Research ArticleRegenerative Medicine

Engineering the Growth Factor Microenvironment with Fibronectin Domains to Promote Wound and Bone Tissue Healing

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Science Translational Medicine  14 Sep 2011:
Vol. 3, Issue 100, pp. 100ra89
DOI: 10.1126/scitranslmed.3002614

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Sweet Synergy

Engineers have long been interested in creating the perfect environment for repairing injured tissues, which range from broken blood vessels to shattered nerves. Such efforts have included both simple materials, like collagen, and complex ones comprising a polymeric labyrinth of biomolecules and cells. As described in this issue, Martino et al. have hit the sweet spot for engineering the cellular microenvironment: a combination of natural polymer and recombinant protein that recruits growth factors to wounds and convinces cells to repair the damage.

Martino and colleagues sought to generate a matrix that would sequester growth factors. The authors started with a fibrin matrix, which is used clinically as a tissue substitute to promote healing. Next, they pieced together two fibronectin (FN) fragments—the 9th to 10th and the 12th to 14th type III repeats—to control integrin and growth factor binding, respectively. Finally, the resulting recombinant FN fragment, FN III9-10/12-14, was covalently immobilized on the fibrin scaffold. The FN III9-10/12-14 matrix was able to bind vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and bone morphogenetic protein (BMP)—three factors that are intricately involved in skin and bone repair. FN III9-10/12-14 in combination with VEGF and PDGF enhanced proliferation of endothelial cells, smooth muscle cells, and mesenchymal stem cells in vitro. The engineered FN fragment, when co-delivered with all three growth factors, also stimulated cell migration to a greater extent than control FN proteins, suggesting improved signaling synergy between growth factors and the recombinant FN.

To see whether the material healed tissues in vivo, Martino and colleagues injected their designer scaffold into the wounds of diabetic mice and into the calvarial defects of skeletally mature rats. Enhanced reepithelialization, granulation tissue formation, and angiogenesis were noted for the wounds. For the bone defects, the authors reported increased bone tissue deposition and recruitment of bone progenitor cells. These preclinical demonstrations in rodent models show promise for the use of the FN III9-10/12-14–modified matrices in humans to heal chronic wounds and repair bones. Although testing in larger animal models might be necessary before translation, it is clear that these engineered microenvironments improve the synergy between endogenous growth factors and cells to restore tissue form and function to normal.

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