Abstract
Metal ions have been identified as important bone metabolism regulators and widely used in the field of bone tissue engineering, however their exact role during bone regeneration remains unclear. Herein, the aim of study was to comprehensively explore the interactions between osteoinductive and osteo-immunomodulatory properties of these metal ions. In particular, the osteoinductive role of zinc ions (Zn2+), as well as its interactions with local immune microenvironment during bone healing process, was investigated in this study using a sustained Zn2+ delivery system incorporating Zn2+ into β-tricalcium phosphate/poly(L-lactic acid) (TCP/PLLA) scaffolds. The presence of Zn2+ largely enhanced osteogenic differentiation of periosteum-derived progenitor cells (PDPCs), which was coincident with increased transition from M1 to M2 macrophages (Mvarphi s). We further confirmed that induction of M2 polarization by Zn2+ was realized via PI3K/Akt/mTOR pathway, whereas marker molecules on this pathway were strictly regulated by the addition of Zn2+. Synergically, this favorable immunomodulatory effect of Zn2+ further improved the osteogenic differentiation of PDPCs induced by Zn2+ in vitro. Consistently, the spontaneous osteogenesis and pro-healing osteoimmunomodulation of the scaffolds were thoroughly identified in vivo using a rat air pouch model and a calvarial critical-size defect model. Taken together, Zn2+-releasing bioactive ceramics could be ideal scaffolds in bone tissue engineering due to their reciprocal interactions between osteoinductive and immunomodulatory characteristics. Clarification of this synergic role of Zn2+ during osteogenesis could pave the way to develop more sophisticated metal-ion based orthopedic therapeutic strategies.
Highlights
To date, the recovery from large segmental bone defects remains a great challenge in the clinical field of orthopedics [1]
To evaluate whether the cells possess features of mesenchymal stem cells (MSCs), including clonogenicity and trilineage differentiation potential, colony formation assay were performed and the cells have the excellent ability of colony formation after 2 weeks culture (Additional file 1: Fig. S1B, C)
These cells expressed a comprehensive series of surface markers, including CD29, CD44 and CD90 (Additional file 1: Fig. S1G–I), which are generally considered to identify periosteum-derived progenitor cells (PDPCs), while were negative for endothelial, myeloid and hematopoietic markers, such as CD45, CD31 and CD79 (Additional file 1: Fig. S1J–L)
Summary
The recovery from large segmental bone defects remains a great challenge in the clinical field of orthopedics [1]. Znloaded β-TCP (Zn/TCP) might be a potential scaffold with the property of sustained releasing Zn ion ( Zn2+) for bone repair. It is quite difficult to maintain and shape TCP scaffolds in defect sites [13]. To address this issue, poly(L-lactic acid) (PLLA) was selected as the substrate material for Zn/TCP incorporation. Recent studies found that PLLA is biocompatible with cell attachment, proliferation and differentiation, and bone regeneration [15,16,17]. Zn/TCP was incorporated into PLLA to form Zn/TCP/PLLA scaffolds for bone defect repair. We believe that Zn/TCP/PLLA scaffolds could promote bone healing by directly inducing the osteogenic differentiation of stem cells
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