Cyclic Adenosine Monophosphate-Enhanced Calvarial Regeneration by Bone Marrow-Derived Mesenchymal Stem Cells on a Hydroxyapatite/Gelatin Scaffold

Abstract

Cyclic adenosine monophosphate (cAMP) plays a significant role in inducing new bone formation by mediating various signal pathways. However, cAMP, combined with biomaterials, is rarely investigated to reconstruct calvarial defects. In this study, cAMP was loaded into a hydroxyapatite (HA)/gelatin (Gel) construct and implanted into critical skull defects in rats to evaluate the potential for enhancing skull regeneration. The physiochemical characteristics, the biocompatibility of Gel and HA/Gel scaffolds, and the regenerated bone tissue were assessed. The resulting HA/Gel scaffolds possessed a 3D interconnected porous structure with extensively distributed HA crystals and favorable physiochemical properties. Rat bone marrow-derived mesenchymal stem cells (rBMSCs) within the HA/Gel scaffold showed greater biocompatibility. Compared with the Gel and HA/Gel groups, the cAMP-HA/Gel group revealed the highest bone density, more mature mineralized tissue, and more favorable integration between the new bone and inherent bone as analyzed by cone beam computed tomography and hematoxylin & eosin and Masson staining, respectively. Collectively, our study verified HA/Gel scaffolds as a prospective biomimetic treatment with biocompatibility and the therapeutic potential of cAMP in promoting new bone growth of a skull, which indicates its promise as a growth factor for bone tissue engineering.

Graphene and its Derivatives for Bone Tissue Engineering: In Vitro and In Vivo Evaluation of Graphene-Based Scaffolds, Membranes and Coatings

“…Allogenous bone transplantation is an alternative approach, but this therapeutic method has to face risks such as disease transmission, infection, and immunogenicity ( Calori et al, 2011 ; Campana et al, 2014 ). Although some existing synthetic biomaterials have achieved favorable clinical efficacy, there is still a lack of outstanding biomaterials that can provide excellent load-bearing, complete biodegradability, osteogenesis and osteoconductivity simultaneously ( Fayyazbakhsh et al, 2017 ; Li et al, 2018a ; Ju et al, 2021 ). As a result, there has been an urgent need for the development and application of synthetic bone graft substitutes.…”

Bioactive Scaffolds as a Promising Alternative for Enhancing Critical-Size Bone Defect Regeneration in the Craniomaxillofacial Region

“…In contrast, hydrogels made with only Gel failed as an osteoinductive biomaterial. 34 Gel/HAp scaffolds loaded with ascorbic acid (AA) and β-glycerophosphate (β-GP) enhanced the calvarial bone regrowth after implantation into rat CSDs. 35 Elastin is another natural polymer used to fabricate scaffolds.…”

“…Then, the stimulated cells were seeded in Gel/HAp hydrogels and implanted into cranial defects in rats, accelerating bone healing. 34 Sphingosine 1-phosphate is a signaling sphingolipid that enhances preosteoblast differentiation and endothelial cell chemokinesis in vitro via binding to G protein-coupled receptors. In rats, PLGA/Col electrospun scaffolds loaded with siponimod, a sphingosine 1-phosphate analog, were implanted into cranial CSDs.…”

Bone Tissue Engineering in the Treatment of Bone Defects

“…Bone marrow mesenchymal stem cells (BMSCs) are a heterogeneous population of cells obtained from the bone marrow stromal fraction [ 104 ]. They have high self-proliferation and multi-directional differentiation potential, which are recognized as favorable cell types in bone tissue engineering [ 105 , 106 , 107 ]. In in-vitro studies, BMSCs can rapidly amplify and differentiate into various mesodermal lineages, such as adipocyte, chondrocytes, and osteocytes, greatly contributing to the regeneration of osteochondral tendon, fat, and muscle [ 108 , 109 ].…”