Research Fellow @ Massachusetts Institute of Technology, Transfusion Medicine Fellow @ Dartmouth-Hitchcock Medical Center

Nanotube-porphyrin molecular structure and applications of same
Patent

Nanotube-porphyrin molecular structure and applications of same

A molecular structure. In one embodiment, the molecular structure includes a nanotube formed With a plurality of carbon atoms having a first end, an opposite, second end, and a body portion defined there between, wherein the body portion has an interior surface defining a cavity, an opposite, exterior surface and a longitudinal axis therethrough the cavity, and a porphyrin molecule having a plurality of carbon atoms and a first plurality of hydrogen atoms, wherein at its original state the porphyrin molecule has a plurality of pyrrole units and each pyrrole unit is coupled to another pyrrole unit through a methine bridge so as to form a ring structure with a second plurality of hydrogen atoms positioned peripherally along the ring structure. The porphyrin molecule is chemically coupled to the interior surface of the nanotube such that at least one of the second plurality of hydrogen atoms positioned peripherally along the ring structure is replaced by a carbon atom of the nanotube.

RGD coated protein microspheres as a dual fluorescent and magnetomotive contrast agent for targeted cancer imaging with magnetomotive optical coherence tomography

Optical coherence tomography (OCT) is a novel technology that has been developed for various clinical applications ranging from ophthalmology to oncology. OCT is analogous to ultrasound technology but with micron by using light waves instead of sound waves providing detailed morphological or structural information at the cellular level about the tissue specimen. Magneto-motive OCT (MM-OCT) is a recently developed modality of OCT in which a magnetic field is modulated on and off during imaging. With the development of this modality, exogeneous contrast agents are becoming more important to target markers that are expressed prior to morphological changes that structural OCT can only detect. Modified protein microspheres consisting of an oil core and a hydrophilic BSA protein shell are being presented as a multi-modal contrast agent vehicle. The protein microspheres are encapsulated with iron oxide in the oil core to provide the magnetic signal contrast and a near infrared dye to provide a fluorescence contrast. The outer surface is functionalized using a layer-by-layer adhesion process to attach RGD peptide sequences to target integrin receptors. Under MM-OCT, these agents have been detected above various levels of background tissue scattering demonstrating that these agents can provide added contrast to OCT through the magnetic signal. These agents were incubated with various cell lines with differing levels of alpha(v)beta(3) integrin receptor expression that were quantified using western blotting and fluorescent antibody immunohistochemical staining. The normal control cell line used was the CRL-4010. The breast cancer cell lines studied included CRL-2314, SK-BR-3, MCF-7, and 13762 MAT B III cells. These studies address the binding specificity and sensitivity of the RGD functionalized protein microspheres to the alpha(v)beta(3) integrin receptors. In addition, a quantitative analysis is being performed to correlate the relative levels of bound microspheres to the cells, measured through MM-OCT measurements and through their fluorescence signals of the microspheres, and the cell’s alpha(v)beta(3) integrin receptor expression derived from the western blot experiments. Preliminary results indicate that these agents have a higher affinity to the cancer cells over the normal epithelial cells and are also internalized by the cells and could have to potential to become localized targeted drug delivery vehicles. In an NMU carcinogen induced rat animal model, the targeted protein microspheres were injected in-vivo. These preliminary results, using a multi-spectral dark box imaging system, demonstrate the localization of the microspheres to the vasculature surrounding the tumor. These microspheres are being presented as a novel contrast agent to a novel high resolution imaging modality targeted at cancer.

Publication

Optical coherence tomography: the intraoperative assessment of lymph nodes in breast cancer

During breast-conserving surgeries, axillary lymph nodes draining from the primary tumor site are removed for disease staging. Although a high number of lymph nodes are often resected during sentinel and lymph-node dissections, only a relatively small percentage of nodes are found to be metastatic, a fact that must be weighed against potential complications such as lymphedema. Without a real-time in vivo or in situ intraoperative imaging tool to provide a microscopic assessment of the nodes, postoperative paraffin section histopathological analysis currently remains the gold standard in assessing the status of lymph nodes. This paper investigates the use of optical coherence tomography (OCT), a high-resolution real-time microscopic optical-imaging technique, for the intraoperative ex vivo imaging and assessment of axillary lymph nodes. Normal (13), reactive (1), and metastatic (3) lymph nodes from 17 human patients with breast cancer were imaged intraoperatively with OCT. These preliminary clinical studies have identified scattering changes in the cortex, relative to the capsule, which can be used to differentiate normal from reactive and metastatic nodes. These optical scattering changes are correlated with inflammatory and immunological changes observed in the follicles and germinal centers. These results suggest that intraoperative OCT has the potential to assess the real-time node status in situ, without having to physically resect and histologically process specimens to visualize microscopic features.

Publication

Intraoperative evaluation of breast tumor margins with optical coherence tomography

As breast cancer screening rates increase, smaller and more numerous lesions are being identified earlier, leading to more breast-conserving surgical procedures. Achieving a clean surgical margin represents a technical challenge with important clinical implications. Optical coherence tomography (OCT) is introduced as an intraoperative high-resolution imaging technique that assesses surgical breast tumor margins by providing real-time microscopic images up to 2 mm beneath the tissue surface. In a study of 37 patients split between training and study groups, OCT images covering 1 cm(2) regions were acquired from surgical margins of lumpectomy specimens, registered with ink, and correlated with corresponding histologic sections. A 17-patient training set used to establish standard imaging protocols and OCT evaluation criteria showed that areas of higher scattering tissue with a heterogeneous pattern were indicative of tumor cells and tumor tissue in contrast to lower scattering adipocytes found in normal breast tissue. The remaining 20 patients were enrolled into the feasibility study. Of these lumpectomy specimens, 11 were identified with a positive or close surgical margin and 9 were identified with a negative margin under OCT. Based on histologic findings, 9 true positives, 9 true negatives, 2 false positives, and 0 false negatives were found, yielding a sensitivity of 100% and specificity of 82%. These results show the potential of OCT as a real-time method for intraoperative margin assessment in breast-conserving surgeries.

Publication

Clinical feasibility of microscopically-guided breast needle biopsy using a fiber-optic probe with computer-aided detection

Needle biopsy of small or nonpalpable breast lesions has a high nondiagnostic sampling rate even when needle position is guided by stereotaxis or ultrasound. We assess the feasibility of using a near-infrared fiber optic probe and computer-aided detection for the microscopic guidance of needle breast biopsy procedures. Specimens from nine consented patients undergoing breast-conserving surgery were assessed intraoperatively using a needle device with an integrated fiber-optic probe capable of assessing two physical tissue properties highly correlated to pathology. Immediately following surgical resection, specimens were probed by inserting the optical biopsy needle device into the tissue, simulating the procedure used to position standard biopsy needles. Needle positions were marked and correlated with histology, which verified measurements obtained from 58 needle positions, including 40 in adipose and 18 in tumor tissue. This study yielded tissue classifications based on measurement of optical refractive index and scattering. Confidence-rating schemes yielded combined sensitivity of 89% (16/18) and specificity of 78% (31/40). Refractive index tests alone identified tumor tissue with a sensitivity of 83% (15/18) and specificity of 75% (30/40). Scattering profiles independently identified tumor tissue with a sensitivity of 61% (11/18) and specificity of 60% (24/40). These results show that a biopsy needle with an integrated fiber optic probe can be used to identify breast tumor tissue for sampling. Integration of this probe into current practices offers the potential to reduce nondiagnostic sampling rates by directly evaluating in situ microscopic tissue properties in real-time, before removal.

Publication

Translational careers

POWERED BY THE COMPUTATIONAL MUSCLE OF BIOINFORMATICS AND THE BROAD PERSPECTIVE
of systems biology, advances in biomedical science now have the capacity to transform medicine. Yet to fully realize the health benefits of new scientific insight, we must ensure a vibrant flow of information between the basic sciences and clinical medicine. This takes both systems and people.
The U.S. government has made an unprecedented investment in the infrastructure required to support a new generation of translational researchers. Through the Clinical and Translational Science Award program (CTSA), the National Institutes of Health has created a national consor- tium that already includes 39 centers in 23 states with an annual funding commitment of $500 million by 2012. Still in its infancy, this initiative seeks to shorten the time required to translate research results into therapies by many means, including training researchers and providing them with an academic home, developing tools for clinical research, streamlining regulatory processes, and fostering interdisciplinary and interinstitutional research.
The potential is clear.
But people are the prerequisite for success. We need an array of inno- vative investigators whose expertise spans all the disciplines of basic discovery and medical science. As a counterpoint to federal efforts, our private, nonprofit organizations have addressed the human capital need in robust ways, training and funding physicians and other clinical scientists, and piloting models for interdisciplinary graduate training involving biologists, physical and computational scientists and engineers, as well as a wide range of clinical and public health professionals.

Publication

Optical properties of tissues quantified by Fourier-transform light scattering

We employ Fourier-transform light scattering, a technique recently developed in our laboratory, to study the scattering properties of rat organ tissues. Using the knowledge of the complex field associated with high-resolution microscope images of tissue slices, we extracted the scattering mean-free path l(s) and anisotropy factor g, which characterize the bulk tissue for three different rat organs. This “bottom up” approach to measuring tissue scattering parameters allows for predicting the wave transport phenomena within the organ of interest at a multitude of scales-from organelle to organ level.

Restructuring MD-PhD programs: career training or broad education?

In his July 2007 editorial,1 Dr. Whitcomb questions the value of U.S. MD–PhD training, citing the low percentage of students desiring research as their primary professional activity2 and their low rate of NIH grant applications.1 He laments the current system of training as having too much time away from the lab and advocates a system more conducive to research.

He makes a number of assumptions, two of which we challenge here. One, the lower than expected percentage of students desiring research is a function of time away from the lab. This is essentially an academic argument, since we cannot randomize students to different training protocols. Yet, we must still consider how best to improve students’ education. While simply increasing the integration of research into early training appears reasonable, it is not the answer. We believe it is too much to ask students (or residents) to effectively integrate both research and doctoring at the earlier stages of learning. Instead, delving deeply into one discipline at a time as a novice, rather than striving for true coherence via integration, is more likely to develop solid foundations. We want our young physicians and scientists to treat their patients and execute their experiments with expertise and not just acceptable competence. The current system should certainly be modified to fit modern needs, but simply more integration and lab time are not the solution.

Two, the need for MD–PhDs to perform more lab research as a part of their profession is a more contentious matter. We must remember that most medical lab research is not performed by MD–PhDs, and the majority of physician scientists are not MD–PhDs. Then what do MD–PhDs do? They are uniquely positioned, by virtue of learning two traditional disciplines, to see complex problems from different perspectives—to be innovators, teachers, integrators, and leaders. It is the duty of dual-degree programs to provide the education to encourage such qualities. To push all MD–PhDs toward the lab or particular subspecialties is shortsighted. All fields of medicine and surgery—and, indeed, pubic health policy and many business disciplines—need those who can integrate the skills of rigorous investigation with an understanding of patient issues.

For the National Institute of General Medical Sciences to truly get its money’s worth, MD–PhD programs should provide exceptional multidisciplinary education, not career training. They need to encourage creativity, exploration, vision, and, especially, leadership. Only then will our society realize its full investment potential.

Optical coherence tomography (OCT) as a diagnostic tool for the real-time intraoperative assessment of breast cancer surgical margins

Background: The decrease in the number of breast cancer deaths has largely been attributed to increased awareness, earlier detection, and improved treatment options. However, as the number of breast-conserving surgeries rose over the years, the need for negative margins and little or no residual disease has become critical to help reduce the chances of local recurrence. OCT is a high resolution imaging modality that has been used to image tumor margins in an NMU-carcinogen-induced rat mammary tumor model. Due to the location of breast lesions, the use of needle-based imaging probes may be used to further extend the reach of the OCT imaging beam by incorporating an optical fiber into biopsy needle tips, providing real-time information to guide biopsies or to place localization wires.
Material & Methods: A clinical spectral domain OCT system was developed with a super luminescent diode light source centered at 1310 nm with a bandwidth of 92 nm yielding an axial resolution of 8.3 µm. The beam delivery sample arm uses a 60 mm achromatic lens to focus 4.75 mW of light to a 35.0 µm spot size (transverse resolution) with a confocal parameter of 1.47 mm. The patients included in this study had primary breast tumors diagnosed by needle-biopsy and were in need of surgical resection, as determined by their physicians. At Carle Foundation Hospital, the OCT system was placed inside the operating room during breast conserving surgical procedures to image the tissue specimens. The OCT images were evaluated by a single operator allowing for consistent classification based on the level of scattering intensity and heterogeneity, scattering profile, and physical extent of the highly scattering area.
Results: An initial training data set of OCT images from 17 patients was used to establish standard imaging protocols and standard evaluation criteria of the surgical margins. Of the 20 additional tissue specimen imaged for the feasibility study, 11 were identified as having a positive or close surgical margin and nine as a negative margin under OCT. In comparing to the H&E histology, there were 9 true positives, 9 true negatives, 2 false positives, and 0 false negatives yielding a sensitivity of 82% and specificity of 100%.
Discussion: With an imaging penetration depth of 2-3 mm, equivalent to that used for histological assessment, OCT provides unique real-time cellular-level imaging to identify positive and close margins. In these studies, areas of higher scattering tissue with an irregular or heterogeneous pattern were identified, differentiating them from the abundant adipose tissue found in normal breast tissue. The small nucleus to cytoplasm (N/C) ratio is observed with low-scattering adipocytes compared with the larger N/C ratio found from highly-scattering tumor cells. These intraoperative imaging studies have demonstrated the ability for OCT to identify positive surgical margins.

Publication

Fourier transform light scattering of inhomogeneous and dynamic structures

Fourier transform light scattering (FTLS) is a novel experimental approach that combines optical microscopy, holography, and light scattering for studying inhomogeneous and dynamic media. In FTLS the optical phase and amplitude of a coherent image field are quantified and propagated numerically to the scattering plane. Because it detects all the scattered angles (spatial frequencies) simultaneously in each point of the image, FTLS can be regarded as the spatial equivalent of Fourier transform infrared spectroscopy, where all the temporal frequencies are detected at each moment in time.

Physician-scientist with extensive experience developing and translating nanotechnologies and biomedical optical technologies from the bench to clinic in areas of genetics, oncology, and cardiovascular diseases. Extensive experience in community building in healthcare innovation, research, medical, and physician-scientist communities through various leadership roles.

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