We couple collocated isogeometric boundary element methods and unstructured analysissuitable T-spline surfaces for linear elastostatic problems. We extend the definition of analysis-suitable T-splines to encompass unstructured control grids (unstructured meshes) and develop basis functions which are smooth (rational) polynomials defined in terms of the Bézier extraction framework and which pass standard patch tests. We then develop a collocation procedure which correctly accounts for sharp edges and corners, extraordinary points, and T-junctions. This approach is applied to several three-dimensional problems, including a real-world T-spline model of a propeller. We believe this work clearly illustrates the power of combining new analysis-suitable computer aided design technologies with established analysis methodologies, in this case, the boundary element method.

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We have previously demonstrated that transforming growth factor-beta1 (TGF-beta1)-mediated fibroblast-myofibroblast differentiation is associated with accumulation of a hyaluronan (HA) pericellular coat. The current study demonstrates failure of fibroblast-myofibroblast differentiation associated with in vitro aging. This is associated with attenuation of numerous TGF-beta1-dependent responses, including HA synthesis and induction of the HA synthase enzyme HAS2 and the hyaladherin tumor necrosis factor-alpha-stimulated gene 6 (TSG-6), which led to an age-related defect in pericellular HA coat assembly. Inhibition of HAS2-dependent HA synthesis by gene silencing, removal of the HA coat by hyaluronidase digestion, or gene silencing of TSG-6 or cell surface receptor CD44 led to abrogation of TGF-beta1-dependent induction of alpha-smooth muscle actin in "young" cells. This result supports the importance of HAS2-dependent HA synthesis and the HA coat during phenotypic activation. Interleukin-1beta stimulation, however, failed to promote phenotypic conversion despite coat formation. A return to basal levels of HA synthesis in aged cells by HAS2 overexpression restored TGF-beta1-dependent induction of TSG-6 and pericellular HA coat assembly. However, this did not lead to the acquisition of a myofibroblast phenotype. Coordinated induction of HAS2 and TSG-6 facilitation of pericellular HA coat assembly is necessary for TGF-beta1-dependent activation of fibroblasts, and both components of this response are impaired with in vitro aging. In conclusion, the HA pericellular coat is integral but not sufficient to correct for the age-dependent defect in phenotypic conversion.

Fibroblast differentiation into myofibroblasts is a key event during normal wound repair. We have previously demonstrated an age-related defect in this process associated with impaired synthesis of hyaluronan (HA) synthase (HAS) 2 but failed to prescribe its role in a mechanistic sense. Here we demonstrate that in addition to HAS2 , there is loss of EGF receptor (EGF-R) in aged cells , and both are required for normal fibroblast functionality. Analysis of molecular events revealed that in young cells , transforming growth factor (TGF)-␤1-dependent phenotypic activation uses two distinct but cooperating pathways that involve TGF-␤ receptor/Smad2 activation and EGFmediated EGF-R/extracellular signal-regulated kinase (ERK) 1/2 signaling , and the latter is compromised with in vitro aging. Pharmacological inhibition of any of the five intermediates (TGF-␤ receptor , Smad2, EGF , EGF-R , and ERK1/2) attenuated TGF-␤1 induction of ␣-smooth muscle actin. We present evidence that the HA receptor CD44 co-immunoprecipitates with EGF-R after activation by TGF-␤1. This interaction is HA-dependent because disruption of HA synthesis abrogates this association and inhibits subsequent ERK1/2 signaling. In aged fibroblasts , this association is lost with resultant suppression of ERK1/2 activation. Forced overexpression of EGF-R and HAS2 in aged cells restored TGF-␤1-mediated HA-CD44/EGF-R association and ␣-smooth muscle actin induction. Taken together , these results demonstrate that HA can serve as a signal integrator by facilitating TGF-␤1-mediated CD44-EGF-R-ERK interactions and ultimately fibroblast phenotype. We propose a model to explain this novel mechanism and the functional consequence of age-dependent dysregulation.