On the biological response to different biomaterials under normal and irradiated conditions

Sammanfattning: There are several challenges when introducing an implant into a host. Concerning soft tissues, major complications are fibrosis and capsule contracture, whereas for bone, failure of osseointegration may occur. In addition to the properties of the biomaterial, compromising conditions of the host can influence the outcome, and in the case of irradiation, the risk increases for both capsule contracture and failed osseointegration. To improve the success of implants, increased knowledge about the mechanisms of integration is needed. In Study II, in vitro, isolated human mononuclear cells showed increased adhesion to ultrathin amorphous hydroxyapatite (HA)-coated titanium (Ti) and increased secretion of the proinflammatory cytokine TNF-α compared to crystalline HA. No difference between Ti and HA was observed. Study I, in vivo, showed no difference between the HA surfaces, but Ti provoked a more intense inflammatory response in regard to HA. The materials were the same in Studies I and II and had similar microscale topography (Study I: Sa 0.24-0.26 µm; Study II: Sa 0.23-0.3 µm), while amorphous HA was the least hydrophilic (Study II: Ti 60.9°, crystalline HA 58.2°, amorphous HA 89.0°). In Study III, the expression of inflammatory and fibrogenic molecular markers was determined after the insertion of silicone implants in irradiated and nonirradiated human soft tissue. Downregulation of IL-8 and upregulation of BCL-2 were detected in the peri-implant tissue in the irradiated side compared with the nonirradiated side. The antifibrotic transcription factor FOXO1 was downregulated in implant-adherent cells on the irradiated side. Correlation and regression analyses showed that irradiation dose and time since irradiation as well as chemotherapy and anti-neutropenic drugs influenced the gene expression response, both in irradiated and nonirradiated sides. The results of Study IV demonstrated that pre-exposure to irradiation significantly reduced bone-implant contact and implant removal torque in the recipient bone. The irradiation-induced detrimental effects on osseointegration were associated with high expression of proinflammatory TNF-α and osteoclastic CatK and reduced expression of bone formation gene ALP in the implant-adherent cells, in parallel with high expression of the inflammatory cell recruiter MCP-1, proinflammatory TNF-α and pro-fibrotic TGF-β genes in the peri-implant soft tissue. All compartments around the implant in the irradiated site revealed reduced expression of FOXO1. It is concluded that under normal experimental conditions, titanium and ultrathin coated HA are associated with cytocompatibility, biocompatibility and a transient inflammatory process, although differences in surface chemistry, nanotopography and hydrophilicity/hydrophobicity can alter the cellular response. In contrast, irradiation of soft and hard tissues causes dysregulation of biological activities in the different tissue compartments around the implant, of which perturbed inflammation and profibrotic propensity seem to hamper tissue healing and regeneration around implanted biomaterials.