To address the increasing costs and time for drug development and poor translation of many pre-clinical models, engineered human “organs on a chip” are increasingly successful in recapitulating organ functions in vitro for modeling homeostasis and pathophysiology. Our team has developed a bioengineered multi-tissue platform in which human organ models are integrated via microfluidic vascular perfusion. In contrast to traditional “organ-on-a-chip” systems, which use multicellular co-cultures in microfluidic chambers, our group is functionally maturing millimeter-scale tissues and integrating sets of tissues by vascular perfusion, with selectively permeable endothelial barriers separating the intratissue and vascular regions. Through our engineered integrated platform, we have validated maintenance of tissue maturation over extended culture periods (4+ weeks; liver, heart, skin, bone, vasculature) and modeled drug toxicity in all-human engineered tissues. Through this work, I was exposed to a number of applications for multi-organ-on-a-chip systems, including drug toxicity and cancer metastasis, showing the breadth of such technologies for studying systemic human conditions.

I have led the application of these technologies towards studying multi-organ systemic radiation injury, especially in the cases of deep space radiation. In addition, I have led a team to scale up such model systems for dissemination to collaborators and the broader scientific community; the most prominent example of this work is the paralleled studies of integrating bone marrow, vasculature, and cardiac muscle tissues (at Columbia) and bone marrow, vasculature, and brain organoid tissues (at Baylor College of Medicine). Through this project funded by NASA, FDA, NIH, and BARDA, we have expanded our tissue inventory and culture lengths, applying 6-month-long culture regimens to our engineered tissue models.

Cosmic radiation is one of the most serious “red risks” encountered during long missions to the Moon and Mars. To develop measures for radiation protection during extended space travel, there is a critical need to understand the chronic effects of radiation on human organ functions. 

With support from NASA and the Translational Institute for Space Health Research (TRISH), I applied our engineered human tissue models and multi-organ platform to study effects of cosmic radiation during space travel to protect astronauts in long-range, deep space missions. As the lead researcher on this project, funded first by TRISH and subsequently by other means from NASA, we have studied the effects of photon (similar to cancer treatment) and neutron (spaceflight) radiation on engineered bone marrow, liver, vasculature, and cardiac muscle models. Through this work, we visualized myeloid skewing of the hematopoietic niche via single cell transcriptomics and cardiac fibrosis in response to neutrons. In addition, in collaboration with the Kam Leong group at Columbia, we have developed radioprotective measures to mitigate long-term radiation damage for astronauts. 

During my postdoctoral work, I continued to support this project by conducting two major, multi-institutional experiments at NASA's Space Radiation Lab at Brookhaven National Labs on Long Island, NY. 

The human bone marrow (BM) is one of the most complex and critical tissues in the adult, functioning as the site for blood and immune cell production in homeostasis, injury, and disease. The marrow acts as an incredibly diverse stem cell niche, containing stromal and blood cells that help support the maintenance and differentiation capacity of hematopoietic stem and progenitor cells (HSPCs). The cell-cell and cell-matrix interactions within the niche help trigger blood cell production in response to injury, and to harbor downstream changes that may persist in the hematopoietic system during disease, such as in cancer metastasis or leukemias. As the development of human organs-on-a-chip (OoC) platforms has emerged over the past decade, there has been an increased relevance of using human BM models to study human- and patient-specific immune interactions in vitro. 

In my time at the EPFL in Switzerland (August 2017-2018), I worked under Dr. Olaia Naveiras in the Lab of Regenerative Hematopoiesis to engineer a 3D, injectable BM niche using collagen-coated carboxymethocellulose scaffolds in a murine stromal co-culture system to support HSPCs in vitro. Our engineered BM maintained HSPCs in vitro without exogenous cytokines for two weeks and maintained hematopoiesis for up to 12 weeks following subcutaneous injection in vivo. 

In line with our engineered multi-OOC platform and my previous experience at EPFL studying hematopoiesis, during my doctoral work I proposed to develop a human, multicellular BM model in the Vunjak-Novakovic lab from both primary cells and iPSCs. We have applied this BM model to study healthy hematopoiesis, injury response, and various blood disorders. Thus far, we have applied the engineered BM model to study myeloid skewing in early colonization in metastatic breast cancer. Ongoing work is continuing to apply this engineered BM model to studies of acute myoid and lymphoblastic leukemia in vitro.

In adults, macrophages are often produced by BM-derived circulating monocytes, which are important components of hematopoiesis. In primitive hematopoiesis in the developing embryo, macrophages are produced as tissue-resident immune cells, remaining within a tissue throughout a human’s lifetime and acting as clearing agents to remodel a tissue. These cells can further specialize, for example becoming microglia in the brain or Kupffer cells in the liver. 

I'm interested in using iPSC-derived macrophages for modeling multiple physiological processes, including modeling of immune responses in ECM interactions of patients with cystic fibrosis (CF), as well as modeling hormonal and sex-specific differences in iPSC-derived macrophages. In addition, we have also applied iPSC-derived macrophages for studying tissue-resident immune populations of the cardiac muscle and osteoclasts in the bone microenvironments.