The host immune response is critical for in situ osteogenesis, but correlations between local inflammatory reactions and biomaterial osteoinduction are still poorly understood. This study used a murine intramuscular implantation model to demonstrate that calcium phosphate ceramics with different phase compositions exhibited divergent osteoinductivities. The osteoinductive potential of each ceramic was closely associated with the immunomodulatory capacity of the material, and especially with the regulation of macrophage polarization and functional status. Biphasic calcium phosphate (BCP) ceramics with superior osteoinductive potential enhanced the fraction of CD206+ M2 macrophages, up-regulated expression of M2 phenotypic markers in vitro, and increased the ARG+ M2 population in vivo. This suggested that BCP ceramics could ameliorate long-term inflammation and build a pro-osteogenic microenvironment. However, β-tricalcium phosphate (β-TCP) ceramics with no obvious osteoinductivity increased the fraction of CCR7+ M1 macrophages, promoted the secretion of M1 phenotypic markers in vitro, and maintained a high proportion of iNOS+ M1 macrophages in vivo. It indicated that β-TCP ceramics could exacerbate inflammation and inhibit ectopic bone formation. Hydroxyapatite ceramics with an intermediate osteoinductivity exhibited a moderate amount of both M1 and M2 macrophages. These findings highlight the critical role of macrophage polarization in biomaterial-dependent osteoinduction, which not only deepens our understanding of osteoinductive mechanisms but also provides a strategy to design bone substitutes by endowing materials with the proper immunomodulatory abilities to achieve the desired clinic performance. STATEMENT OF SIGNIFICANCE: Calcium phosphate (CaP) ceramics with osteoinductive capacities are able to induce ectopic bone formation in non-osseous sites. However, its underlying mechanism is largely unknown. Previous studies have demonstrated an indispensable role of macrophages in osteogenesis, inspiring us that local inflammatory reaction may affect material-dependent osteoinduction. This study indicated that CaP ceramics with different phase composition could present divergent osteoinductive capacities through modulating polarization and functional status of macrophages, as biphasic calcium phosphate with potent osteoinductivity ameliorated long-term inflammation and induced a healing-associated M2 phenotype to initiate bone formation. These findings not only get an insight into the mechanism of CaP-involved osteoinduction, but also help the design of tissue-inducing implants by endowing biomaterials with proper immunomodulatory ability.

中文翻译：

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巨噬细胞极化与多孔磷酸钙陶瓷骨诱导的相关性。

宿主的免疫反应对于原位成骨至关重要，但对局部炎症反应与生物材料成骨诱导之间的相关性仍知之甚少。这项研究使用鼠肌内植入模型来证明具有不同相组成的磷酸钙陶瓷表现出不同的骨诱导性。每种陶瓷的骨诱导电位与材料的免疫调节能力密切相关，特别是与巨噬细胞极化和功能状态的调节密切相关。具有优越的骨诱导潜力的双相磷酸钙（BCP）陶瓷可提高CD206 + M2巨噬细胞的比例，在体外上调M2表型标记的表达，并在体内增加ARG + M2群体。这表明BCP陶瓷可以减轻长期炎症并建立促成骨的微环境。然而，无明显骨诱导性的β-磷酸三钙（β-TCP）陶瓷增加了CCR7 + M1巨噬细胞的比例，促进了M1表型标志物的分泌，并在体内维持了高比例的iNOS + M1巨噬细胞。这表明β-TCP陶瓷可加剧炎症并抑制异位骨的形成。具有中等骨诱导性的羟基磷灰石陶瓷表现出适量的M1和M2巨噬细胞。这些发现突显了巨噬细胞极化在生物材料依赖性骨诱导中的关键作用，这不仅加深了我们对骨诱导机制的理解，而且还提供了一种通过赋予材料适当的免疫调节能力来实现所需临床表现的设计骨替代品的策略。意义声明：具有骨诱导能力的磷酸钙（CaP）陶瓷能够在非骨部位诱导异位骨形成。但是，其基本机制尚不清楚。先前的研究表明巨噬细胞在成骨中起着不可或缺的作用，这启发了我们，局部炎症反应可能会影响物质依赖性的骨诱导。这项研究表明，具有不同相组成的CaP陶瓷可以通过调节巨噬细胞的极化和功能状态来表现出不同的骨诱导能力，由于双相磷酸钙具有有效的骨诱导作用，可改善长期炎症并诱导与愈合相关的M2表型，从而开始骨形成。这些发现不仅深入了解了CaP参与的骨诱导机制，而且还通过赋予具有适当免疫调节能力的生物材料来帮助组织诱导植入物的设计。