Foundation
Select a Project from one of the Four Categories Below and Apply
I. Optical Coherence Tomography
II. In Vivo Microscopy
III. Micro-Optical and Point-of-Care Devices
IV. Photodynamic Therapy (PDT)
I. Optical Coherence Tomography
Goal: Develop new techniques for interferometric sensing, imaging, and the integration of diagnostics with therapy via narrow diameter fibers, catheters and endoscopes for biomedical applications.
Project 1: Novel optical coherence tomography devices and techniques.
(Faculty Mentor: Prof. Brett Bouma, WCP)
OCT provides high-resolution cross-sectional images of biological tissue. Commercial instruments are now widely available for research as well as clinical applications. There remains, however, a pressing need for advanced instrumentation including new laser sources, novel techniques for beam scanning in miniature probes, and methods that provide functional information in addition to structural imaging. In addition, machine learning is increasingly important tool for signal and image processing. Advances will draw from expertise in physics, mechanical engineering, electrical engineering, and computer science.
For further information regarding Dr. Bouma and his research interests please refer to: http://wellman.massgeneral.org/faculty-bouma-pi.htm and http://wellman.massgeneral.org/faculty-bouma-projects.htm
Project 2: Micromechanical mapping of cancer invasiveness
(Faculty Mentor: Prof. Seemantini Nadkarni, WCP)
The goal of this proposal is to develop a new tool that measures micromechanical properties and residual stresses in tumors. This innovation will enable comprehensive mechanical profiling of tumor biopsies for improved treatment planning, and for advancing research on tumor mechanobiology. The viscoelastic behavior of the extracellular matrix (ECM) is a powerful regulator of many oncogenic processes including proliferation, invasion, differentiation, and metastasis. Increased ECM stiffening or elasticity, primarily due to collagen deposition by fibroblasts, drives the malignant transformation of cells. Macrophage infiltration on the other hand degrades and liquidizes the ECM, resulting in viscous or ‘liquid-like’ stromal properties that aid cancer cells in metastasizing by squeezing through stromal boundaries. Thus, elastic, and viscous behaviors of the ECM co-exist and act concurrently to drive malignant transformation and metastasis. As the tumor grows, residual stresses develop that compress lymphatic vessels, suppress favorable T-cell infiltration, aiding lymph node metastasis. Thus, the crosstalk between various mechanical factors and oncogenic signaling, drives malignant transformation, invasion and metastasis. Comprehensive profiling of the mechanical landscape of cancers is therefore a crucial need, directly addressed in this project. Our objective is to develop a new tool for micromechanical mapping of the tumor landscape to comprehensively interrogate critical mechanical markers that promote oncogenic signaling. This project is well suited for a postdoctoral fellow with expertise in optical instrumentation and machine learning approaches.
For further information regarding Dr. Nadkarni and her research interests please refer to: http://wellman.massgeneral.org/faculty-nadkarni-pi.htm
Project 3: Development and Translation of Circular Ranging OCT.
(Faculty Mentor: Prof. Ben Vakoc, WCP)
We have recently demonstrated circular ranging OCT platforms that open new opportunities for three-dimensional imaging in uncontrolled and/or dynamic settings [see Siddiqui et al., Nature Photonics, Feb. 1 (2018)]. Potential applications of this technology include intraoperative imaging, laparoscopic imaging, or imaging in large and geometrically complex organs. In this project, we will develop the core technology, build systems to perform pilot studies, and work with external partners to explore commercial opportunities. This project is ideal for a post-doctoral fellow with a background in physics, applied physics, or electrical engineering and interest in the development and translation of next-generation biomedical imaging technologies.
Project 4: Development of high-speed frequency comb laser sources for circular ranging OCT.
(Faculty Mentor: Prof. Ben Vakoc, WCP)
New circular ranging OCT architectures operate with novel frequency-comb laser sources [see Siddiqui et al., Nature Photonics, Feb. 1 (2018)]. We are actively researching new frequency-comb laser architectures based on stretched-pulse mode-locking (SPML) architectures. There are opportunities for post-doctoral fellows to improve performance, reduce size, and increase stability through innovations in laser design. This project is ideal for a post-doctoral fellow with a background in physics, applied physics, or electrical engineering with experience in laser source development.
For further information regarding Dr. Vakoc and his research interests please refer to: http://wellman.massgeneral.org/faculty-vakoc-pi.htm
Project 5: Elastography to measure mechanical properties.
(Faculty Mentor: Prof. S. H. Andy Yun, WCP)
Changes in mechanical properties of tissues are linked to underlying structural and molecular changes. Optical coherence elastography (OCE) based on acoustic wave analysis has high potential for mapping the mechanical properties of tissues and bioengineering materials. The project will develop this technique for assessing various tissues and analyzing elastic properties at high resolution using finite element analysis and machine learning.
For further information regarding Dr. Yun and his research interests please refer to: http://www.intelon.org
Goal: Cellular and molecular imaging for more accurate and less invasive diagnosis of disease in living human patients and in animal models of human disease.
Project 1: Targeted intracoronary imaging for inflammatory activity.
(Faculty Mentor: Prof. Guillermo Tearney, WCP)
Our laboratory has pioneered multimodal intracoronary imaging technology, combining intravascular optical coherence tomography (OCT) with near-infrared autofluorescence (NIRAF) and near-infrared fluorescence (NIRF) detection. Recently, a multi-cathepsin protease molecular beacon called LUM015 has been developed and clinically approved for NIRF imaging of inflammation in human cancer in vivo. In this project, we aim to advance intracoronary NIRF-OCT imaging so that it can be optimally used with LUM015 to enable the assessment of coronary microstructure and inflammatory activity in living patients. This project will involve development of a clinical NIRF-OCT imaging system, novel multimodal imaging catheters and rotary junction interfaces, and advanced multichannel spectral detection and unmixing methods. This system will be validated in preclinical studies of atherosclerotic animal models and subsequently translated to clinical use. The capacity to evaluate active coronary inflammation at the individual patient level could enable more effective, personalized CAD management, potentially preventing many heart attacks from occurring.
For further information regarding Dr. Tearney and his research interests please refer to: http://www.tearneylab.org
Project 2: Transepithelial Voltage/Current Measurement
(Faculty Mentor: Prof. Guillermo Tearney, WCP)
Our lab has developed an OCT image-guided intraluminal transepithelial voltage/current measurement technology for real-time investigation of epithelial transport function in living patients. Studies have shown that conditions such as celiac disease, irritable bowel syndrome, type II diabetes, and epithelial malignancies lead to changes in the permeability of the accompanying epithelium that can be probed by the proposed voltage/current measurement techniques. In addition, genetic defects that impact ion transport across these epithelia such as cystic fibrosis, which affects the airway epithelium, can be diagnosed using this method. We have projects open to develop and clinically validate this image-guided physio-electrical measurement platform, with clinical applications in the gut and the airway.
For further information regarding Dr. Tearney and his research interests please refer to: http://www.tearneylab.org
Project 3: Dynamic micro-optical coherence tomography (µOCT) of tissues
(Faculty Mentor: Prof. Guillermo Tearney, WCP)
A high-resolution form of OCT, termed µOCT, is capable of visualizing sub-cellular microanatomy of a wide range of organs, tissues, and cells. Recently, we have introduced dynamic µOCT (dµOCT) that images metabolism-driven intracellular motion within living tissues. By detecting differences in intracellular motion of different cells, dµOCT can be used to distinguish cell types, monitor metabolic status, and enhance image contrast. A variety of projects are open in the lab to advance dµOCT’s capabilities with applications in label-free optical biopsy and longitudinal evaluation of chemotherapeutics for personalized cancer therapy.
For further information regarding Dr. Tearney and his research interests please refer to: http://www.tearneylab.org
Project 4: Retina as a natural window for noninvasive imaging of CNS inflammation.
(Faculty Mentor: Prof. Charles Lin, WCP)
Many disorders of the central nervous system (CNS), such as brain injury and multiple sclerosis, are associated with marked infiltration of inflammatory cells into the brain or the spinal cord that are difficult to assess. We are developing a method for noninvasive imaging of inflammatory cells in the retina, which is an optically accessible compartment of the CNS.
Project 5: Counting blood cells without drawing blood.
(Faculty Mentor: Prof. Charles Lin, WCP)
Blood count is one of the most frequently ordered clinical laboratory tests. Standard blood count requires taking blood samples that can be difficult in certain patients. We are developing a method called in vivo flow cytometry that enables noninvasive detection and quantification of blood cells as they circulate in the blood vessels.
Project 6: Blood stem cells, blood cancer, and the bone marrow microenvironment.
(Faculty Mentor: Prof. Charles Lin, WCP)
All blood cells are made from hematopoietic stem cells in the bone marrow. Blood cancers such as leukemia and multiple myeloma also originate in the bone marrow. We are developing an optical platform that integrates multiphoton intravital microscopy with image-guided single cell sequencing (Image-seq) to enable spatial, temporal, and molecular analysis of the bone marrow.
For further information regarding Dr. Lin and his research interests please refer to: http://wellman.massgeneral.org/faculty-lin-pi.htm and http://wellman.massgeneral.org/faculty-lin-projects.htm
Project 7: Visualizing and Quantifying Dermal Pharmacokinetics and Pharmacodynamics
(Faculty Mentor: Prof. Conor Evans, WCP)
There are numerous challenges in the development of topical drugs, from identification of potential molecules, formulation of the active pharmaceutical ingredients, tracking drug transport, and determining therapeutic effect. While the pharmacokinetics (PK) of systemically- delivered agents can be traced via chromatographic assessment of blood samples, the targets for topical drugs are in the skin itself, requiring direct measurement of drug flux and flow. We have developed chemical imaging tools that make use of coherent Raman imaging to directly visualize and quantify the uptake of pharmaceuticals in skin. Combined with machine learning approaches, these imaging tools are now being applied to measure and map, on the cellular level in humans, PK and PD.
For further information regarding Dr. Evans and his research interests please refer to: http://scholar.harvard.edu/conorlevans
Project 8: Brillouin microscopy.
(Faculty Mentor: Prof. S. H. Andy Yun, WCP)
Brillouin microscopy uses Brillouin light scattering to probe the hydromechanical properties of tissues and cells. This project aims to improve the speed and sensitivity of this technique and explore various applications in basic sciences, bioengineering, and clinical medicine.
For further information regarding Dr. Yun and his research interests please refer to: http://www.intelon.org
Project 9: Cardiac intravital microscopy.
(Faculty Mentor: Prof. Aaron Aguirre, WCP)
Intravital microscopy can offer an unprecedented window into cellular pathophysiology of disease and has found widespread application in the neurosciences and in cancer biology. These techniques have been very difficult to apply in the cardiovascular field due to cardiac motion. Our laboratory has developed novel approaches for high-speed gated imaging of the heart and major blood vessels in small animal models. This project will develop new methods for two-photon microscopy and optical coherence tomography to study remodeling of the heart after myocardial infarction. Specifically, the research fellow will work with cardiologists and cardiovascular scientists to use advanced imaging to study alterations in the microvasculature of the heart after injury and to explore new therapies to promote recovery.
For further information about Dr. Aguirre and his research interests, please refer to: https://csb.mgh.harvard.edu/aaron_aguirre
III. Micro-Optical and Point-of-Care Devices
Goal: To develop micro-optical devices for point-of-care diagnosis and light-based therapy.
Project 1: Blood Coagulation sensing at the point-of-care.
(Faculty Mentor: Prof. Seemantini Nadkarni, WCP)
The goal of this project is to design, fabricate and translate a low-cost, multi-functional and portable blood coagulation sensor that can measure a patient’s coagulation status within a few minutes using a drop of blood. This device addresses the critical unmet need to identify and manage patients with an elevated risk of life-threatening bleeding or thrombosis, the major cause of preventable death in hospitals. The coagulation sensing technology is based on a novel optical rheology approach developed in our laboratory to quantify the mechanical properties of tissues with microscale resolution. This project is well suited for a post-doctoral fellow with entrepreneurial interests with expertise in optical instrumentation and/or microfluidic devices who is interested in working with a collaborative team of physicists, engineers and clinicians focused on the development and rapid translation of low-cost diagnostic technologies towards point of care use in patients.
For further information regarding Dr. Nadkarni and her research interests please refer to: http://wellman.massgeneral.org/faculty-nadkarni-pi.htm
Project 2: Nano-lasers.
(Faculty Mentor: Prof. S. H. Andy Yun, WCP)
This project aims to develop ultra-small lasers with the size of bacteria and viruses. Progress has been made using inorganic and organic semiconductor materials as the gain media and plasmonic cavities.
Project 3: Biodegradable photonics.
(Faculty Mentor: Prof. S. H. Andy Yun, WCP)
This project aims to develop novel optical devices made entirely of biocompatible and biodegradable polymers. Such implantable devices may be used in the body for diagnostic and therapeutic purposes and absorbed in situ over time without the need for invasive removal.
Project 4: Application of laser particles to multi-dimensional single-cell analysis.
(Faculty Mentor: Prof. S. H. Andy Yun, WCP)
Biomolecular analyses to probe the genome, epigenome, transcriptome, and proteome of single-cells have led to identification of new cell types and discovery of novel targets for diagnosis and therapy. While these analyses are performed predominantly on dissociated single cells, emerging techniques seek understanding of cellular state, function and cell-cell interactions within the native tissue environment, by combining optical microscopy and single-cell molecular analyses. This project aims to develop novel multiplexed imaging probes, called laser particles, which allow individual cells to be tagged in tissue and analyzed subsequently using high-throughput, comprehensive single-cell techniques such as flow cytometry and single-cell sequencing
For further information regarding Dr. Yun and his research interests please refer to: http://www.intelon.org
Project 5: Optical microneedle arrays for point-of-care diagnosis.
(Faculty Mentor: Prof. Mei X. Wu, WCP)
Hemoglobin-specific absorbance of green laser can alter the permeability of capillaries within the skin specifically and locally, resulting in extravasation and accumulation of blood biomarkers beneath a small area of the skin involved by 1,000~10,000-fold without incurring any damage of the capillaries. The accumulated biomarkers are readily captured and quantified by a surface modified microneedle array in a sample-free manner. A small and portable optical device is being fabricated by integrating the microneedle array with an optical lens and software to record and analyze the biomarkers bound on the individual microneedles for onsite diagnosis and prognosis.
Project 6: Laser source for prophylaxis and therapeutics of thrombocytopenia.
(Faculty Mentor: Prof. Mei X. Wu, WCP)
The major function of platelets is for blood clotting and abnormally low platelet counts or thrombocytopenia increases risks of hemorrhage and death owing to uncontrollable bleeding. We found that noninvasive and whole body illumination with near infrared laser at specific settings can augment platelet regeneration greatly diminishing the risk of thrombocytopenia in small animal models. A new laser prototype can be engineered to accelerate platelet regeneration in large animal models like pigs and then in humans.
For further information regarding Dr. Wu and her research interests please refer to: http://wellman.massgeneral.org/faculty-wu-pi.htm and http://wellman.massgeneral.org/faculty-wu-projects.htm.
IV. Photodynamic Therapy (PDT)
Goal: To develop molecular mechanism and optical imaging-based combination treatment regimens in which the first treatment primes/sensitizes cancer cells for the second treatment.
Project 1: Development of bioengineered/patient derived 3D tumor models to design and evaluate PDT-based combinations.
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
In this project, postdoctoral fellows will learn the basic concepts and techniques relevant to culturing cancer cells in heterocellular 3D in vitro models that integrate stromal cells and physical forces such as flow. Also, this project will evaluate generating patient derived tumor organoids that recapitulate original tumor microenvironment. These models established for assessing pancreatic cancer, oral cancer, brain tumors or ovarian cancer will be used to evaluate drug delivery strategies for cancer, employing rationally designed combination treatments and targeted multi-agent nanocarrier-based treatments. Following treatment, the in vitro tumors will be imaged to characterize delivery and uptake of the therapeutic agents and to assess cell death. The outcome of these studies will assist in developing biologically relevant models and a platform for rapid image-based screening of therapeutic agents.
Project 2: Image-based quantification of molecular responses to cancer therapy.
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
This project involves the development of a hyperspectral fluorescence microendoscope for online multi-molecular imaging to quantify tumor cell phenotypes and their spatio-temporal location during various modes of treatment in mouse cancer models. Our goal is to determine both the key time points and spatial localizations of tumor signaling factors responsible for post-treatment survival and disease recurrence. This information will be used to rationally design and optimize new combination treatments. Postdoctoral fellows will participate in molecular imaging using the hyperspectral fluorescence microendoscope, including GPU programming, video-rate image analysis, and ex vivo histopathological validation. Substantial image analysis will be involved in the project. The anticipated outcome of these studies is a clear understanding of mechanisms that ensue after therapy administration and image guided treatments.
Project 3: Multi-inhibitor nanoconstructs for Cancer Therapeutics: addressing tumor heterogeneity and drug resistance
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
A major barrier to cancer therapy is drug resistance and tumor heterogeneity. This project addresses the problem by the combined use of hyperspectral imaging and nanoconstructs. The nanoconstructs are designed to complementarily interrupt several tumor cell growth pathways. These pathways may be intrinsic or may have evolved due to extrinsic forces. The multi-inhibitor nanoconstructs will be developed to uniquely deliver multiple treatments including, photosensitizers, chemotherapy agents, receptor tyrosine kinase inhibitor or imaging agents, with consideration of their mechanistic interactions. Hyperspectral imaging allows us to monitor therapeutics delivery, reduction of normal tissue toxicity and the specific cell population that is destroyed. Postdoctoral fellows will work on many aspects of the problem collaboratively. These are the synthesis, physical characterization, and optimization of tumor-targeting, photo-activatable nanoconstructs that can co-deliver multiple inhibitors without pre-mixing the agents. The anticipated outcome of this study is technology development, fabricating multi-inhibitor agents and establishing their efficacy in-vitro and in-vivo.
Projects 4-6 are Global Health Related Projects
Project 4: 3D Printed Technology for PDT of Oral Cancer.
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
Oral cancer is major cause of death in India. The current NCI funded project is aimed at developing a low-cost technology that can be used in low resource settings. The goals of this project are to develop a low-cost light device for easy use and to develop a simple protocol for treatment of early oral cancers. An interface with smart phone to add imaging is also part of the study. Currently patient treatment is ongoing with our proto-types. Out of 21 patients treated with this simple system, 17 remain cancer free post 6-12 months of treatment. Postdoctoral fellows will work on image guided treatments for oral cancer.
Project 5: Dual function theranostic constructs for photoacoustic guided surgery and photodynamic therapy.
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
Survival rates in patients with oral cavity tumors (e.g., tongue cancers) have remained nearly stagnant in the past decade with exceptional morbidity. The goal of this project is to develop, for the first time, a single theranostic agent namely targeted Dual Function Antibody Conjugate (DFAC) enabling deep tissue photoacoustic imaging (PAI) with targeted photodynamic therapy (PDT), and an integrated PAI-ultrasound imaging (US) module for surgery guidance such that the two main barriers to oral cancer treatment outcomes are overcome. The project has 3 parts that will enable deep tissue image-guided surgery and treat residual disease in one intraoperative setting.
1. A DFAC, that enables both imaging and therapy by targeting Epidermal growth factor receptor (EGFR), as an established biomarker in oral cavity tumors.
2. A custom-built, PAI integrated clinical USI module for surgical guidance.
3. Targeted PDT. DFAC is composed of cetuximab, an FDA-approved EGFR targeting antibody, conjugated to a new near-infrared (>850 nm) naphthalocyanine dye for deep-tissue PAI and an FDA-approved photosensitizer Benzoporphyrin Derivative (BPD).
We postulate that DFAC-enabled deep-tissue PAI-guided surgery and intraoperative PDT of residual disease will achieve local tumor control. This is a project requiring multiple skills and the postdoctoral fellow will work on aspects that are most aligned with training and interests. For example, chemistry/biology training will involve creating DFACS, in vitro testing, in vivo testing, patient sample evaluation. If engineering and physics are the strengths, the work will be more focused on the building and testing of the integrated PAI-US system. The study offers deep tissue imaging and targeted therapy in a single intraoperative session, resulting in lower recurrence, lower cost, higher overall survival and improved quality of life. The modular design of DFAC and integrated PAI-US enables adaptation of the platform to other cancers.
Project 6: Bacterial resistance strategy foiled by light activatable molecular systems: identification of appropriate antibiotics for infection control.
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
The broad goal of this application is to develop a platform for rapidly identifying antibiotic susceptibility for a broad class of bacterial infections. The long-term goal is to develop chemistries for recognition of an array of bacterial targets (Erdem et al., 2014; Khan et al., 2014; Zheng et al., 2009), particularly those responsible for drug resistance, and integrate these with a simple microfluidic device and a small cell phone based optical readout system. Toward that goal, in the past several years, we have focused on the penicillin and cephalosporin classes of antibiotics where the target has been the lactam/β-lactamase system. While that work progresses toward development of an integrated clinical system, we propose to broaden the platform to the carbapenem class of antibiotics because of their emerging role in infections, particularly in wounds. This proposal will initiate the preliminary development of chemistry for targeting the carbapenemase enzyme (which destroys carbapenem antibiotics) and explore the development of a cell phone based optical reader. Preliminary work has been done in a clinical trial set in Thailand. The postdoctoral fellow will be involved in developing chemistries for cleavable probes and evaluating in a broad spectrum of bacteria along with technological developments to make a portable sized system for detection.
Project 7: Real time monitoring of immune responses to cancer immunotherapy
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
Immunotherapy using immune checkpoint blocking antibodies such as PD-1/PD-L1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. This is also attributed to lack of robust methods to stratify patients into responders/non-responders and identify treatment outcomes in real-time that help to distinguish success or failure of a therapeutic approach during the course of treatment. This project leverages our recently developed hyperspectral fluorescence microendoscope (HFME) to identify real-time cell-cell interactions and spatial correlations with cancer cell/stromal and cancer/immune cell components in vivo. The current imaging platform offers simultaneous imaging of 5 immune/tumor cell markers. The selected postdoctoral fellows will participate in validating HFME imaging in different in vivo and in vitro tumor models, and photodynamic therapy/immunotherapy combination therapy response monitoring in real time. Further, the fellows will participate in expanding the existing imaging platform to image eight markers. There will be substantial image analysis involved in the project. We anticipate this project will provide a new platform, for multi-dimensional immune/tumor cell dynamics monitoring along with a new treatment paradigm of customizing patient-specific immunotherapy to maximize therapeutic benefits while minimizing associated toxicities.
Project 8: QLED activated kit for infection control to prevent functional disability
(Faculty Mentor: Prof. Tayyaba Hasan, WCP)
Antimicrobial PDT has established efficacy against microorganism infections (including the multidrug resistant ones) in animal models, however, its clinical translation has been hampered by the difficulty of providing illumination. This project aims to develop a flexible and portable light-emitting quilt system to prevent wound colonizing bacteria from progressing to infection and limit concomitant patient disability. Postdoctoral fellows will participate in the following tasks:
1. Prototyping and packaging of a flexible quantum dot light-emitting diode (QLED) which is suitable for use as a wound illuminator.
2. Development of optimal QLED protocols for use in early wound disinfection using an in vitro model of pathogen colonization.
3. Validation of optimal QLED protocols with an excisional wounding mouse model of bacterial infection. The ultimate goal of this project is to promote the broad clinical use of antimicrobial PDT.
For further information regarding Dr. Hasan and her research interests please refer to: http://wellman.massgeneral.org/faculty-hasan-pi.htm and http://wellman.massgeneral.org/faculty-hasan-projects.htm
