Dipyridamole Augments Three-Dimensionally Printed Bioactive Ceramic Scaffolds to Regenerate Craniofacial Bone

Abstract

Purpose: Autologous bone grafts remain a standard of care for the reconstruction of large bony defects, but limitations persist. We explored the bone regenerative capacity of customized, 3D printed bioactive ceramic (3DBC) scaffolds with Dipyridamole (DIPY), adenosine A2A receptor (A 2A R) indirect agonist known to enhance bone formation. Methods: Critical-sized bony defects (10mm height, 10mm length, full thickness) were created at the mandibular rami of rabbits (n=15). Defects were replaced by a custom-to-defect, 3DBC scaffold composed of β-tricalcium phosphate. Scaffolds were uncoated (control), collagen-coated (COLL), or immersed in 100μM Dipyridamole (DIPY). At t=8 weeks, animals were euthanized and the rami retrieved. Bone growth was assessed exclusively within scaffold pores, and evaluated by microCT/advanced reconstruction software. MicroCT quantification was calculated. Nondecalcified histology was performed. A general linear mixed model was performed to compare group means and 95% confidence intervals (CI). Results: Qualitative analysis did not show an inflammatory response. The control and COLL groups (12.3±8.3% and 6.9±8.3% bone occupancy of free space, respectively) had less bone

Dipyridamole-loaded 3D-printed bioceramic scaffolds stimulate pediatric bone regeneration in vivo without disruption of craniofacial growth through facial maturity

“…In the alveolus, defects repaired with DIPY-3DPBC scaffolds also regenerated bone volumes significantly increased compared to previously reported bone volumes of scaffolds at 8 weeks 33 (20.0 ± 8.2, p = 0.001) this was significantly increased compared to bone graft and un-operated bone (52.9 ± 7.1% vs. 40.7 ± 8.5% vs. 39.3 ± 4.1%; ANOVA p = 0.01 Fig. 2b).…”

“…Our group has previously demonstrated that 3DPBC scaffolds significantly generate vascularized bone in vivo across critically-sized defects compared to unfilled controls, which do not regenerate both in adult and pediatric translational animal models 22,27–31 . Dipyridamole has been shown to significantly augment the osteogenic capacity of 3DPBC scaffolds compared to scaffolds without dipyridamole 24,32,33 . Importantly, optimization studies have identified a dose of 1,000 µM to maximally promote osteogenic regeneration when used in combination with 3DPBC scaffolds in animal models without observed negative side-effects including premature suture fusion or exuberant bone formation in the short-term 27,28 .…”

Signaling of the Purinergic System in the Joint

“…Administration of Dipyridamole (440 mg/day), a drug that blocks adenosine re-uptake increasing its extracellular availability, was tested on RA patients and it has been shown that the drug does not raise blood purine levels and does not change patients symptoms . Instead, local administration of Dipyridamole by using 3D printed scaffolds was able to regenerate bone defects in mice and rabbits (Ishack et al, 2017;Conesa-Buendia et al, 2019;Witek et al, 2019;Lopez et al, 2019). These different outcomes could be explained by the rapid metabolism of adenosine in the bloodstream an effect avoided by the continuous and sustained local release mediated by the scaffold implant.…”

Biomaterials for bone regeneration: an orthopedic and dentistry overview

“…Bone growth was evaluated by microCT. The results showed a larger percentage of bone in the dipyridamole group, which means that incorporation of dipyridamole increased the bioactivity of the scaffold ( 53 ).…”