Srinivas Sridhar - US grants

This Research Initiation Award focusses on high frequency electromagnetic studies of high-transition-temperature superconductors, between frequencies covering "dc" to 75 GHz. The proposed work involves: (1) Fundamental studies of the electromagnetic response via measurements of the surface resistance and the penetration depth as functions of temperature, frequency and applied magnetic field. The results will be interpreted to yield fundamental information regarding the nature of the superconducting state, and the dynamics of vortices and fluxoids in these materials. (2) Materials fabrication and processing in bulk monolithic, single crystal forms and also coatings. The effects of materials processing on the ideal high frequency response of the superconductors will be studied. (3) Fabrication and testing of devices in bulk monolithic and coated forms. The specific devices that will be studied are: high Q fully superconducting cavities at microwave and mmwave frequencies, interdigital filters, and waveguides at X-band and higher frequencies. the device performance will be determined, correlated with expected ideal estimates, and the effects of materials processing will be examined.

High frequency electrodynamic measurements are used as sensitive probes of the Meissner and mixed states of superconductors. Measurements of the surface resistance and penetration depth at several frequencies in the MHz and GHz ranges will be carried out as a function of temperature and magnetic field. The results will be analyzed to extract information regarding the dynamics of the condensate, quasiparticles and vortices, and will be compared with fundamental models. The materials which will be studied are several of the high and low Tc superconductors. The vortices will be paramaterized and the resulting measurements will be used to test theories of vortex formation, melting, vortex glass, and other thermodynamic states %%% This project explores the response of high temperature superconductors to alternating electric and magnetic fields. The results are expected to be important for both fundamental understanding and for applications of superconducting devices at high frequencies.

Superconducting microwave devices are posed for entry into the telecommunications markets. A combined experimental and theoretical research program will be undertaken to market. A combined experimental and theoretical research program will be undertaken to study the microwave response of high Tc superconductors in superconducting circuits. The proposed activities will impact a nascent technology by providing a database of materials parameters, and new circuits and systems realizations.

Left-handed Metamaterials (LHM) are artificially constructed media that exhibit negative index of refraction for incident electromagnetic waves and that have been recently realized at microwave frequencies. Research on LHM including the PI's reports published in Nature and Physical Review Letters, has been selected by the journal Science as one of the breakthroughs of the year 2003.

The PI has established a state-of-the-art program that combines microwave experiments, quasi-classical analytical and numerical simulation capabilities. These capabilities will be used to explore new phenomena and applications arising from negative refraction in LHM.
The group will design and fabricate LHM either from composite metamaterials (Type I) or photonic crystals (Type II). LHM drastically affect the spectra and eigenfunctions of cavities partially filled by them, and may lead to new applications in microcavity lasing. New approaches to imaging using negative refraction will be explored, including sub-wavelength resolution due to amplification of evanescent waves. Flat lenses and Superlenses made of a slab of LHM, which aim to achieve near perfect image reconstruction by both propagating and evanescent waves, will be fabricated and studied. New optical elements using negative refraction will be developed, such as plano-concave lenses for focusing distant objects. In these media, coherent scattering leads to image formation even though the classical or ray optics limit is chaotic. The general principles of image reconstruction using negative refraction will be developed and established. The laboratory scale microwave experiments will be scaled down to nanometer lengths to study imaging using photonic crystals and chaotic scattering at optical frequencies.

Graduate and undergraduate students and post-doctoral fellows will be trained in areas of cutting edge research. The concepts of quantum chaos and negative refraction will be incorporated into the educational curriculum. The results will be disseminated by publications and presentations. A web site will be created to disseminate the principal results to the wider public.

This three-year award supports US-France cooperative research aimed at the study of transport dynamics in magnetic and correlated electron systems in novel materials. The collaboration brings together the complementary expertise of Srinivas Sridhar of Northeastern University and A. Revcolevschi of the University of Paris at Orsay. The US investigator brings to this collaboration expertise in microwave measurement techniques. He will conduct measurements of surface impedance. This is complemented by French experience in the area of crystal growth. The French investigator's group will prepare high temperature superconducting cuprates. These materials were chosen for this study because of their high quality and low dimensionality. The collaboration will advance our knowledge of phenomena related to the dynamics of charge, spin, superconducting pairs and quasi-particles, and superconducting vortices. ?> / ?ÁÂ%Á?¥??Á ¢Á/?Á? ¿> ¥©?¢ ??%%/???/¥??> ¥©Á?? À?/% ?¢ ¥? ??Á>¥?Â` ?> ?Á/% ¥?_Á / ¥©?ÁÁ ??_Á>¢??>/% ??ÕÁ?¥ ?> / >?> ©?_?ÀÁ>??¢ ¢Á/ ¼©?¢ ??%%/???/¥??> ¥/,Á¢ /??/>¥/ÀÁ ? ??_?%Á_Á>¥/?` Á??Á?¥?¢Á ? ¡½ />? Ñ?Á>?© ?>?Á¢¥?À/¥??¢ ¼©Á ?Á¢?%¥¢ _/` Á?Á>¥?/%%` ?Á /??%?Á? ¥? ¢Á/??©Á¢ Â?? _?>Á¢ >/??À/¥??>/% ??¢¥/?%Á¢ ??Á?,¢ ??%%?¥?>À ?/¢¥Á ?Á??¢?¥¢ />? ¢??_/??>Á¢

This action supports an ultra-high resolution scanning electron microscope (SEM) for research, education, and training in nanoscience and biotechnology. Twenty faculty from Physics, Chemistry, Biology, Pharmacy, Electrical and Computer Engineering, and Mechanical, Manufacturing and Mechanical Engineering will use the instrument to carry out research on several projects. Research areas include bacterial biofilms, microbial diversity in marine environments, protozoan biochemistry and metabolism, nanostructures in spintronic materials, collective electrodynamics of nanostructured oxides and borides, metal-insulator transition in two-dimensional semiconductors, novel green routes to the synthesis of conducting polymers, chemical vapor deposition of metals, and structure-property relations of thin films for electronic applications.

The SEM will facilitate research programs that are supported by awards from several Federal agencies: NSF, AFOSR, ONR, DOE, NIH, as well as from industrial companies and private foundations. The instrument will catalyze new interdisciplinary collaborations in nanoscience and biotechnology. The SEM will be integrated into interdisciplinary graduate courses in nanotechnology and biotechnology offered by several departments. It will be used in undergraduate laboratory courses, undergraduate projects and co-op internships. The SEM will be integrated into the "Building Bridges" and the ACS Project SEED outreach programs for middle and high school students, and the Connections. Program for women and underrepresented populations.

Nanomedicine is a new interdisciplinary paradigm emerging from the timely convergence of two parallel recent developments - the decoding of the human genome that has led to greater understanding of the molecular basis of medicine and biology, and nanotechnology, which offers the means to control molecular interactions. IGERT Nanomedical Science and Technology is a new integrated doctoral education program that emphasizes interdisciplinary research training in diverse areas including nanostructured materials, nanomagnetism, cell biology and trafficking, optical microscopy and imaging, sensors and diagnostic systems, drug and gene targeting and delivery, and synthesis and surface functionalization and characterization of nanostructures, and theoretical computational modeling. Significant research breakthroughs are anticipated in cellular biosensors, magnetic bio-control, drug delivery, mitochondrial gene therapy, bio-nano machines and nanomanufacturing. Interdisciplinary pedagogical coursework is integrated with practical real-world experience through graduate internships in biotechnology, pharmaceutical and medical device companies and research hospitals, with co-mentoring by industrial and medical research scientists. A key feature is a strong diversity component, incorporating significant involvement of women and minorities in the student body and the teaching, mentoring, and administrative aspects of the project. The program aims to educate the next generation of scientists and technologists with the requisite skill sets to address scientific and engineering challenges, with the necessary business, ethical and global perspectives that will be needed, in the rapidly emerging area of applying nanotechnology to human health. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

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The goal of this NER application is to develop nano-biodevices for recording and stimulating nerves that are reliable and long lasting. This exploratory proposal addresses some of the critical issues entailed. These issues include gold nano-wire size, cell growth and motion artifacts, and cell viability at the electrode-cell interface. The research plan calls for fabrication of an array of nano-wires in three sizes ranging of 50, 100, and 200 nm. Measurements will be performed by culturing two types of neural (rat hippocampal and human neuroblastoma) cells onto the surface of Au and peptide conjugated Au nano-wires.

This Integrative Graduate Education and Research Training (IGERT) award supports the further development of the inter-disciplinary Nanomedicine Science and Technology doctoral program at Northeastern University. The purpose of this program is to train the next generation of scientists and technologists who are skilled in research at the interface of nanotechnology, biology and medicine, are aware of the path to translate fundamental knowledge to marketplace products, are informed of the ethical and social issues relating to the discipline, and have a strong sense of community involvement as well as a global perspective.

Mentored by a team of internationally renowned scientists, technologists, and medical researchers, IGERT Nanomedicine trainees will participate in a state-of-the-art interdisciplinary research program that utilizes revolutionary developments in nanotechnology to develop therapeutic and diagnostic agents of nanometer dimensions with multi-functional capabilities for diagnostics, imaging and therapeutic benefit. The program will create a unique partnership between Northeastern University, minority-serving institutions University of Puerto Rico Mayaguez and Tuskegee University, and Harvard Medical School member hospitals, and is committed to a target goal that a majority of the IGERT Nanomedicine trainees will come from under-represented populations. The interdisciplinary model of graduate education will serve as a model to academic institutions world-wide. The vigorous outreach program will impact a broad segment of K-12 schools in Massachusetts, Alabama and Puerto Rico, and will encourage K-12 students from under-represented communities to enter science, technology, engineering, and mathematics areas of higher study.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

PHYSICO-CHEIVIICAL NANOCHARACTERIZATION CORE . The role of this core will be to provide the necessary physico-chemical characterization of nanopreparations such as polymeric nanoparticles, lipid nanoparticles, dendrimers, and selfassembling nanosystems prepared in all the CCNE projects. An array of sophisticated microscopic, spectroscopic and analytical tools are available to study the size, size distribution, stability, surface charge, and drug loading/release from these nanopreparations. This core brings expertise in the basic science and engineering aspects of nanotechnology that is essential to understand the fundamental properties of these nanopreparations. Feedback from this core will help the scientists engaged in these projects to optimize these nanopreparations for successful use in cancer therapy. This core will also work in parallel with Nano Characterization Laboratory (NCL) to facilitate the overall mission of this CCNE to translate basic research to industrial production of nanomedicines.

The I-Corps team is developing an electric field measurement technology for brain signal monitoring. This technology is a system of measuring and analyzing the electric fields generated by the brain arising from intrinsic activity or external stimuli. It is comprised of a system of high density array of sensors, accompanied by electronics and signal processing algorithms. This technique used through this technology has several advantages over current modalities, Electroencephalography (measuring the electric potential on the scalp) and Magneto-encephalography (measuring the magnetic field). This technology has higher spatial resolution, is unaffected by stray magnetic fields, does not cryogenic equipment and improves source reconstruction precision. Technologies developed through this project have the potential to provide new information for understanding brain activity and obtaining clues to a variety of neurological disorders.

The technology developed through this project is a new brain signal measurement system for researchers and clinicians, which would be cost-effective and fully portable/mobile. The ability to measure bioelectric brain signals at high spatial resolution and in a user-friendly manner may lead to new civilian and military applications. Some of the immediate areas of impact of this technology could include: Functional brain imaging at high temporal and spatial resolution, pattern recognition, cognition; insights into neural correlates of vision and speech; again, sleep, epilepsy and mental health research and applications; military applications of traumatic brain injury, war-fighter performance assessment and enhancement and; human-machine and brain-computer interfaces.

This is a renewal application for years 5-10 of an experiential research training program in cancer nanomedicine for undergraduate students in STEM fields. Known as CaNCURE: Cancer Nanomedicine Co-ops for Undergraduate Research Experiences, this program was created to encourage young scientists & engineers, particularly those from underrepresented minorities, to pursue careers in cancer research. To achieve this objective, the following specific aims are proposed: 1. Provide a hands-on research experience with a focus in cancer nanomedicine through a 6-month co-op internship mentored by world-class cancer researchers at Dana- Farber / Harvard Cancer Center. 2. Provide year-round activities for co-op enrichment, including weekly seminars, instrumentation training, a reflective e-portfolio, and conference travel. 3. Provide professional preparation for a career in cancer research, including professional skills training, opportunities to network and present research, and resources to enhance career preparation. 4. Increase the diversity of the cancer research workforce by targeted recruitment and retention of students from underrepresented minorities and disadvantaged backgrounds. This renewal will support 80 undergraduate traineeships (16 per year) to be paid over 15 weeks of the 6-month research experience. New features of this proposal include: an online library of research techniques briefs for on-demand instrumentation training, research e-portfolios that allow trainee reflection within the framework of their individual development plan, new educational programming in cancer disparities and inequities, and mentoring of trainees by CaNCURE alumni. The CaNCURE program will continue to leverage Northeastern University?s model of co-operative education and Dana-Farber / Harvard Cancer Center?s vast network of cancer research laboratories to create an immersive training environment for cancer research. Our evaluation shows that CaNCURE consistently provides trainees with knowledge and skills unavailable through more conventional co-ops, as well as increases trainee interest in and their likelihood of pursuing a career in cancer research. The successful implementation of this program will continue to create a pipeline of young scientists & engineers, particularly those from underrepresented minorities, with the interest, skills, and knowledge necessary to pursue interdisciplinary cancer research.

NRT-IGE: Nanomedicine Academy of Minority Serving Institutions

Nanomedicine is an emerging paradigm that seeks to develop engineered nanometer size particles to solve key problems in modern medicine, such as early diagnosis of disease and targeted delivery of therapeutics. This field is exciting to students and there is worldwide demand for training in this area. This National Science Foundation Research Traineeship (NRT) award in the Innovations in Graduate Education (IGE) track to Northeastern University will translate cutting-edge advances in nanomedicine research into an education model to pilot and test a scalable, interactive network that empowers low-resource institutions to build capacity in nanomedicine training and develop degree programs in this emerging field. This project will create a reciprocal knowledge-sharing relationship among a large national pool of students across five institutions. The successful implementation of this new model of higher education is expected to broaden the participation of minorities in the nanomedicine workforce thus reducing disparities in the health workforce, establish new degree programs, and serve as a blueprint for the creation of similar education programs in other disciplines.

The goal of the project is to create a scalable network for knowledge delivery and scientific collaboration that is designed to enable student learning from expert instructors as well as from peers unrestricted by geographical location. The partners include five research universities with a tradition of providing higher education to underrepresented communities ? Northeastern University, University of Puerto Rico Mayaguez, Tuskegee University, Morgan State University, and Florida International University. The project will offer synchronous content through live, web-based videoconferencing protocols, allowing students to interact with instructors and peers at other universities in real-time. A parallel enterprise-level online learning environment will be created to enable team-based discussions and assignments. Courses to be offered include Introduction to Nanomedicine, Nanomedicine Research Techniques, Nano/Biomedical Commercialization, and a Nanomedicine Seminar Series. Faculty facilitators at each institution will coordinate the physical and online classroom environments, contribute to cross-institutional assignments, and provide supplementary instruction. Students will receive degree credit at their home institution through the establishment of course-equivalency at each partner institution. The implementation of these learning tools, together with the assessment of student learning, student demographics, and career development, is expected to generate sufficient new knowledge to enable expansion of this new and unique higher education model to a nationwide program.

The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new, potentially transformative, and scalable models for STEM graduate education training. The Innovations in Graduate Education Track is dedicated solely to piloting, testing, and evaluating novel, innovative, and potentially transformative approaches to graduate education.

This work is supported, in part, by the EHR Core Research (ECR) program. The ECR program emphasizes fundamental STEM education research that generates foundational knowledge in the field. Investments are made in critical areas that are essential, broad and enduring: STEM learning and STEM learning environments, broadening participation in STEM, and STEM workforce development.

Obtaining absolute quantitative information is a formidable task given the complex nature of the MR signal. We have developed a new technique Quantitative Ultra-short Time-to-Echo Contrast-Enhanced (QUTE- CE) MRI utilizing UTE sequences with SuperParamagnetic Iron Oxide Nanoparticles (SPION) that leads to quantifiable vascular images with unprecedented clarity and definition. The ultra-short time scale limits susceptibility dependent signal dephasing by giving T2 effects negligible time to propagate, and also limits the influence of physiological effects, resulting in snapshots of the vasculature that are independent of flow velocity, arterial or venous systems, or vessel orientation. We have shown in mice models at 7T that with optimized pulse sequences (TE, TR, FA), we can acquire UTE images with signal predicted by the Spoiled Gradient Echo (SPGR) equation as a function of concentration, thus defining a new approach to Quantitative MRI. We have found that QUTE-CE is particularly optimal with SPIONs, specifically ferumoxytol an FDA approved iron-oxide nanopharmaceutical. The nanoparticles lead to long blood circulation with minimal leakage from vasculature, resulting in very high vascular delineation and highest vascular/tissue contrast. Here we propose to optimize QUTE-CE at 7T in rat models, and validate our hypothesis that QUTE-CE can be implemented for quantitative functional MRI (qfMRI) in rat brains by establishing a vascular brain atlas, and then studying changes under drug insults. The specific aims of this project are summarized below. Specific Aim 1. Establish and optimize QUTE-CE MRI for quantitative functional neuroimaging (qfMRI). We hypothesize that the unique ability of QUTE-CE to provide an absolute quantitative signal can be extended to measuring the CBV per voxel in the brain by using a partial-voluming model, in which each voxel consists of a linear combination of signal from both tissue and blood within it. Task 1 will optimize the QUTE-CE protocol for neuroimaging, by developing a robust trajectory for improved image reconstruction and signal quantification. Task 2 will measure tissue intensity, IT, and blood intensity, IB, per image. The CBV will be calculated using a two-volume partial-voluming model for tissue and blood. Task 3 will construct a vascular atlas using a custom 174 region anatomical atlas to segment specific regions within the brain. Specific Aim 2. Evaluate the change in neuropathies due to drug insults. We hypothesize a compensatory increase in capillary density as measured by QUTE-CE in brain areas such as hypothalamus and basal ganglia e.g. accumbens and striatum, when animals are continuously exposed to oxycodone. Task 1 will test the technique by exposing animals to oxycodone administration, analyzing resulting vascular abnormalities, and quantifying CBV and associating changes in them with the 174 regions of the Vascular Brain Atlas. Task 2 will compare measured vascularity to histological studies using staining of histological slices. Task 3 will compare QUTE-CE with other methods including DTI, ?R2, steady-state susceptibility contrast mapping (SSGRE), and steady state CBV (SS_CBV).

Contrast Enhanced Magnetic Resonance Angiography (CEMRA) with gadolinium (Gd) provides high resolution visualization of the vascular compartment, but is rarely used in patients with advanced chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2) due to the risk of nephrogenic systemic fibrosis (NSF). There is thus an unmet need to develop MRI techniques that can both replace Gd and provide new insights into the etiology and severity of CKD. PI Sridhar and his team at Northeastern University (NEU) have developed a new technique, Quantitative Ultra-short Time-to-Echo Contrast-Enhanced (QUTE-CE) MRI, leads to quantifiable positive contrast images of the vasculature with unprecedented clarity and definition. QUTE-CE is particularly optimal using Ferumoxytol (Feraheme), an FDA approved iron-oxide nanopharmaceutical, that is already routinely used for iron-deficient anemia therapy in CKD patients. Under an ongoing clinical trial (NCT03266848) we have demonstrated QUTE- CE MRI for renal and cerebral imaging in humans at 3T. This R21 project will develop the QUTE-CE MRI method for kidney imaging in patients with both normal kidney function as well as with CKD. We propose to scan 25 total patients (10 in Year 1 and 15 in Year 2) who are already scheduled to receive ferumoxytol infusion for iron-deficiency anemia therapy. The specific aims of this project are summarized below. Specific Aim 1: Renal Vascular Angiograms of CKD Patients. These studies will be conducted at NEU and Massachusetts General Hospital (MGH) using Siemens Prisma MRI scanners. Three tasks will be pursued to develop the optimizing protocol. Task 1: Develop a robust QUTE-CE imaging protocol. Task 2: Implement a robust methodology for accounting for B1 inhomogeneity. Task 3: Develop a robust trajectory for improved image reconstruction including motion correction. We hypothesize that QUTE-CE MRI will lead to high resolution angiograms that will allow for the safe diagnosis of existing pathologies such as renal artery stenosis in addition to the novel identification of kidney micro-vascular disease. Specific Aim 2: Obtain quantitative renal blood volume (RBV) maps and develop machine learning algorithms (MLA) to better understand the severity of kidney disease. The renal angiograms will be analyzed to obtain renal blood volume (RBV) maps. The RBV maps will be analyzed in terms of Machine-Learning algorithms (MLA) to explore whether we can identify common etiologies of CKD as well as estimate the severity of kidney disease. The MLA will enable organ segmentation, automatized renal parenchyma volumetry, as well as automated extraction and labeling of lesions. The MLA results will be compared with radiological scoring, estimated GFR, and degree of albuminuria. We hypothesize that the absolute RBV maps will enable quantitative monitoring of blood volume in cortex and medulla, and that RBV could be a surrogate parameter for renal microvascular rarefaction, a central mechanism in CKD initiation and progression.