Summary Invadopodia are actin-rich subcellular protrusions with associated proteases used by cancer cells to degrade extracellular matrix (ECM) [1]. Molecular components of invadopodia include branched actin assembly proteins, membrane trafficking proteins, signaling proteins and transmembrane proteinases[1]. Similar structures exist in nontransformed cells, such as osteoclasts and dendritic cells, but are generally called podosomes and are thought to be more involved in cell-matrix adhesion than invadopodia [2–4]. Despite intimate contact with their ECM substrates, it is unknown whether physical or chemical ECM signals regulate invadopodia function. Here, we report that ECM rigidity directly increases both the number and activity of invadopodia. Transduction of ECM rigidity signals depends on the cellular contractile apparatus [5–7], as inhibition of nonmuscle myosin II, myosin light chain kinase, and Rho kinase all abrogate invadopodia-associated ECM degradation. Whereas myosin IIA, IIB, and phosphorylated myosin light chain do not localize to invadopodia puncta, active phosphorylated forms of the mechanosensing proteins p130Cas (Cas) and focal adhesion kinase (FAK) are present in actively degrading invadopodia and the levels of phospho-Cas and phospho-FAK in invadopodia are sensitive to myosin inhibitors. Overexpression of Cas or FAK further enhances invadopodia activity in cells plated on rigid polyacrylamide substrates. Thus, in invasive cells, ECM rigidity signals lead to increased matrix-degrading activity at invadopodia, via a myosin II-FAK/Cas pathway. These data suggest a potential mechanism, via invadopodia, for the reported correlation of tissue density with cancer aggressiveness.

Biostable polyurethanes (PURs) have been incorporated in biomedical devices since the 1960s. The mechanisms of degradation and compositions with improved in vivo biostability have been investigated extensively. In recent years, biodegradable PURs have been investigated for applications in regenerative medicine. In contrast to the biostable implants, these biomaterials are designed to undergo controlled degradation in vivo and promote ingrowth of new tissue. Tissue-engineered scaffolds have been fabricated from biodegradable PURs using a variety of techniques, including thermally induced phase separation, salt leaching, wet spinning, electrospinning, and carbon dioxide foaming. These materials have been reported to support the ingrowth of cells and tissue in vitro and in vivo, and undergo controlled degradation to noncytotoxic decomposition products. Due to their tunable biological, mechanical, and physicochemical properties, biodegradable PURs present compelling future opportunities as scaffolds for regeneration of tissue. This review article summarizes recent advances made in the synthesis of biodegradable PURs and the application of these materials as scaffolds for regenerative medicine.

Effective strategies to guide cell alignment and the deposition of an oriented extracellular matrix are critical for the development of anisotropic engineered tissues suitable for the repair of ligament defects. Electrospinning is a promising means to create meshes that can align adherent cells, but the effect of fiber mesh architecture on differentiation has not been examined closely. Therefore, the goal of this study was to determine the effect of fiber diameter and the degree of fiber alignment on mesenchymal progenitor cell morphology, proliferation, and ligament gene expression. Specifically, a poly(ester urethane)urea elastomer was electrospun onto rigid supports under conditions designed to independently vary the mean fiber diameter (from 0.28 to 2.3 microm) and the degree of fiber alignment. Bone marrow stromal cells--seeded onto supported meshes--adhered to and proliferated on all surfaces. Cells assumed a more spindle-shaped morphology with increasing fiber diameter and degree of fiber alignment, and oriented parallel to fibers on aligned meshes. Expression of the ligament markers collagen 1alpha1, decorin, and tenomodulin appeared to be sensitive to fiber diameter and greatest on the smallest fibers. Concurrently, expression of the transcription factor scleraxis appeared to decrease with increasing fiber alignment. These results suggest that the formation of a ligament-like tissue on electrospun scaffolds is enhanced when the scaffolds consist of aligned submicron fibers.

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