Abstract
Low correlations of cell culture data with clinical outcomes pose major medical challenges with costly consequences. While the majority of biomaterials are tested using in vitro cell monocultures, the importance of synergistic interactions between different cell types on paracrine signalling has recently been highlighted. In this proof-of-concept study, we asked whether the first contact of surfaces with whole human blood could steer the tissue healing response. This hypothesis was tested using alkali-treatment of rough titanium (Ti) surfaces since they have clinically been shown to improve early implant integration and stability, yet blood-free in vitro cell cultures poorly correlated with in vivo tissue healing. We show that alkali-treatment, compared to native Ti surfaces, increased blood clot thickness, including platelet adhesion. Strikingly, blood clots with entrapped blood cells in synergistic interactions with fibroblasts, but not fibroblasts alone, upregulated the secretion of major factors associated with fast healing. This includes matrix metalloproteinases (MMPs) to break down extracellular matrix and the growth factor VEGF, known for its angiogenic potential. Consequently, in vitro test platforms, which consider whole blood-implant interactions, might be superior in predicting wound healing in response to biomaterial properties.
Highlights
Interplay of different immune cells either entrapped in the blood clot or attracted to a wound site, among others, neutrophils and monocytes, of which the latter can differentiate into macrophages
During the process of early tissue formation, fibroblasts and osteogenic progenitor cells are attracted to the wound site[22] and invade the blood clot formed on the implant surface in order to degrade the blood clot and synthesize new extracellular matrix (ECM) to restore tissue homeostasis[15]
Since fibroblasts are the most abundant cell type that infiltrates into blood clots in early wound healing stages and initiates the remodelling of the first provisional ECM into granulation tissue, rich in fibronectin (Fn) and collagen, we tested the hypothesis whether the presence of a blood clot can accelerate remodelling and assembly of the first de novo ECM and promote fast healing
Summary
Interplay of different immune cells either entrapped in the blood clot or attracted to a wound site, among others, neutrophils and monocytes, of which the latter can differentiate into macrophages. Since fibroblasts are the most abundant cell type that infiltrates into blood clots in early wound healing stages and initiates the remodelling of the first provisional ECM into granulation tissue, rich in fibronectin (Fn) and collagen, we tested the hypothesis whether the presence of a blood clot can accelerate remodelling and assembly of the first de novo ECM and promote fast healing In this proof-of-concept study and with a focus on early events, clinically used dental implant surfaces, namely sandblasted and acid-etched Ti surfaces, native or alkali-treated, were exposed to human whole blood from healthy patients, to fibroblasts or to a co-culture of whole blood with subsequently seeded fibroblasts. We assessed whether this in vitro model that includes the contribution of blood-borne ECM and immune cells might be better suited as a test platform with improved clinical predictive power
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