Blood prefabricated hydroxyapatite/tricalcium phosphate induces ectopic vascularized bone formationviamodulating the osteoimmune environment

Abstract

Successful bone healing depends significantly on the structure of blood clots and the functional responses of blood cells. Despite the importance of blood clots in osteogenesis, few studies have investigated the effects of blood clots during material-mediated bone regeneration. In this study, we implanted the bone graft substitute hydroxyapatite/tricalcium phosphate (HA/TCP) subcutaneously, with or without blood prefabrication, to evaluate the effects of blood clots on material-mediated bone formation. We observed that blood prefabricated HA/TCP induced ectopic vascularized bone-like structures, implying that blood prefabrication can induce a microenvironment sufficient for HA/TCP-mediated bone formation. The possible mechanisms were related to (1) modification of the fibrin network, which facilitates MSCs recruitment and differentiation, (2) modulation of the early osteoimmune environment with the upregulation of osteogenic factor BMP2, and (3) improved expression of VEGF and the enhancement of angiogenesis. These results demonstrate the multifaceted effects of blood clots in regulating osteogenesis, osteoclastogenesis, immune responses, and angiogenesis. Therefore, blood prefabrication can serve as a valuable strategy to improve the osteogenic capacity of materials, and prefabricating materials with blood clots prior to implantation should be encouraged. New generation bone substitute materials could target the modulation of a favorable blood clot response for improved bone regeneration.

Insights into the angiogenic effects of nanomaterials: mechanisms involved and potential applications

“…Several different biomaterials for bone tissue regeneration have been extensively studied, but single-scaffold materials cannot meet the requirements of good biocompatibility, vascular regeneration, new bone formation and the mechanical properties at the same time [19]. Therefore, researchers are working on fabricating novel micronano scaffolds to drive angiogenesis and promote bone regeneration [20].…”

Biomaterials Regulating Bone Hematoma for Osteogenesis

“…[114] To investigate the influence of blood clots on materialguided bone regeneration, blood prefabricated hydroxyapatite/ tricalcium phosphate (HA/TCP) were subcutaneously implanted in rats for different periods. [115] HA/TCP was prefabricated by thorough mixing with rat blood for 15 min, with 2% CaCl 2 serving as the coagulation promoter. The blood prefabricated HA/TCP induced thread-like and net-like clots with a loose structure prior to implantation, while the control showed a tightly packed fibrin network.…”

“…[116] Thus, significantly enhanced new bone-like formation was found in the blood-treated group by 6 weeks postimplantation. [115] For potential applications in dental implants, preincubation with blood enhanced the expression of ALP and collagen-Ι from primary human bone cells cultured on both microroughened hydrophobic and hydrophilic Ti. [71] Early and effective integration with bone tissue plays an essential role in determining the longterm stability of implants.…”

“…[ 116 ] Thus, significantly enhanced new bone‐like formation was found in the blood‐treated group by 6 weeks postimplantation. [ 115 ]…”

Mesopore Controls the Responses of Blood Clot‐Immune Complex via Modulating Fibrin Network

“…[ 7 , 8 ] Particularly, inappropriate fiber thickness during blood clotting may jeopardize long‐term regenerative outcomes. [ 9 , 10 , 11 ] When the original fiber thickness is increased, the efficiency of bone regeneration becomes considerably decreased. [ 10 , 11 ] Importantly, decreased fiber diameter would favor a thread‐like or net‐like morphology of fibrin, which further increased expression of M2 makers of macrophages (MΦ) and improved the bone regeneration efficiency.…”