Soft Tissue Engineering Laboratory
About the Soft Tissue Engineering Lab
A major challenge of tissue engineering is to build three-dimensional (3D) in vitro models for studying tissue physiology and pathology. 3D in vitro models are the bridge between conventional two-dimensional (2D) tissue culture, which does not capture the complexity of human tissue, and animal models, which are costly, time consuming and raise ethical concerns.
One area in which 3D models are underrepresented but where they can have an immediate impact is the development of platforms for toxicology screening. Such models have the potential to address the growing concerns about drug failures in clinical trials due to lack of efficacy or unexpected side effects. Further, they can play a role in preventive medicine by answering the urgent need for efficient platforms enabling the screening of the plethora of environmental hazards linked to incidences of diseases such as cancer.
The goal of our lab is to engineer and characterize synthetic biomaterials, in order to provide a complete toolbox for building 3D in vitro models as platforms for toxicology screening and for the study of disease progression. Our current focus is on models of solid tumors as well as models to study neurotoxicity, a side effect associated with chemotherapy. In addition, we actively seek to apply our work towards other disease systems and congruous research areas such as biosensors and drug delivery.
- Contact lead coordinator, Dr. Silviya Zustiak
Decoupling key cell-matrix interactions that affect cancer cell responsiveness to anticancer drugs in bioengineered 2D extracellular matrix
The overall goal of this project is to gain a fundamental grasp of key cell-matrix interactions that affect the cells’ responsiveness to anticancer drugs, with emphasis on matrix stiffness, integrin adhesions and their synergistic effects, since these parameters profoundly affect cancer cell fate including the onset of malignancy. The underlying hypothesis for this work is that matrix stiffness and integrin presentation are also important in drug resistance mechanisms (e.g. by altering cytoskeletal tension or integrin expression).
- Role of matrix stiffness on cancer cell responsiveness to anticancer drugs. For this project, we are performing methodical and quantitative analysis of the impact of substrate stiffness on anticancer drug cytotoxicity. We use polyacrylamide (PA) gels that span a range of stiffness (0.3 to 300 kPa), coated with extracellular matrix (ECM) proteins to promote cell attachment. High-throughput assays are being developed. Gel stiffness is measured by rheometry and by atomic force microscopy (AFM). Various cancer cell types are subjected to treatment with different concentrations of anticancer drugs for a pre-determined amount of time. We then quantitatively measure cell fate including cell viability, proliferation, morphology, apoptosis, signaling, cell cycle as well as drug IC50.
- Role of integrin adhesions on cancer cell responsiveness to anticancer drugs. The aim of this project is to isolate the effect of integrin presentation (by precisely controlling the concentration and type of integrin binding sites) from other matrix properties (such as stiffness) and assess its impact on the responsiveness of cancer cells to anticancer drugs. In this project, we use methods, drugs, and cell types similar to those indicated above, and we quantify similar outputs. In addition, we explore the synergistic effects of ligand density and substrate stiffness.
- Role of 3D environment in the evaluation of anticancer drug sensitivity
Despite overwhelming evidence on the impact of the microenvironment on tumorogenesis and drug resistance, over 85% of tumor research is still conducted on 2D plastic, mainly due to lack of suitable biomaterial-based alternatives. This project utilizes biomaterial scaffolds for elucidating cell-matrix interactions as related to drug toxicity in 3D environments. We methodically investigate cell responses such as viability, proliferation, apoptosis, cell cycle, and cell signaling to various microenvironmental conditions such as matrix stiffness, porosity, and adhesion sites. Specific mechanisms responsible for drug sensitivity in 3D versus 2D environments are investigated.