Employing Indirect Adenosine 2_A Receptors (A_2AR) to Enhance Osseointegration of Titanium Devices: A Pre-Clinical Study

The present study aimed to evaluate the effect of dipyridamole, an indirect adenosine 2A receptors (A(2A)R), on the osseointegration of titanium implants in a large, translational preclinical model. Sixty tapered, acid-etched titanium implants, treated with four different coatings ((i) Type I Bovine Collagen (control), (ii) 10 mu M dipyridamole (DIPY), (iii) 100 mu M DIPY, and (iv) 1000 mu M DIPY), were inserted in the vertebral bodies of 15 female sheep (weight similar to 65 kg). Qualitative and quantitative analysis were performed after 3, 6, and 12 weeks in vivo to assess histological features, and percentages of bone-to-implant contact (%BIC) and bone area fraction occupancy (%BAFO). Data was analyzed using a general linear mixed model analysis with time in vivo and coating as fixed factors. Histomorphometric analysis after 3 weeks in vivo revealed higher BIC for DIPY coated implant groups (10 mu M (30.42% +/- 10.62), 100 mu M (36.41% +/- 10.62), and 1000 mu M (32.46% +/- 10.62)) in comparison to the control group (17.99% +/- 5.82). Further, significantly higher BAFO was observed for implants augmented with 1000 mu M of DIPY (43.84% +/- 9.97) compared to the control group (31.89% +/- 5.46). At 6 and 12 weeks, no significant differences were observed among groups. Histological analysis evidenced similar osseointegration features and an intramembranoustype healing pattern for all groups. Qualitative observation corroborated the increased presence of woven bone formation in intimate contact with the surface of the implant and within the threads at 3 weeks with increased concentrations of DIPY. Coating the implant surface with dipyridamole yielded a favorable effect with regard to BIC and BAFO at 3 weeks in vivo. These findings suggest a positive effect of DIPY on the early stages of osseointegration.