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Our prior characterization of 4\u2010day postnatal rat tooth bud cells grown on hexafluoro\u20102\u2010propanol (HFIP) silk scaffolds showed that the silk scaffolds not only supported osteodentin formation, but also guided the size and shape of the formed osteodentin. In this study, interactions between human dental pulp cells and HFIP and aqueous based silk scaffolds were studied under both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> conditions. Silk scaffold porosity and incorporation of RGD and DMP peptides were examined. We found that the degradation of aqueous based silk is much faster than HFIP based silk scaffolds. Also, HFIP based silk scaffolds supported the soft dental pulp formation better than the aqueous based silk scaffolds. No distinct hard tissue regeneration was found in any of the implants, with or without additional cells. We conclude that alternative silk scaffold materials, and hDSC pre\u2010seeding cell treatments or sorting and enrichment methods, need to be considered for successful dental hard tissue regeneration. \u00a9 2011 Wiley Periodicals, Inc. 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