Our research program focuses on the design and implementation of extracellular matrix-inspired hydrogel biomaterials for the biofabrication of tissue and tumor organoids, organ-on-a-chip systems, and cancer-on-a-chip systems for drug screening, disease modeling, and personalized medicine. Our team’s work has broad applicability across tissue types and diseases but has focused primarily in development of cancer models and recently neural models. Our biomaterial systems are largely hyaluronic acid-based with additional custom ECM component addons, synthetically modified in the lab. These are often combined with microfluidic devices for fluid handling capabilities. In particular, we have a significant interest in patient biospecimen-derived models that can facilitate and improve current precision medicine and precision oncology efforts in the clinic.
Glioblastoma subtype evolution in patient-derived glioblastoma tumor organoids
Glioblastoma (GBM) is a lethal, incurable form of cancer in the brain that universally recurs more aggressively even with maximally aggressive surgery followed by chemoradiotherapy. These tumors are extremely heterogenous with regions of genetically distinct subclones that evolve differently over time and in response to treatments making designing effective therapies for each individual patient difficult. Here are using GBL cell lines and a patient-specific ex vivo tumor-on-a-chip system to analyze tumor heterogeneity and drift over time to predict clonal evolution for patients, which could subsequently have substantial impact on treatment decisions.
Personalized drug screening in patient-derived tumor organoids
Our team has developed a technology portfolio comprised of a range of bioengineered 3D tissue and tumor models, which in the last several years has expanded to include tumor organoids created from patient tumor biospecimens. These patient-derived tumor organoids (PTOs) fill a critical experimental gap, facilitating screening studies that can provide patient-specific empirical data to better predict a patient’s drug response, and that addresses the heterogeneity between patients and individual tumors. We combine organ micro-engineering with microfluidics, and PTOs formed to generate tumor-on-a-chip (TOC) systems. To date, the lab has created PTOs from a range of tumor types, including colorectal, appendiceal, lung, melanoma, myeloma, glioma, ovarian, and mesothelioma tumors.
Immune-enhanced organoids for immunotherapy screening in vitro
Reconstructing the patient’s own tumor in the form of patient derived tumor organoids (PTOs) recapitulates the tumor microenvironment by incorporating tumor cells along with associated stroma and tumor infiltrating leucocytes (TILs). Due to the variable infiltration of tumors by (TILs) with inconsistent functional status, PTOs were thought as not being suitable to recapitulate the complex interactions between tumors and the patient’s own immune system. To address this limitation, we have conceived of mixing lymph node-derived cells and tumor-derived cells from the same patient creating personalized tumor/node organoids, allowing for individual patient tumor and stroma and immune system to remain viable and operational, recapitulating the interaction between host patient and its own tumor. Importantly, these immune-enhanced organoids allow for successful screening of immunotherapy agent such as immune checkpoint blockade therapies.
Metastatic disease remains one of the primary reasons for cancer-related deaths, yet the majority of in vitro cancer models focus on the primary tumor sites. Our lab has developed a series of metastasis-on-a-chip devices that house multiple bioengineered three-dimensional (3D) organoids, established by a 3D photopatterning technique employing extracellular matrix-derived hydrogel biomaterials. Specifically, cancer cells begin in primary site organoid, which resides in a single microfluidic chamber connected to multiple downstream chambers in which other target site organoids such as liver, lung, endothelial constructs, or other tissue types are housed. Under recirculating fluid flow, tumor cells grow in the primary site, eventually enter circulation, and can be tracked via fluorescent imaging. Studies on this platform can be implemented to better understand the mechanisms underlying metastasis, perhaps resulting in the identification of targets for intervention.
Neurovascular unit (NVU)-on-a-chip
Our group is working on establishing a more advanced NVU within a microfluidic device, complete with a functional BBB. These models will allow for the direct study of BBB mass transport, effects of fluid flow, shear stress and pressure, and systemic versus direct-to-brain drug delivery in both normal and diseased states.
Extracellular matrix bioinks for 3D bioprinting
3D bioprinting has advanced rapidly since its inception, particularly with respect to hardware platforms, yet much less attention has been paid to understanding the interactions between the biomaterials, or bioinks, with the hardware and the cells beyond simple viability metrics. Unfortunately, most researchers employ outdated biomaterials that were never designed to be compatible with the dynamic events encountered during bioprinting. As a result, there is a need for novel biomaterials with more advanced, stimuli-responsive mechanical properties that will be simple to implement in a variety of bioprinter platforms, thus enabling acceleration of technologies that will drive biomanufacturing of replacement tissue products for patients.