INSERM, UMR 1238, PHY-OS, Faculty of Medicine, University of Nantes, 1 Rue Gaston Veil, Nantes 44035, France; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Biomedical Engineering, School of Engineering; and Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland (NUIG), Galway, Ireland.
Biomedical Engineering, School of Engineering; and Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland (NUIG), Galway, Ireland.
Acta Biomater. 2021 Nov;135:689-704. doi: 10.1016/j.actbio.2021.09.007. Epub 2021 Sep 12.
In contrast to sintered calcium phosphates (CaPs) commonly employed as scaffolds to deliver mesenchymal stromal cells (MSCs) targeting bone repair, low temperature setting conditions of calcium deficient hydroxyapatite (CDHA) yield biomimetic topology with high specific surface area. In this study, the healing capacity of CDHA administering MSCs to bone defects is evaluated for the first time and compared with sintered beta-tricalcium phosphate (β-TCP) constructs sharing the same interconnected macroporosity. Xeno-free expanded human bone marrow MSCs attached to the surface of the hydrophobic β-TCP constructs, while infiltrating the pores of the hydrophilic CDHA. Implantation of MSCs on CaPs for 8 weeks in calvaria defects of nude mice exhibited complete healing, with bone formation aligned along the periphery of β-TCP, and conversely distributed within the pores of CDHA. Human monocyte-osteoclast differentiation was inhibited in vitro by direct culture on CDHA compared to β-TCP biomaterials and indirectly by administration of MSC-conditioned media generated on CDHA, while MSCs increased osteoclastogenesis in both CaPs in vivo. MSC engraftment was significantly higher in CDHA constructs, and also correlated positively with bone in-growth in scaffolds. These findings demonstrate that biomimetic CDHA are favorable carriers for MSC therapies and should be explored further towards clinical bone regeneration strategies. STATEMENT OF SIGNIFICANCE: Delivery of mesenchymal stromal cells (MSCs) on calcium phosphate (CaP) biomaterials enhances reconstruction of bone defects. Traditional CaPs are produced at high temperature, but calcium deficient hydroxyapatite (CDHA) prepared at room temperature yields a surface structure more similar to native bone mineral. The objective of this study was to compare the capacity of biomimetic CDHA scaffolds with sintered β-TCP scaffolds for bone repair mediated by MSCs for the first time. In vitro, greater cell infiltration occurred in CDHA scaffolds and following 8 weeks in vivo, MSC engraftment was higher in CDHA compared to β-TCP, as was bone in-growth. These findings demonstrate the impact of material features such as surface structure, and highlight that CDHA should be explored towards clinical bone regeneration strategies.
与常用作递送间充质基质细胞 (MSCs) 以靶向骨修复的烧结钙磷 (CaP) 相比，缺钙羟基磷灰石 (CDHA) 的低温凝固条件可产生具有高比表面积的仿生拓扑结构。在这项研究中，首次评估了 CDHA 给药 MSC 治疗骨缺损的愈合能力，并将其与具有相同互连通孔率的烧结 β-磷酸三钙 (β-TCP) 构建体进行了比较。无动物来源的扩增人骨髓 MSCs 附着在疏水性 β-TCP 构建体的表面，同时渗透到亲水性 CDHA 的孔中。将 MSC 植入裸鼠颅骨缺损中的 CaP 8 周后，完全愈合，骨形成沿 β-TCP 的周边排列，而在 CDHA 的孔内则呈相反分布。与β-TCP 生物材料相比，CDHA 可直接抑制体外培养的单核细胞-破骨细胞分化，而通过在 CDHA 上生成 MSC 条件培养基间接抑制单核细胞-破骨细胞分化，同时 MSC 可在体内两种 CaP 中促进破骨细胞形成。CDHA 构建体中的 MSC 植入明显更高，并且与支架中的骨向内生长呈正相关。这些发现表明，仿生 CDHA 是 MSC 治疗的理想载体，应进一步探索用于临床骨再生策略。
将间充质基质细胞 (MSCs) 递送到磷酸钙 (CaP) 生物材料上可增强骨缺损的重建。传统的 CaP 是在高温下生产的，但在室温下制备的缺钙羟基磷灰石 (CDHA) 会产生更类似于天然骨矿物质的表面结构。本研究的目的是首次比较仿生 CDHA 支架与烧结 β-TCP 支架在 MSC 介导的骨修复中的能力。体外研究表明，CDHA 支架中细胞渗透更多，体内 8 周后，与 β-TCP 相比，CDHA 中的 MSC 植入更高，骨向内生长也更高。这些发现证明了材料特性（如表面结构）的影响，并强调了应该探索 CDHA 以用于临床骨再生策略。
