Paper53-Engineering-mulitfunctional-gels-EPCs-Bcl-2-FASEB-J-Saltzman-2008

Paper53-Engineering-mulitfunctional-gels-EPCs-Bcl-2-FASEB-J-Saltzman-2008

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The FASEB Journal Research Communication Engineering of multifunctional gels integrating highly efficient growth factor delivery with endothelial cell transplantation Steven M. Jay,* ,‡ Benjamin R. Shepherd, †,‡ James P. Bertram,* Jordan S. Pober, †,‡ W. Mark Saltzman* ,‡,1 *Department of Biomedical Engineering, Department of Immunobiology, and Interdepartmental Program in Vascular Biology and Therapeutics, Yale University, New Haven, Connecticut, USA ABSTRACT Transplantation of Bcl-2-transduced hu- man umbilical vein endothelial cells (ECs) in protein gels into the gastrocnemius muscle improves local reperfusion in immunodeficient mouse hosts with in- duced hind limb ischemia. We tested the hypothesis that incorporation of local, sustained growth factor delivery could enhance and accelerate this effect. Tis- sue engineering scaffolds often use synthetic polymers to enable controlled release of proteins, but most synthetic delivery systems have major limitations, most notably hydrophobicity and inefficient protein loading. Here, we report the development of a novel alginate- based delivery system for vascular endothelial growth factor-A 165 (VEGF) that exhibits superior loading effi- ciency and physical properties to previous systems in vitro . In vivo , VEGF released from alginate micropar- ticles within protein gels was biologically active and, when combined with EC transplantation, led to in- creased survival of transplanted cells at 28 days. The composite graft described also improved early (14 days) tissue perfusion and late (28 days) muscle myo- globin expression, a sign of recovery from ischemia, compared with EC transplantation and VEGF delivery separately. We conclude that our improved approach to sustained VEGF delivery in tissue engineering is useful in vivo and that the integration of high efficiency protein delivery enhances the therapeutic effect of protein gel-based EC transplantation.—Jay, S. M., Shep- herd, B. R., Bertram, J. P., Pober, J. S., Saltzman, W. M. Engineering of multifunctional gels integrating highly efficient growth factor delivery with endothelial cell transplantation. FASEB J. 22, 2949–2956 (2008) Key Words: tissue engineering VEGF therapeutic revascu- larization Transplantation of healthy cells within a stable vehicle to sites of acute or chronic injury represents a promising strategy for the treatment of disease through regenerative medicine. For example, transplantation of progenitor or fully differentiated endothelial cells (ECs) may be used in therapeutic revascularization as a treatment for ischemia (1). The use of synthetic poly- mer scaffolds to support cells is a popular approach for tissue engineering; however, many of the most com- monly used materials poorly support EC viability or vessel formation, and in general, the therapeutic effi- cacy of cell transplantation is typically limited by low viability and/or lack of physiological functionality of transplanted cells (2). Furthermore, these synthetic polymers create additional problems, often impeding
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