title: Synergistic interactions of blood-borne immune cells, fibroblasts and extracellular matrix drive repair in an in vitro peri-implant wound healing model.
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.
authors.affiliation: Department of Health Sciences and Technology, Laboratory of Applied Mechanobiology, ETH Zurich, Zurich, 8093, Switzerland.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Burkhardt
authors.affiliation: Thommen Medical AG, Grenchen, 2540, Switzerland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Waser
authors.affiliation: Department of Obstetrics, Laboratory of Cell and Tissue Engineering, University Hospital Zurich, Zurich, 8091, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Milleret
authors.affiliation: Department of Health Sciences and Technology, Laboratory of Applied Mechanobiology, ETH Zurich, Zurich, 8093, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gerber
authors.affiliation: Swiss Center for Regenerative Medicine, Zurich, 8091, Switzerland.
authors.forename: Maximilian Y
authors.initials: MY
authors.lastname: Emmert
authors.affiliation: Department of Health Sciences and Technology, Laboratory of Applied Mechanobiology, ETH Zurich, Zurich, 8093, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Foolen
authors.affiliation: Swiss Center for Regenerative Medicine, Zurich, 8091, Switzerland.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hoerstrup
authors.affiliation: Thommen Medical AG, Grenchen, 2540, Switzerland.|School of Life Sciences, University of Applied Science Northwestern Switzerland, Muttenz, 4132, Switzerland.
authors.forename: Falko
authors.initials: F
authors.lastname: Schlottig
authors.affiliation: Department of Health Sciences and Technology, Laboratory of Applied Mechanobiology, ETH Zurich, Zurich, 8093, Switzerland.
authors.forename: Viola
authors.initials: V
authors.lastname: Vogel
mesh_terms: D000328:Adult; D001672:Biocompatible Materials; D001773:Blood Cells / Q000378:metabolism*; D002448:Cell Adhesion; D002450:Cell Communication; D049109:Cell Proliferation; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008954:Models, Biological; D013499:Surface Properties; D013927:Thrombosis; D014025:Titanium; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing; D055815:Young Adult
chemical_list: D001672:Biocompatible Materials; D042461:Vascular Endothelial Growth Factor A; D014025:Titanium; D020782:Matrix Metalloproteinases