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Blood clots stop bleeding and provide cell-instructive microenvironments. Still, in vitro models used to study implant performance typically neglect any possible interactions of recruited cells with surface-adhering blood clots. Here we study the interaction and synergies of bone marrow derived human mesenchymal stem cells (hMSCs) with surface-induced blood clots in an in vitro model by fluorescence microscopy, scanning and correlative light and electron microscopy, ELISA assays and zymography. The clinically used alkali-treated rough titanium (Ti) surfaces investigated here are known to enhance blood clotting compared to native Ti and to improve the healing response, but the underlying mechanisms remain elusive. Here we show that the presence of blood clots synergistically increased hMSC proliferation, extracellular matrix (ECM) remodelling and the release of matrix fragments and angiogenic VEGF, but did not increase the osteogenic differentiation of hMSCs. While many biomaterials are nowadays engineered to release pro-angiogenic factors, we show here that clot-entrapped blood cells on conventional materials in synergy with hMSCs are potent producers of pro-angiogenic factors. Our data might thus not only explain why alkali-treatment is beneficial for Ti implant integration, but they suggest that the physiological importance of blood clots to create pro-angiogenic environments on implants has been greatly underestimated. The importance of blood clots might have been missed because the pro-angiogenic functions get activated only upon stimulation by synergistic interactions with the invading cells.

Polyetheretherketone (PEEK) generally exhibits physical and chemical characteristics that prevent osseointegration. To activate the PEEK surface, we applied oxygen and ammonia plasma treatments. These treatments resulted in surface modifications, leading to changes in nanostructure, contact angle, electrochemical properties and protein adhesion in a plasma power and process gas dependent way. To evaluate the effect of the plasma-induced PEEK modifications on stem cell adhesion and differentiation, adipose tissue-derived mesenchymal stem cells (adMSC) were seeded on PEEK specimens. We demonstrated an increased adhesion, proliferation, and osteogenic differentiation of adMSC in contact to plasma-treated PEEK. In dependency on the process gas (oxygen or ammonia) and plasma power (between 10 and 200 W for 5 min), varying degrees of osteogenic differentiation were induced. When adMSC were grown on 10 and 50 W oxygen and ammonia plasma-treated PEEK substrates they exhibited a doubled mineralization degree relative to the original PEEK. Thus plasma treatment of PEEK specimens induced changes in surface chemistry and topography and supported osteogenic differentiation of adMSC in vitro. Therefore plasma treated PEEK holds perspective for contributing to osseointegration of dental and orthopedic load-bearing PEEK implants in vivo.