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Singh Lab Research Areas

IMMUNO-ENGINEERING

Engineered Immune Organoids

Immuno-engineering of biomaterials at micro-and-nanometer scale can exploit the intrinsic biological and mechanical cues in human body to directly modulate and train the immune cells. Our work has led to the development of a first artificial immune tissue that can produce antibodies at controlled rates, outside of the body, via germinal center-like process. The ability to drive immune reactions ex vivo could grant scientists the ability to reproduce immunological events with tunable parameters for (1). mechanistic understanding of poorly understood B cell development; (2) Advance rapid development of large number of activated B cells; (3). Facilitate rational screening of immunotherapeutics, and (4) Determine immune toxicity of therapeutics and environment factors. We anticipate that the organoid could also help researchers design immunotherapeutics and vaccines against HIV, Zika, and other infectious diseases. This research was published in the journal Biomaterials, highlighted as Top 100 discoveries of 2015 by the Discover Magazine and recently received the 2015 Biomaterials Outstanding Paper Award from Elsevier

See Cornell Chronicle: http://news.cornell.edu/stories/2015/06/engineers-synthetic-immune-organ-produces-antibodies

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Figure: Ex vivo 3D bioengineered immune organoids induce rapid differentiation of naive B cells into germinal center-like phenotype (green marker) within 4 days and at ~ 100-fold faster rate than conventional ex vivo immunology approaches. 

Engineered Lymphoma Cancer Organoids and Microscale Technologies

Our research focus has been on understanding the role of lymphoid tumor microenvironment in B and T cell lymphomas and developing innovating biomaterials-based platform technologies to determine tumor heterogeneity and causes of  drug resistance in lymphoma patients. We apply concepts of tissue mechanics, tissue bio-adhesivity, and fluid mechanics integrated with cancer cell biology to engineer platform technologies that enable fundamental discoveries in cancers biology and rational translation of therapeutics. Our recent findings with collaborators at Weill Cornell Medical College, published in Blood, demonstrated the role of integrin signaling in patient-derived T cell lymphoma survival and progression, in vitro and vivo. In a parallel study published in Biomaterials, we have provided evidence that integrins are critical for the growth, clustering, BCR activity, and chemo-resistance of activated B cell-like Diffuse Large B cell lymphoma (ABC-DLBCL), which are the most chemo-resistant lymphomas (5-year overall survival ~ 30%). These biological discoveries led to the development of the first 3D lymphoma organoids (hydrogels) that presented lymphoma-specific integrin ligands to ABC-DLBCL and induced enhanced proliferation, cell signaling, and drug resistant. 

See Cornell Chronicle: http://www.news.cornell.edu/stories/2015/10/3-d-organoids-allow-tests-lymphoma-treatments

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Figure: B cell lymphomas grow in bulk and micro organoids as clusters, similar to those in patients. The green fluorescent areas represent lymphoma cells

Nanogels for modulating immunity and safer cancer immunotherapy

Tumors and pathogens causing chronic infections have the unique ability to evade or manipulate our immune system. Current immunotherapy approaches often result in partial immunity that predisposes the patient to a risk of reinfection or serious toxicity issues. In Singh Lab, we focus on understanding the immunology behind tumors and infections, mechanism of tumor development, and develop immune-engineering strategies using engineered biomaterials, biomolecules, and robust quantitative analysis. In a recent study published in Advanced Healthcare Materials, we engineered a self-assembly protein-biomaterial nanogel system for inducing robust immunity at low protein doses. Soluble antigen-based cancer vaccines have poor retention in tissues along with suboptimal antigen processing by dendritic cells. Multiple booster doses are often needed, leading to dose-limiting systemic toxicity. A versatile, immunomodulatory, self-assembly protein nanogel vaccine is reported that induces robust immune cell response at lower antigen doses than soluble antigens, an important step towards biomaterials-based safer immunotherapy approaches.

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ENGINEERING HUMAN STEM CELLS AND MECHANOBIOLOGY

Human Stem Cells: Understanding cell reprogramming, differentiation, and engineering stem cells for therapeutic applications

Stem cells represent a highly promising strategy to produce autologous, patient-specific cell sources for numerous therapeutic approaches as well as novel models of human development and disease. Pluripotent stem cells such as iPS and embryonic stem cells have the ability form nearly any cell in the body. Multipotent stem cells, on the other hand, progress into a family of closely related cells. Example: Mesenchymal cells can form bone cells and cartilage cells, but have less potential to form a neural cell. Singh Lab is interested in understanding the process of stem cell differentiation and cellular reprogramming (conversion from one state to another, such as adult to pluripotent). Singh Lab is interested in developing technologies that are relevant to both pluripotent and adult stem cells of the animal and human origin with focus on microenvironment control, stem cell bioprocessing, and tissue engineering applications. We achieve this by working at the interface of mechanical forces in cells, biomaterials, and microfluidics.

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Cell Matrix Interactions and Mechanobiology

Mechanical responses of human body and its cells to applied mechanical stress, chemical and physical stimulus are essential for tissue functions and cells biologically respond to the applied signals through changes in shape, adhesion, migration, and biochemical composition. For example, mechanical signals are key modulators of cartilage regeneration, cancer invasion and biofluid shear mediated lymphatic contractions. Singh Lab's interests center on understanding the role of cell biomechanics and signaling in human development and disease progression through application of innovative bioengineering approaches such nanopatterning of proteins.  

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