Employing Indirect Adenosine 2A Receptors (A2AR) to Enhance Osseointegration of Titanium Devices: A Pre-Clinical Study

Abstract

The present study aimed to evaluate the effect of dipyridamole, an indirect adenosine 2A receptors (A2AR), on the osseointegration of titanium implants in a large, translational pre-clinical model. Sixty tapered, acid-etched titanium implants, treated with four different coatings ((i) Type I Bovine Collagen (control), (ii) 10 μM dipyridamole (DIPY), (iii) 100 μM DIPY, and (iv) 1000 μM DIPY), were inserted in the vertebral bodies of 15 female sheep (weight ~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 μM (30.42% ± 10.62), 100 μM (36.41% ± 10.62), and 1000 μM (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 μM 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 intramembranous-type 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.

Translational Experimental Basis of Indirect Adenosine Receptor Agonist Stimulation for Bone Regeneration: A Review

“…DIPY, an indirect adenosine agonist, is an extensively studied biologic compound [ 55 , 62 , 63 , 64 , 65 , 65 , 66 , 67 , 67 , 68 , 68 , 69 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. Historically, it has been used as a vasodilatory and antiplatelet agent [ 98 , 99 , 100 , 101 ].…”

“…Other large animal models have studied different devices in different anatomical locations. Where, Pacheco-Vergara et al investigated the impact of DIPY on the osteointegration of titanium implants in sheep vertebrae [ 62 ]. It was found that DIPY-treated animals showed further bone integration and regeneration at 3 weeks post-operation.…”

“…It was found that DIPY-treated animals showed further bone integration and regeneration at 3 weeks post-operation. No differences were seen at 6 or 12 weeks post-operation, indicating that DIPY may play a beneficial role in the early stages of osteointegration [ 62 ]. While there have been extensive pre-clinical models, DIPY has yet to be tested clinically.…”

“…3.3.1. DIPY DIPY, an indirect adenosine agonist, is an extensively studied biologic compound [55,[62][63][64][65][65][66][67]67,68,68,69,[81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97]. Historically, it has been used as a vasodilatory and antiplatelet agent [98][99][100][101].…”