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Abstract:

Recently our lab has developed self-seeding matrices for the field of cardiovascular tissue engineering based on both cellular and molecular mechanisms of foreign body reaction. First we defined and validated a model of in vivo stem cell homing. Based on granulation tissue development and the known mechanisms of a specific immune response (foreign body reaction) our group studied short term intraperitoneal implants as a model of primitive cell attraction. It was shown that the implants attracted primitive cells of different subclasses very early on, i.e. 2 to 3 days post implantation, and that when properly induced these cells differentiated along adipogenic, osteogenic and myogenic pathways [1].Having confirmed the homing of primitive cells we then turned to genetic profiling by means of microarrays. Comparison of different stages of the development of granulation tissue at the time when the primitive cells were attracted resulted in a list of possible candidate genes [2]. Since it was known that macrophages are the initiators of the reaction their differential gene expression, activated vs. non-activated, was used to define the macrophage specific signalling molecules in this setting. From this analysis 2 significantly expressed candidates with known function, stem cell factor (SCF) and stromal cell derived factor (SDF-1), were chosen for the development of bioactive coatings. Short term coated matrices (24h) implanted in the carotid artery of rats, confirmed enhanced homing of CD117+ cells. More dramatic changes were observed in preclinical coated prosthetic valve evaluation in sheep. SDF-1 coated valve prostheses showed a normal cell count compared to native valves, as well as a normal constitution of cell phenotypes. However, a small residue of inflammatory cells, also apparent in spontaneous recellularisation [3], was observed.At this moment further fine tuning of the coating is being performed as well as the evaluation of other candidates previously identified [2]. Additionally, we have applied the microarray gene profiling technique, to determine genes specifically expressed in developing blood vessels or valves. In this way we could obtain genetic markers to be used as a quality control of our bioactive coatings. In conclusion, using a combination of cellular/molecular techniques and in vivo evaluation we have been able to develop matrices for cardiovascular tissue engineering that induce self seeding. However, the obtained knowledge is also relevant for other targets, especially in stem cell – and immunobiology.1. Vranken et al., Biomaterials. (in press) 2. Lebacq et al., Int.J.Lower Extremity Wounds. 20073. De Visscher et al., Eur.Heart J. 2007