Engineered in vitro disease models.

The ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics. Although great advances have been made in terms of developing disease models in animals, such as transgenic mice, many of these models fail to faithfully recapitulate the human condition. In addition, it is difficult to identify critical cellular and molecular contributors to disease or to vary them independently in whole-animal models. This challenge has attracted the interest of engineers, who have begun to collaborate with biologists to leverage recent advances in tissue engineering and microfabrication to develop novel in vitro models of disease. As these models are synthetic systems, specific molecular factors and individual cell types, including parenchymal cells, vascular cells, and immune cells, can be varied independently while simultaneously measuring system-level responses in real time. In this article, we provide some examples of these efforts, including engineered models of diseases of the heart, lung, intestine, liver, kidney, cartilage, skin and vascular, endocrine, musculoskeletal, and nervous systems, as well as models of infectious diseases and cancer. We also describe how engineered in vitro models can be combined with human inducible pluripotent stem cells to enable new insights into a broad variety of disease mechanisms, as well as provide a test bed for screening new therapies.

Tunable mechanical behavior of synthetic organogels as biofidelic tissue simulants.

Solvent-swollen polymer gels can be utilized as mechanical simulants of biological tissues to evaluate protective systems and assess injury mechanisms. However, a key challenge in this application of synthetic materials is mimicking the rate-dependent mechanical response of complex biological tissues. Here, we characterize the mechanical behavior of tissue simulant gel candidates comprising a chemically crosslinked polydimethylsiloxane (PDMS) network loaded with a non-reactive PDMS solvent, and compare this response with that of tissue from murine heart and liver under comparable loading conditions. We first survey the rheological properties of a library of tissue simulant candidates to investigate the effects of solvent loading percentage, reactive functional group stoichiometry, and solvent molecular weight. We then quantify the impact resistance, energy dissipation capacities, and energy dissipation rates via impact indentation for the tissue simulant candidates, as well as for the murine heart and liver. We demonstrate that by tuning these variables the silicone gels can be engineered to match the impact response of biological tissues. These experiments inform the design principles required for synthetic polymer gels that are optimized to predict the response of specific biological tissues to impact loading, providing insight for further tuning of this gel system to match the impact response of other "soft tissues".

Mechanical properties of human fetal talus.

Mechanical characterization of human cartilage anlagen is required to effectively model congenital musculoskeletal deformities. Such modeling can effectively explore the effect of treatment procedures and potentially suggest enhanced treatment methods. Using serial MRI, we have noted shape changes of the cartilaginous hindfoot anlagen in patients with clubfoot, suggesting they are soft and deformable. We therefore determined the stress relaxation behavior of cartilage plugs obtained from third-trimester stillborn fetuses in unconfined and confined compression geometries. The material parameters determined were the aggregate modulus H(A) = 0.15 +/- 0.07 MPa, Poisson's ratio nu = 0.4 +/- 0.06, Young's modulus E(s) = 0.06 +/- 0.03 MPa, and permeability coefficients k(0) = 2.01 +/- 0.8 x 10(-14) m(4) N(-1) s(-1) and M = 4.6 +/- 1.0. As compared with adult articular cartilage, stiffness was an order of magnitude lower than the values reported in the literature, suggesting the relative softness of the tissue, and the permeability was an order of magnitude higher, indicating relative ease of flow in the tissue. Poisson's ratio also was close to the higher end of the range reported in previous studies. Such material is expected to deform and relax to larger extents. These findings are consistent with the deformability of the cartilage anlagen during manipulation and casting for treatment of clubfoot.