Project Application

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. Advances will draw from expertise in physics, mechanical engineering, electrical engineering, and software for image and signal processing.

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


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Project 2: Polarization-sensitive OCT for human coronary assessment.

(Faculty Mentor: Prof. Seemantini Nadkarni, WCP)

The capability to measure collagen architecture in coronary vessels will significantly advance our understanding of the mechanisms of plaque rupture leading to myocardial infarction. In this project, we aim to develop a new imaging tool for intravascular polarimetry that measures collagen architecture as a marker of treatment response, and we apply this new approach to examine the effects of inflammatory inhibition on plaque collagen remodeling in patients. This project is well suited for a postdoctoral fellow with expertise in optical instrumentation and signal processing with an interest in the clinical translation of new imaging technologies.

For further information regarding Dr. Nadkarni and her research interests please refer to: http://wellman.massgeneral.org/faculty-nadkarni-pi.htm


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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.

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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

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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 shear 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 in vivo, including the cornea for improving diagnosis and treatment of degenerative diseases.

For further information regarding Dr. Yun and his research interests please refer to: http://www.intelon.org

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II. In Vivo Microscopy 

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: Multimodality µOCT imaging technologies.

(Faculty Mentor: Prof. Guillermo Tearney, WCP)

Our lab has developed a unique, 1-µm-resolution imaging technology termed µOCT that is capable of visualizing individual cells and subcellular structures, dynamically, in living patients. Studies have shown that µOCT enables four-dimensional (x, y, z, t) imaging of beating respiratory cilia, malignant nuclear morphology, inflammatory cells, fibrin, platelets, endothelial cells, and individual bacteria – all without requiring exogenous contrast. While the unprecedented microscopic µOCT datasets are very powerful and, in many ways, superior to histopathology, complementary molecular and genomic signatures obtained via spectroscopy and fluorescence provide additional, important data that informs pathobiology, diagnosis, and prognosis.  As such, we have projects open to develop and clinically translate new imaging technologies that combine µOCT with fluorescence imaging and spectroscopy. These devices will be designed to address specific clinical applications for diseases ranging from atherosclerosis to cancer.

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Project 2: Spectrally encoded confocal microscopy (SECM) capsules for minimally invasive diagnosis of gastrointestinal inflammatory diseases and cancer.

(Faculty Mentor: Prof. Guillermo Tearney, WCP)

Our laboratory has developed a tethered, swallowable capsule that implements a new, high speed form of in vivo microscopy termed spectrally encoded confocal microscopy (SECM). Once swallowed, the capsule acquires microscopic, confocal images of the entire GI tract. Preliminary data indicates that this capsule can identify and counting inflammatory and cancer cells in patients. The goal of this project is to design, fabricate, and test new SECM imaging capsules that can be used to diagnose inflammatory bowel disease and cancer. Tasks will include the creation of a custom optics and mechanics that reduce the capsule’s diameter and length. Once the devices have been fabricated and tested, pilot clinical imaging studies will be conducted to demonstrate the capability of these devices to be swallowed and obtain high quality images of cells in the gut.

For further information regarding Dr. Tearney and his research interests please refer to: http://www.tearneylab.org

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Project 3: 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.

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Project 4: 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.

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Project 5: Tracking cancer cells in the bone.

(Faculty Mentor: Prof. Charles Lin, WCP)

All blood cells are made from blood stem cells in the bone marrow. Blood cancers such as leukemia and multiple myeloma also originate in the bone marrow. We are developing minimally invasive methods to track cancer cells in the bone, and to track blood stem cells after bone marrow transplantation. More broadly, we are developing methods to characterize the bone marrow microenvironment using a combination of optical and molecular profiling techniques. A related project is to track osteosarcoma cells and especially osteosarcoma stem cells that may be responsible for therapy resistance, recurrence, and metastasis.

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

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Project 6: Assessing cancer heterogeneity.

(Faculty Mentor: Prof. Conor Evans, WCP)

Heterogeneity in cancer is a major obstacle in the development of effective therapies. Heterogeneity exists across genetic, epigenetic, proteomic, cellular, microenvironmental, and tumoral levels in cancer, requiring "multidimensional landscaping" approaches capable of following growth and treatment response spatiotemporally in vitro and in vivo. We are developing optical imaging, ultrasensitive antigen detection, cell identification, and cell capture methods that will to probe the emergence and mechanisms of treatment resistance and identify potential therapeutic targets.

For further information regarding Dr. Evans and his research interests please refer to: http://wellman.massgeneral.org/faculty-evans-pi.htm and http://wellman.massgeneral.org/faculty-evans-projects.htm

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Project 7: Brillouin microscopy.

(Faculty Mentor: Prof. S. H. Andy Yun, WCP)

Brillouin microscopy is a novel modality originated from WCP, which 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

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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 lab that can measure a patient’s coagulation status within 5 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 highly motivated post-doctoral fellow 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

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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.

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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.


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Project 4: Multiplex laser particles for spatially resolved 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.

For further information regarding Dr. Yun and his research interests please refer to: http://www.intelon.org

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Project 5: Optical microneedle arrays for point-of-care diagnosis.

(Faculty Mentor: Prof. Mei X. Wu, WCP)

Hemoglobin-specific absorbance of light can alter the permeability of capillaries beneath the skin specifically and locally, resulting in extravasation and accumulation of blood biomarkers within a small area of the skin involved by 1,000~10,000-fold without injuring 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 can be 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.
 
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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 source will be investigated for accelerating platelet regeneration 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.

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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 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 3D in vitro models that integrate stromal cells and physical forces such as flow. These models will be used to evaluate treatments and drug delivery strategies for cancer, including rationally-designed combinations and targeted multi-agent nanocarriers. Following treatment, the in vitro tumors will be imaged to assess cell death and to characterize delivery and uptake of the agents. The outcome of these studies will be developing biologically relevant models and a platform for rapid image based screening of therapeutic agents.

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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 pro-survival signaling during various modes of treatment in mouse cancer models. Our goal is to determine both the key time points and spatial localizations of the 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 validating molecular imaging using the hyperspectral fluorescence microendoscope, including: GPU programming, video-rate image analysis and biological assays. 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.

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Project 3: Multi-inhibitor nanoconstructs for Cancer Therapeutics combination treatment. 

(Faculty Mentor: Prof. Tayyaba Hasan, WCP)

The multiple inhibitors include a photosensitizer, a chemotherapy agent or a receptor tyrosine kinase inhibitor. Postdoctoral fellows will learn the synthesis, physical characterization and optimization of tumor-targeted, photo-activatable nanoconstructs that can co-deliver multiple inhibitors without pre-mixing the agents. The anticipated outcome of these studies will be technology development for fabricating multi-inhibitor agents and evaluating their efficacy in-vitro and in-vivo.

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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. On the oral cancer project, the goals 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 at 6-12 months. Postdoctoral fellows will work on image guided treatments for oral cancer.

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Project 5: Dual function theranostic constructs for photoacoustic guided surgery and photodynamic therapy.

Survival rates in patients with oral cavity tumors have remained nearly stagnant in the past decade with exceptional morbidity e.g., tongue cancers. The goal of this project is to develop, for the first time, a single theranostic agent namely targeted Dual Function Antibody Conjugate (DFAC) amenable to 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 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) napthalocyanine 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 multi-skill requiring project and the postdoctoral fellow will work on aspects that are most aligned with training and interests.  For example, for chemistry/biology training, 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 more 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.

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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. This work is ongoing with clinical samples in Thailand. Postdoctoral fellow will be involved in developing chemistries for cleavable probes and evaluating in a broad spectrum of bacteria.

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Project 7: Exploiting the Malaria parasite’s intrinsic behavior for killing: photosensitizer synthesis via parasite dependent nutrient acquisition pathways.

(Faculty Mentor: Prof. Tayyaba Hasan, WCP)

Malaria is caused by intracellular protozoa of the Plasmodium genus. Among the five species that infect humans Plasmodium falciparum (P. falciparum) is the most lethal. Primarily transmitted by the bite of an infected female Anopheles mosquito, the protozoa first target the liver before spreading through the blood stream to invade red blood cells (erythrocytes). To this end, a logical, but resource-intensive technique involves the direct removal of the parasitized red blood cells with exchange transfusions. This procedure also carries the risk of blood-born infection. However, these problems would be obviated if the patient's blood itself were used for the transfusion. Postdoctoral fellow will be involved in two potential sub projects on this study:

  1. Commercially available sheep RBCs will be infected with P. falciparum in vitro and incubated with ALA to determine the kinetics of PPIX production. This information will be used to inform the timing of light administration post ALA administration. To optimize the application of light, a matrix of PDT conditions (light intensity and duration) will be studied for efficacy against parasite growth.
  2. Using the optimal set of parameter from Aim 1, a flow chamber for PDT light application suitable for integration into commercial apheresis systems will be designed. Proof of principle measurements will be made using the red blood cell fraction from commercially available sources and syringe pumps to simulate apheresis output.

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

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