Abstract
The regeneration of load-bearing segmental bone defects remains a significant clinical problem in orthopedics, mainly due to the lack of scaffolds with composition and 3D porous structure effective in guiding and sustaining new bone formation and vascularization in large bone defects. In the present study, biomorphic calcium phosphate bone scaffolds (GreenBone™) featuring osteon-mimicking, hierarchically organized, 3D porous structure and lamellar nano-architecture were implanted in a critical cortical defect in sheep and compared with allograft. Two different types of scaffolds were tested: one made of ion-doped hydroxyapatite/β-tricalcium-phosphate (GB-1) and other made of undoped hydroxyapatite only (GB-2). X-ray diffraction patterns of GB-1 and GB-2 confirmed that both scaffolds were made of hydroxyapatite, with a minor amount of β-TCP in GB-1. The chemical composition analysis, obtained by ICP-OES spectrometer, highlighted the carbonation extent and the presence of small amounts of Mg and Sr as doping ions in GB-1. SEM micrographs showed the channel-like wide open porosity of the biomorphic scaffolds and the typical architecture of internal channel walls, characterized by a cell structure mimicking the natural parenchyma of the rattan wood used as a template for the scaffold fabrication. Both GB-1 and GB-2 scaffolds show very similar porosity extent and 3D organization, as also revealed by mercury intrusion porosimetry. Comparing the two scaffolds, GB-1 showed slightly higher fracture strength, as well as improved stability at the stress plateau. In comparison to allograft, at the follow-up time of 6 months, both GB-1 and GB-2 scaffolds showed higher new bone formation and quality of regenerated bone (trabecular thickness, number, and separation). In addition, higher osteoid surface (OS/BS), osteoid thickness (OS.Th), osteoblast surface (Ob.S/BS), vessels/microvessels numbers, as well as substantial osteoclast-mediated implant resorption were observed. The highest values in OS.Th and Ob. S/BS parameters were found in GB-1 scaffold. Finally, Bone Mineralization Index of new bone within scaffolds, as determined by micro-indentation, showed a significantly higher microhardness for GB-1 scaffold in comparison to GB-2. These findings suggested that the biomorphic calcium phosphate scaffolds were able to promote regeneration of load-bearing segmental bone defects in a clinically relevant scenario, which still represents one of the greatest challenges in orthopedics nowadays.
Highlights
The regeneration of load-bearing segmental bone defects is today considered among the greatest challenges in orthopedics, due to the lack of biomaterials effective for long bone substitution and to the frequent occurrence of various complications such as nonunions (Giannoudis and Atkins, 2007).In the last 20 years, there have been numerous attempts in the development of new materials for the treatment of long bone defects, based on hydroxyapatite (HA) and other calcium phosphates (CaPs), which most closely resemble the mineral composition of natural bone (Habraken et al, 2016)
Despite preclinical promising results, the clinical application of these materials in various forms and with different physicochemical features is still restricted for long bone defects consequent to excision of tumors, infection, major trauma, and nonunion (Ebrahimi et al, 2017; Roffi et al, 2017)
SEM micrographs in Figure 3 show the typical hierarchical structure and pore morphology of biomorphic scaffolds at different size scales
Summary
The regeneration of load-bearing segmental bone defects is today considered among the greatest challenges in orthopedics, due to the lack of biomaterials effective for long bone substitution and to the frequent occurrence of various complications such as nonunions (Giannoudis and Atkins, 2007).In the last 20 years, there have been numerous attempts in the development of new materials for the treatment of long bone defects, based on hydroxyapatite (HA) and other calcium phosphates (CaPs), which most closely resemble the mineral composition of natural bone (Habraken et al, 2016). Currently available CaP-based devices for large bone defects often fail in recreating the anatomical and functional features of the lost tissue, due to the complexity of bone in terms of composition, structural, and mechanical properties (Hutmacher et al, 2004). This is a critical issue when it comes to regenerate load-bearing segmental bones where multiaxial biomechanical stresses are demanding, so that insufficient structural organization of the newly formed bone tissue can result in impaired functionality. The typical osteon structure of the long bone has a multi-scale hierarchical architecture which is highly functional in ensuring: 1) the propagation of mechanical forces from the macro- to micro-scale and 2) the activation of mechano-transduction processes responsible for the bone self-repair ability
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