, and cancer. Worldwide, over 1,000,000 people die every year from vitamin A and zinc deficiencies alone. Domestically, as many as half of patients with hip fractures are thought to be vitamin D deficient. Fortunately, many deficiencies and their symptoms are reversible through changes in diet or by taking supplements, particularly if detected early. Very few people, however, have information as to their own personal micronutrient status, what the potential outcomes of their deficiencies are, or the recommended treatments. Having nutritional status information could significantly enable healthier living. In addition to commercial outreach, NutriPhone technology will be integrated into Cornell's Division of Nutritional Sciences' community extension programs both domestically and internationally, including the NutritionWorks program (nutritionworks.cornell.edu), to improve and strengthen capacity, particularly around nutrition and health.

A unique nanoparticle-based binding reaction allows the creation of an optical contrast depending on the level of the particular marker (e.g., vitamin D). The technology allows the measurement of this optical contrast using the smartphone camera, which is integral to every smartphone. Among the important aspects of this use of the smartphone camera is that it dramatically reduces the cost of the accessory. The state of the art currently is to use liquid chromatograph mass spectrometry (LCMS) to measure vitamin D. A nanoparticle-based optical contrast assay is a major advancement. The research program is structured to address the scientific and engineering challenges with the development of the NutriPhone in parallel with the equally important consumer uptake and business model development challenges. This is done through a series of user trials that will be conducted throughout the program at Cornell and extensive product development support, market research, consumer focus groups, and business model development support provided by the industrial partner, Amway. The most transformative aspect of this type of technology is that it will enable quantitative diagnostics to be deployed directly to the consumer rather than through an intermediary. Amway represents a particularly appealing industrial partner to enable this as they have extremely broad experience in direct-to-consumer marketing and sales.

At the inception of the project, the partners are the lead institution, Cornell University, and a large company, Amway (Ada, MI).

? DESCRIPTION (provided by applicant): In this work we will develop and field validate FeverPhone technology for point-of-care differential diagnosis of six common causes of acute febrile illness (namely: Dengue, Malaria, Chikungunya, Leptospirosis, Typhoid fever, and Chagas). The FeverPhone system builds on our team's extensive background on the development of smartphone based diagnostics, infectious disease, and global health. The technical effort of this program comprises of the development of: a specialized 6-plexed colorimetric IgM/IgG assay cartridge that exploits our previous work on color discrimination assays on mobile devices, associated iPad based hardware that allows rapid interpretation of the cartridge results on a platform already used by our field technicians, and software that will combine differential molecular diagnosis with a confirmatory symptomatic interface used by the operator. The final system will enable actionable diagnosis in around 15 minutes. In parallel with technical development, we will perform a staged field validation study at our existing infectious diseases monitoring site in Machala, Ecuador. In addition to clinical and engineering expertise, we have incorporated a translation partner into the program that will ensure that our system is fully validated and ready for FDA approval by the end of the effort.

? DESCRIPTION (provided by applicant): In this project, we will field-test and clinically validate a rapid, point-of-care platform for the diagnosis of Kaposi's sarcoma (KS) in limited resource settings. Our KS-Detect diagnostic platform uses solar- power and smartphone technology enabling it to be operated without reliance on any external infrastructure, while maintaining a high degree of usability with low per-unit cost. The ability to provide rapid confirmatory diagnosi of KS promises to facilitate earlier detection of KS in the community at a clinical stage when it i more responsive to therapy. Specific diagnosis of KS also prevents inappropriate therapy of clinical mimickers of KS. By the end of the project, we will have demonstrated both the field efficacy of the diagnostic technology as well as quantifiably evaluated its effect on promoting earlier detection of KS. To achieve this, we have brought together a team of engineers, local physicians, clinical epidemiologists, business people, translation partners, and entrepreneurs from Cornell, UC-San Francisco and the Infectious Diseases Institute in Kampala, Uganda. Prof. David Erickson (Contact- PI, Cornell), an engineer and entrepreneur from Cornell University, is the original developer of the KS- Detect technology and will lead the engineering and product development efforts while Prof. Jeff Martin (PI, UCSF), a KS epidemiologist and Prof. Toby Maurer (UCSF), a clinician, will lead the clinical and deployment efforts along with our partners in Uganda. Dr. Ethel Cesarman (Weill Cornell) as one of the original discoverers of the virus that causes KS, will lead the local molecular pathology effort. With our translation partner, A'As inc., we will develop a dual-use platform that can be powered by either direct solar heating, solar panels, or conventional electrical outlet to enable both field and lab operation without changing the analysis method. In Phase I of this project, we will (1) collect 500 samples from our Ugandan partner site and validate the PCR based assay; (2) construct a set of field ruggedized dual use KS-Detect systems and consumables; and (3) deploy 5 units for 3 months with local health technicians. If successful, in Phase II we will perform an extensive field study deploying 17 KS-Detect units in Uganda, operated and serviced by locally trained clinicians, and demonstrate the ability of the system to enable earlier stage detection of KS than existing diagnostic procedures.

The broader impact/commercial potential of this Small Business Technology Transfer (STTR) project relates to the fact that the extraction and consumption of fossil carbon accounts for over 6 billion metric tons of CO2 emissions each year. While some mitigation approaches are fairly mature, like capturing CO2 for equestration or for enhanced oil recovery, they are very expensive in terms of both variable and capital costs and have little chance of ever providing a return on investment. By not viewing fossil fuels and feedstocks through a circular economy lens, we estimate these companies miss an opportunity for approximately $50 billion per year in potential profit from hydrocarbons, including methanol, that could be made with waste CO2. If successful, our HI-Light reactor will enable a new economy based on the conversion of fugitive CO2 into useful hydrocarbons and solve the return on investment problem.

This STTR Phase I project proposes to develop HI-Light, a solar-thermocatalytic "reverse combustion" technology that enables the conversion of CO2 and water to methanol and other hydrocarbons at rate significantly greater than the state of the art. Previous approaches are limited by two roadblocks: (1) the semiconductor catalysts can only use photons with energies greater than their bandgap, which is a small fraction of those present in sunlight and (2) a large fraction of the catalyst material in these reactors is under-utilized due to sub-optimal light and reactant delivery. Our unique reactor uses a patented, multiscale approach to enhance light and reagent transport directly to the reaction site and makes use of traditionally unused photons to provide heat and enhance reaction efficiency. The unique features of our reactor are (1) optimized light delivery to ensure that all of the catalyst material has enough light to activate the reaction and (2) an advanced nano-engineered photocatalyst which is functionalized with ligands to enhance CO2 capture and conversion. The goal of this Phase I effort is to construct an integrated prototype reactor and evaluate its productivity in terms of the grams of hydrocarbon produced per gram of catalyst per hour and demonstrate a 10x improvement over the state of the art.

Project Summary Anemia is one of the most widespread clinical conditions, affecting over 1.6 billion individuals globally, with the greatest burden among pregnant women and young children. Anemia has been associated with increased risk of adverse health outcomes, including maternal and infant mortality, and impaired cognitive function in children and work capacity in adults. The burden of anemia in India is among the highest in the world, where it exacts a heavy toll in terms of maternal and infant mortality, disability, and lost productivity. Anemia affects an estimated 56% of women of reproductive age, 59% of pregnant women, 63% of lactating women, and 70% of young children in India. Iron deficiency is the leading cause of anemia worldwide, and iron supplementation is the standard of care for prevention and treatment of anemia. However, it is estimated that only approximately 50% of anemia is due to iron deficiency. Other nutritional factors, particularly vitamins B12 and folate, and non-nutritional factors such as inflammation, also contribute to the etiology of anemia and impact human health. Treating anemia with the incorrect micronutrient may exacerbate the condition or mask the true deficiency. Accurate determination of the multifactorial causes of anemia is critical to implement successful interventions; however, existing diagnostic methods for anemia are typically time consuming, expensive, require cold chain, and are not easily accessible in resource-limited settings. In this application, we propose to develop and validate AnemiaPhone, a point-of-care, low-cost, smartphone-based platform for a multiplexed, quantitative assessment of B-vitamin status (vitamin B12 and folate), in addition to iron status, and inflammation, the leading causes of anemia. The technology consists of a disposable test-strip containing reagents required for a multiplex sandwich ELISA, a reusable low-cost smartphone accessory, which accepts the test strip after the finger stick blood sample has been introduced and attaches it to the smartphone, and a smartphone application that extracts images of the test strip captured by the smartphone camera, interprets image data to provide quantitative test results, and communicates and catalogues data. This application directly responds to the call in the funding opportunity announcement for re-engineering of existing medical devices to significantly improve conditions of the poorest populations by providing affordable and accessible healthcare in resource-limited settings. It brings together a team of experts from St. John's Research Institute in India and Cornell University in the United States in diverse areas including nutrition, medicine, perinatal health, infectious disease, nanotechnology, microfluidic technologies, and engineering to target anemia, an urgent public health problem in India and other resource-limited settings. Availability of AnemiaPhone within the next two years will make it possible to reliably and accurately diagnose anemia in even the most remote parts of India with little training required. Furthermore, given the widespread prevalence of anemia, this technology will benefit low-resource settings globally. The impact of this translational research and the development of a point-of-care, low-cost, smartphone-based platform to reduce the adverse health and development consequences associated with anemia in resource-limited settings cannot be overemphasized.

The broader impact/commercial potential of this STTR Phase II project will result in significant economic activity through the utilization of waste carbon dioxide. The photo-catalytic reactors funded in the project will lead to novel methods to chemically store energy from the sun. Each year, human activity releases 38 billion tons of carbon dioxide into the atmosphere. Dimensional Energy envisions a future in which we can utilize this carbon dioxide as a feedstock for industrial production of hydrocarbon fuels and chemical intermediaries by harnessing the power of the sun.

This STTR Phase II project proposes to develop HI-Light - a photo-thermo-catalytic reactor platform technology that enables the conversion of CO2 and water to synthesis gas at a rate significantly greater than the state of the art. The unique feature of the technology is that it uses embedded optical waveguides to evenly distribute light within the reactor, increasing the efficacy of the catalyst and ultimately the productivity of the system. In Phase I a fully functional integrated prototype reactor was constructed, demonstrating continuous operation, and showing productivity in terms of the grams of hydrocarbon produced per gram of catalyst per hour more than 10x greater than the state of the art. The approach solves the two major roadblocks in photo-conversion of CO2: (1) the semiconductor catalysts can only use photons with energies greater than their bandgap, which is a small fraction of those present in sunlight and (2) a large fraction of the catalyst material in these reactors is under-utilized due to sub-optimal light and reactant delivery. Our unique reactor uses a patented, multi-scale approach to enhance light and reagent transport directly to the reaction site and makes use of traditionally unused photons to provide heat and enhance reaction efficiency.

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.

Project Summary Biological sex and nutritional status influence immune function, and the proposed research in this supplement seeks to understand the relationships between sex, nutrition, and immune response in the context of dengue virus infection. Nutritional deficiencies and dengue illness contribute substantially to the burden of disease in resource limited settings. The proposed research will address gaps in how biological sex and nutritional status relate to dengue immunopathology. Our goal is to better understand the role of sex and nutritional factors in differential disease risk, vulnerability, and outcome with an ultimate goal of advancing scientific knowledge about women?s health. As part of a parent R01 award, we are collecting detailed information on demographics and health status, anthropometry measures, and blood specimens from 300 consenting pediatric participants who present to hospital with symptoms of acute febrile illness. Participants attend acute and convalescent study visits, and confirmatory dengue diagnostics is included in the parent study. The supplement research proposes to measure a comprehensive panel of nutritional and immune response biomarkers in stored serum specimens of confirmed dengue participants and analyze the resulting data for associations stratified by sex. By conducting basic and translational research on sex differences in the pathobiology, prevention, and treatment of dengue, we aim to inform both clinical care and public health programs for best practices that account for men and women in any setting. In addition, this work will also inform the design and development of our personalized diagnostics platform, the focus of the parent R01 award.

Abstract The COVID-19 pandemic represents a worldwide infectious disease challenge that disrupted our economic, educational, and social norms in a way that was largely unimaginable just months ago. At present the most efficacious method of limiting the spread of the disease has been to test those that exhibit symptoms ? typically by nucleic acid based viral identification methods ? and isolate those that are positive. Even at this early stage this approach has put significant strain on the diagnostic infrastructure of advanced countries, let alone those with fewer resources. As we move beyond symptom-initiated confirmation diagnoses to the larger scale screening that may be required to identify asymptomatic carriers and to restart sections of our economy, much more rapid and higher throughput techniques will be required. Under ongoing NIH/NCI UH2/UH3 (UH3CA202723) funding we have been developing TINY (Tiny Isothermal Nucleic acid quantification sYstem). The TINY system is a self-contained, portable device for the detection and LAMP-based quantification of viral nucleic acids designed for use in settings with limited resources. Through that program, the system is currently deployed within Uganda for identifying Kaposi?s Sarcoma Herpes Virus (KSHV) in human biopsies as a novel diagnostic technique for Kaposi?s Sarcoma. The system has been validated on over 500 samples showing sensitivity and specificity of 93% and 95%. Through this supplement request, we propose to upscale the TINY system to enable much high-throughput screening ? from 6 parallel samples to 96 - and adapt it to a run a recently developed LAMP assay for SARS- CoV-2 detection which has already been validated on 182 patients in New York City. We believe that this will simultaneously contribute to the need for higher throughout COVID-19 diagnostics and advance the NCIs desire for platforms that can enable broader screening for viruses which are known to cause cancers (e.g. HPV in the case of cervical cancer).

Abstract At present, most of the diagnostic testing for COVID-19 has been done through local sampling of those who are symptomatic followed by centralized laboratory testing ? returning results in 3-4 days. This is now supplemented by several point-of-care (PoC) systems who can perform the same test on site, returning the result much quicker, but at much lower throughput. To return many elements of the US economy to closer to normal function, such as international air travel, large-scale employers, and campus-based institutes of higher learning, will require us to shift from diagnostic testing to large scale, distributed, and repeated screening of asymptomatic (or pre- symptomatic) individuals. The length of time-to-result for traditional centralized testing and the relatively low throughput of existing PoC systems will make this a challenge. Here we propose to develop Paper-COVID ? a modular platform that combines a clinically validated LAMP assay (already with FDA EUA approval) with a mobile phone based paper testing platform that enables much higher throughput screening for asymptomatic SARS-CoV-2 and facilitates automated contact tracing. The goal for this effort is to validate a novel sample processing technique, port the previously developed LAMP assay to a paper- based format, construct three modular prototype systems, and validate it on clinical samples from New York City.