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.

No abstract

Vascular endothelial cells are known to respond to a range of biochemical and time-varying mechanical cues that can promote blood vessel sprouting termed angiogenesis. It is less understood how these cells respond to sustained (i.e., static) mechanical cues such as the deformation generated by other contractile vascular cells, cues which can change with age and disease state. Here we demonstrate that static tensile strain of 10%, consistent with that exerted by contractile microvascular pericytes, can directly and rapidly induce cell cycle re-entry in growth-arrested microvascular endothelial cell monolayers. S-phase entry in response to this strain correlates with absence of nuclear p27, a cyclin-dependent kinase inhibitor. Further, this modest strain promotes sprouting of endothelial cells, suggesting a novel mechanical “angiogenic switch.” These findings suggest that static tensile strain can directly stimulate pathological angiogenesis, implying that pericyte absence or death is not necessarily required of endothelial cell re-activation.

No abstract

Objective Fetal cartilage anlage provides a framework for endochondral ossification and organization into articular cartilage. We previously reported differences between mechanical properties of talar cartilage anlagen and adult articular cartilage. However, the underlying development-associated changes remain to be established. Delineation of the normal evolvement of mechanical properties and its associated compositional basis provides insight into the natural mechanisms of cartilage maturation. Our goal was to address this issue. Materials and methods Human fetal cartilage anlagen were harvested from the tali of normal stillborn fetuses from 20 to 36 weeks of gestational age. Data obtained from stress relaxation experiments conducted under confined and unconfined compression configurations were processed to derive the compressive mechanical properties. The compressive mechanical properties were extracted from a linear fit to the equilibrium response in unconfined compression, and by using the nonlinear biphasic theory to fit to the experimental data from the confined compression experiment, both in stress-relaxation. The molecular composition was obtained using FTIR, and spatial maps of tissue contents per dry weight were created using FTIR imaging. Correlative and regression analyses were performed to identify relationships between the mechanical properties and age, compositional properties and age, and mechanical versus compositional parameters. Results All of the compositional quantities and the mechanical properties excluding the Poisson’s ratio changed with maturation. Stiffness increased by a factor of ~2.5 and permeability decreased by 20% over the period studied. Collagen content and degree of collagen integrity increased with age by ~3-fold, while the proteoglycan content decreased by 18%. Significant relations were found between the mechanical and compositional properties. Conclusion The mechanics of fetal talar cartilage is related to its composition, where the collagen and proteoglycan network play a prominent role. An understanding of the mechanisms of early cartilage maturation could provide a framework to guide tissue-engineering strategies.