New MRI Techniques for Nanoparticle Based Functional and Molecular Imaging

Although in clinical use for several decades, magnetic resonance imaging: MRI) is undergoing a transition from a qualitative anatomical imaging tool to a quantitative technique for evaluating myriad diseases. Furthermore, MRI has made great strides as a potential tool for molecular imaging of cellular and tissue biomarkers. Of the candidate contrast agents for molecular MRI, the excellent bio-compatibility and adaptability of perfluorocarbon nanoparticles: PFC NP) has established these agents as a potent targeted imaging agent and as a functional platform for non-invasive oxygen tension sensing. Direct readout and quantification of PFC NP can be achieved with fluorine: 19F) MRI because of the unique 19F signal emanating from the core PFC molecules. However, the signal is usually limited by the modest accumulated concentrations as well as several special NMR considerations for PFC NP, which renders 19F MRI technically challenging in terms of detection sensitivity, scan time, and image reconstruction. In the present dissertation, some of the pertinent NMR properties of PFC NP are investigated and new 19F MRI techniques developed to enhance their performance and expand the biomedical applications of 19F MRI with PFC NP. With the use of both theoretical and experimental methods, we evaluated J-coupling modulation, chemical shift and paramagnetic relaxation enhancement of PFC molecules in PFC NP. Our unique contribution to the technical improvement of 19F MRI of small animal involves:: 1) development of general strategies for RF 1H/19F coil design;: 2) design of novel MR pulse sequences for 19F T1 quantification; and: 3) optimization of imaging protocols for distinguishing and visualizing multiple PFC components: multi-chromatic 19F MRI). The first pre-clinical application of our novel 19F MRI techniques is blood vessel imaging and rapid blood oxygen tension measurement in vivo. Blood vessel anatomy and blood oxygen tension provide pivotal physiological information for routine diagnosis of cardiovascular disease. Using our novel Blood: flow)-Enhanced-Saturation-Recovery: BESR) sequence, we successfully visualized reduced flow caused by thrombosis in carotid arteries and jugular veins, and we quantified the oxygen tension in the cardiac ventricles of the mouse. The BESR sequence depicted the expected oxygenation difference between arterial and venous blood and accurately registered the response of blood oxygen tension to high oxygen concentration in 100% oxygen gas. This study demonstrated the potential application of PFC NP as a blood oxygen tension sensor and blood pool MR contrast agent for angiography. Another pre-clinical application investigated was functional kidney imaging with 19F MRI of circulating PFC NP. Conventional functional kidney imaging typically calls for the injection of small molecule contrast agents that may be nephrotoxic, which raises concerns for their clinical applications in patients with renal insufficiency. We demonstrated that our 19F MRI technique offers a promising alternative functional renal imaging approach that generates quantitative measurement of renal blood volume and intrarenal oxygenation. We successfully mapped the expected heterogeneous distribution of renal blood volume and confirmed the presence of an oxygenation gradient in healthy kidneys. We validated the diagnostic capability of 19F MRI in a mouse model of acute ischemia/reperfusion kidney injury. We also employed 19F MRI as a tool to test the therapeutic efficacy of a new nanoparticle-based drug, i. e. PPACK: D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone) PFC NP, which was postulated to inhibit microvascular coagulation during acute kidney injury. Based on our preliminary 19F MRI findings, we observed that PPACK PFC NP effectively reduced coagulation in our animal model, as evidenced by lesser accumulation of particles trapped by the clotting process. This finding suggests the potential for 19F MRI to be used as a drug monitoring tool as well in common medical emergencies such as acute kidney failure

MEMS Technology for Biomedical Imaging Applications

Biomedical imaging is the key technique and process to create informative images of the human body or other organic structures for clinical purposes or medical science. Micro-electro-mechanical systems (MEMS) technology has demonstrated enormous potential in biomedical imaging applications due to its outstanding advantages of, for instance, miniaturization, high speed, higher resolution, and convenience of batch fabrication. There are many advancements and breakthroughs developing in the academic community, and there are a few challenges raised accordingly upon the designs, structures, fabrication, integration, and applications of MEMS for all kinds of biomedical imaging. This Special Issue aims to collate and showcase research papers, short commutations, perspectives, and insightful review articles from esteemed colleagues that demonstrate: (1) original works on the topic of MEMS components or devices based on various kinds of mechanisms for biomedical imaging; and (2) new developments and potentials of applying MEMS technology of any kind in biomedical imaging. The objective of this special session is to provide insightful information regarding the technological advancements for the researchers in the community

Non-Destructive Bio-Assay of Single Living Cell

For more than a decade, researchers are trying to find out practical commercial tool for particle/cell detection and characterization with portable, low cost, specific and sensitive characteristics. The advance of Micro Electro Mechanical Systems (MEMS) and microfluidic technologies opened a major challenge for a large number of researchers, industrial health and bio companies to invest their time and budget into the avenue of point of care health instruments or devices helping the early detection of cancer cells within the human blood via circulating malignant cells. Actual existing commercial flow cytometer that detects and identifies the type and size of cells are costly, time consuming and need the assistance of highly qualified operators. Moreover, in certain research activities, micro cytometers are investigated and assessed with different detection techniques such as optical, impedance spectroscopy, electromagnetic spectroscopy and many other techniques. The aim of this research is to investigate an innovative mechanism that enables to characterize, identify and differentiate among various living cells including malignant tumor cells through the use of the electromagnetic energy detection technique. Cells are spatially centered in a microfluidic channel through dielectrophoresis technique then detected and characterized by measuring and interpreting the RF signal transmission of the cells passing one by one through the interrogation region in the microchannel. The outcome of this research might help the clinical end user to gain certain important information about the condition of the patient, establish personalized treatment or track the effect of a treatment. Detection and counting of tumor cells may help identification of early stages of illness and help patient with early care that may significantly cut the overall cost of cancer management

Numerical and Analytical Methods in Electromagnetics

Like all branches of physics and engineering, electromagnetics relies on mathematical methods for modeling, simulation, and design procedures in all of its aspects (radiation, propagation, scattering, imaging, etc.). Originally, rigorous analytical techniques were the only machinery available to produce any useful results. In the 1960s and 1970s, emphasis was placed on asymptotic techniques, which produced approximations of the fields for very high frequencies when closed-form solutions were not feasible. Later, when computers demonstrated explosive progress, numerical techniques were utilized to develop approximate results of controllable accuracy for arbitrary geometries. In this Special Issue, the most recent advances in the aforementioned approaches are presented to illustrate the state-of-the-art mathematical techniques in electromagnetics

The Boston University Photonics Center annual report 2012-2013

This repository item contains an annual report that summarizes activities of the Boston University Photonics Center in the 2012-2013 academic year. The report provides quantitative and descriptive information regarding photonics programs in education, interdisciplinary research, business innovation, and technology development. The Boston University Photonics Center (BUPC) is an interdisciplinary hub for education, research, scholarship, innovation, and technology development associated with practical uses of light.This report summarizes activities of the Boston University Photonics Center during the period July 2012 through June 2013. These activities span the Center’s complementary missions in education, research, technology development, and commercialization. The Photonics Center continues to grow as an international leader in photonics research, while executing the Center’s strategic plan and serving as a university-wide resource for several affiliate Centers. For more information about the strategic plan, read the Photonics Center Strategic Plan section on page 10. In research, Photonics Center faculty published nearly 150 journal papers spanning the field of photonics. A number of awards for outstanding achievement in education and research were presented to Photonics Center faculty members, including a Peter Paul Professorship for Professor Xue Han, an NSF Career Award for Professor Ajay Joshi, and the 2012 Innovator of the Year Award from Boston University for Professor Theodore Moustakas. New external grant funding for the 2012- 2013 fiscal year totaled over $21.8M. For more information on our research activities, read the Research section on page 24. In technology development, the Photonics Center has turned a chapter, by completing the transition from a focus on Defense/ Security applications to a focus on the healthcare market sector. The commercial sector is expected to energize the technology development efforts for the foreseeable future, but the roots in defense/security are still important and the Center will continue to pursue new research grants in this area. For more information on our technology development program and on specific projects, read the Technology Development section on page 45. In education, 20 Photonics Center graduate students received Ph.D. diplomas. Photonics Center faculty taught 32 photonics courses. The Center supported a Research Experiences for Teachers (RET) site in Biophotonic Sensors and Systems for 10 middle school and high school teachers. The Photonics Center sponsored the Herbert J. Berman “Future of Light” Prize at the University’s Scholars Day. For more on our education programs, read the Education section on page 54. In commercialization, Boston University’s Business Innovation Center (BIC) currently hosts seven technology start-up companies. There is a healthy turnover in the Innovation Center space with a total of 19 companies residing at BIC over the past year. The mix of companies includes: life sciences, biotechnology, medical devices, photonics, and clean energy; and nine of the 19 companies originated from within BU. All the BIC tenants are engaged in the commercialization of new technologies of importance to society and all are active in the BU community in terms of offering internships, employment opportunities or research collaborations. For more information about Business Innovation Center activities, read the Business Innovation Center chapter in the Facilities and Equipment section on page 66

The Boston University Photonics Center annual report 2012-2013

This repository item contains an annual report that summarizes activities of the Boston University Photonics Center in the 2012-2013 academic year. The report provides quantitative and descriptive information regarding photonics programs in education, interdisciplinary research, business innovation, and technology development. The Boston University Photonics Center (BUPC) is an interdisciplinary hub for education, research, scholarship, innovation, and technology development associated with practical uses of light.This report summarizes activities of the Boston University Photonics Center during the period July 2012 through June 2013. These activities span the Center’s complementary missions in education, research, technology development, and commercialization. The Photonics Center continues to grow as an international leader in photonics research, while executing the Center’s strategic plan and serving as a university-wide resource for several affiliate Centers. For more information about the strategic plan, read the Photonics Center Strategic Plan section on page 10. In research, Photonics Center faculty published nearly 150 journal papers spanning the field of photonics. A number of awards for outstanding achievement in education and research were presented to Photonics Center faculty members, including a Peter Paul Professorship for Professor Xue Han, an NSF Career Award for Professor Ajay Joshi, and the 2012 Innovator of the Year Award from Boston University for Professor Theodore Moustakas. New external grant funding for the 2012- 2013 fiscal year totaled over $21.8M. For more information on our research activities, read the Research section on page 24. In technology development, the Photonics Center has turned a chapter, by completing the transition from a focus on Defense/ Security applications to a focus on the healthcare market sector. The commercial sector is expected to energize the technology development efforts for the foreseeable future, but the roots in defense/security are still important and the Center will continue to pursue new research grants in this area. For more information on our technology development program and on specific projects, read the Technology Development section on page 45. In education, 20 Photonics Center graduate students received Ph.D. diplomas. Photonics Center faculty taught 32 photonics courses. The Center supported a Research Experiences for Teachers (RET) site in Biophotonic Sensors and Systems for 10 middle school and high school teachers. The Photonics Center sponsored the Herbert J. Berman “Future of Light” Prize at the University’s Scholars Day. For more on our education programs, read the Education section on page 54. In commercialization, Boston University’s Business Innovation Center (BIC) currently hosts seven technology start-up companies. There is a healthy turnover in the Innovation Center space with a total of 19 companies residing at BIC over the past year. The mix of companies includes: life sciences, biotechnology, medical devices, photonics, and clean energy; and nine of the 19 companies originated from within BU. All the BIC tenants are engaged in the commercialization of new technologies of importance to society and all are active in the BU community in terms of offering internships, employment opportunities or research collaborations. For more information about Business Innovation Center activities, read the Business Innovation Center chapter in the Facilities and Equipment section on page 66

In Vivo Vascular Imaging with Photoacoustic Microscopy

Photoacoustic (PA) tomography (PAT) has received extensive attention in the last decade for its capability to provide label-free structural and functional imaging in biological tissue with highly scalable spatial resolution and penetration depth. Compared to modern optical modalities, PAT offers speckle-free images and is more sensitive to optical absorption contrast (with 100% relative sensitivity). By implementing different regimes of optical wavelength, PAT can be used to image diverse light-absorbing biomolecules. For example, hemoglobin is of particular interest in the visible wavelength regime owing to its dominant absorption, and lipids and water are more commonly studied in the near-infrared regime. In this dissertation, one challenge was to quantitatively investigate red-blood-cell dynamics in nailfold capillaries with single-cell resolution PA microscopy (PAM). We recruited healthy volunteers and measured multiple hemodynamic parameters based on individual red blood cells (RBCs). Statistical analysis revealed the process of oxygen release and changes in flow speed for RBCs in a capillary. For the first time on record, oxygen release from individual RBCs in human capillaries was imaged with nearly real-time speed, and the work paved the way for our following study of a specific blood disorder. We next conducted a pilot study on sickle cell disease (SCD), measuring and comparing the parameters related to RBC dynamics between healthy subjects and patients with SCD. In the patient group, we found that capillaries tended to be more tortuous, dilated, and had higher number density. In addition, abnormal RBCs tended to have lower oxygenation in the inlet of a capillary, from where they flowed slower and released a larger fraction of oxygen than normal RBCs. As the only imaging modality able to observe the real-time dynamics of the oxygen release of individual RBCs, PAM provides medically valuable information for diagnostic purposes. As the last focus of this dissertation, we tackled the limited view problem in PAM by introducing an off-axis illumination technique for complementing the original detection view. We demonstrated this technique numerically and then experimentally on phantoms and animals. This simple but very effective method revealed abundant vertical vasculature in a mouse brain that had long been missed by conventional top-illumination PAM. This technique greatly advances future studies on neurovascular responses in mouse brains

Novel miniaturised and highly versatile biomechatronic platforms for the characterisation of melanoma cancer cells

There has been an increasing demand to acquire highly sensitive devices that are able to detect and characterize cancer at a single cell level. Despite the moderate progress in this field, the majority of approaches failed to reach cell characterization with optimal sensitivity and specificity. Accordingly, in this study highly sensitive, miniaturized-biomechatronic platforms have been modeled, designed, optimized, microfabricated, and characterized, which can be used to detect and differentiate various stages of melanoma cancer cells. The melanoma cell has been chosen as a legitimate cancer model, where electrophysiological and analytical expression of cell-membrane potential have been derived, and cellular contractile force has been obtained through a correlation with micromechanical deflections of a miniaturized cantilever beam. The main objectives of this study are in fourfold: (1) to quantify cell-membrane potential, (2) correlate cellular biophysics to respective contractile force of a cell in association with various stages of the melanoma disease, (3) examine the morphology of each stage of melanoma, and (4) arrive at a relation that would interrelate stage of the disease, cellular contractile force, and cellular electrophysiology based on conducted in vitro experimental findings. Various well-characterized melanoma cancer cell lines, with varying degrees of genetic complexities have been utilized. In this study, two-miniaturized-versatile-biomechatronic platforms have been developed to extract the electrophysiology of cells, and cellular mechanics (mechanobiology). The former platform consists of a microfluidic module, and stimulating and recording array of electrodes patterned on a glass substrate, forming multi-electrode arrays (MEAs), whereas the latter system consists of a microcantilever-based biosensor with an embedded Wheatstone bridge, and a microfluidic module. Furthermore, in support of this work main objectives, dedicated microelectronics together with customized software have been attained to functionalize, and empower the two-biomechatronic platforms. The bio-mechatronic system performance has been tested throughout a sufficient number of in vitro experiments.Open Acces

Nanoantennas for visible and infrared radiation

Nanoantennas for visible and infrared radiation can strongly enhance the interaction of light with nanoscale matter by their ability to efficiently link propagating and spatially localized optical fields. This ability unlocks an enormous potential for applications ranging from nanoscale optical microscopy and spectroscopy over solar energy conversion, integrated optical nanocircuitry, opto-electronics and density-ofstates engineering to ultra-sensing as well as enhancement of optical nonlinearities. Here we review the current understanding of optical antennas based on the background of both well-developed radiowave antenna engineering and the emerging field of plasmonics. In particular, we address the plasmonic behavior that emerges due to the very high optical frequencies involved and the limitations in the choice of antenna materials and geometrical parameters imposed by nanofabrication. Finally, we give a brief account of the current status of the field and the major established and emerging lines of investigation in this vivid area of research.Comment: Review article with 76 pages, 21 figure

Modifying Ultrasound Waveform Parameters to Control, Influence, or Disrupt Cells

Ultrasound can be focused into deep tissues with millimeter precision to perform non-invasive ablative therapy for diseases such as cancer. In most cases, this ablation uses high intensity ultrasound to deposit non-selective thermal or mechanical energy at the ultrasound focus, damaging both healthy bystander tissue and cancer cells. Here we describe an alternative low intensity pulsed ultrasound approach known as “oncotripsy” that leverages the distinct mechanical properties of neoplastic cells to achieve inherent cancer selectivity. We show that when applied at a specific frequency and pulse duration, focused ultrasound selectively disrupts a panel of breast, colon, and leukemia cancer cell models in suspension without significantly damaging healthy immune or red blood cells. Mechanistic experiments reveal that the formation of acoustic standing waves and the emergence of cell-seeded cavitation lead to cytoskeletal disruption, expression of apoptotic markers, and cell death. The inherent selectivity of this low intensity pulsed ultrasound approach offers a potentially safer and thus more broadly applicable alternative to non-selective high intensity ultrasound ablation. In this dissertation, I describe the oncotripsy theory in its initial formulation, the experimental validation and investigation of testable predictions from that theory, and the refinement of said theory with new experimental evidence. Throughout, I describe how careful modifications to the ultrasound waveform directly can significantly impact how the ultrasound bio-effects control, influence, or disrupt cells in a selective and controlled manner.</p