The role of actively released fibrin-conjugated VEGF for VEGF receptor 2 gene activation and the enhancement of angiogenesis.

A major challenge for therapeutic delivery of angiogenic agents such as vascular endothelial growth factor (VEGF) is to achieve sustained, low dose signaling leading to durable neovessel formation. To this end, we recently created a variant of VEGF(121), TG-VEGF(121) that directly binds to fibrin and gets released locally in proteolysis-triggered manner. Here we combined noninvasive biophotonic monitoring of VEGF receptor 2 gene activation in transgenic VEGFR2-luc mice and histomorphometry to compare endothelial activation and long-term neovascularization by actively released TG-VEGF(121)versus passively released, diffusible wild-type VEGF(121) in subcutaneous fibrin implants.

A novel, tissue occlusive poly(ethylene glycol) hydrogel material.

The use of guided bone regeneration (GBR) techniques requires new materials meeting the needs of clinical application. Design criteria for GBR devices are biocompatibility, tissue occlusion, space provision, and clinical manageability. This study evaluates a novel biodegradable poly (ethylene glycol) (PEG) based material as tissue occlusive membrane.

Part II: Fibroblasts preferentially migrate in the direction of principal strain.

A growing body of evidence suggests that the sensory information from the cytoskeleton and integrins may be responsible for guiding migration during mechano- and haptotaxis. However, the dual function of these subcellular structures as mechano-sensors and -actuators is only partially understood. Using a new cell chamber described in the preceding companion paper (Ref to part I, Raeber et al.

Mechanisms of 3-D migration and matrix remodeling of fibroblasts within artificial ECMs.

The elucidation of molecular cell-extracellular matrix (ECM) interactions regulating tissue dynamics necessitates straightforward model systems that can dissect the associated physiological complexity into a smaller number of distinct interactions. Here we employ a previously developed artificial ECM model system to study dynamic cell-matrix interactions involved in proteolytic three-dimensional (3-D) migration and matrix remodeling at the level of single cells. Quantitative time-lapse microscopy of primary human fibroblasts exposed to exogenous physiological matrix metalloproteinase (MMP) inhibitors revealed that 3-D migration is dependent on cell seeding density and occurred via highly localized MMP- and tissue inhibitor of metalloproteinases-2-dependent processes.

Part I: A novel in-vitro system for simultaneous mechanical stimulation and time-lapse microscopy in 3D.

To investigate the migration response of cells to changes in their biophysical environment, a novel uniaxial cell stimulation device (UCSD) has been designed and tested. The device is capable of applying very precise user-defined static or dynamic mechanical stimuli in a physiologically relevant strain window (up to 50%) and frequency bandwidth (up to 2 Hz) to cells residing in a three-dimensional (3D) environment while single-cell migration is simultaneously measured by time-lapse microscopy. The system is an advancement over uniaxial loading devices reported to date in that it allows temporal and spatial quantification of migration as a function of the micromechanical environment.