Development of an Accurate and Proactive Immunomodulatory Strategy to Improve Bone Substitute Material-Mediated Osteogenesis and Angiogenesis

Abstract

Background: Treatment of large bone defects represents a major clinical problem worldwide. Suitable bone substitute materials are commonly required to achieve successful bone regeneration, and much effort has been spent to optimize their chemical compositions, 3D architecture and mechanical properties. However, material-immune system interactions are increasingly being recognized as a crucial factor influencing regeneration. Here, we envisioned an accurate and proactive immunomodulation strategy via delivery of IL-4 (key regulator of macrophage polarization) to promote bone substitute material-mediated regeneration.Methods: Four different IL-4 doses (0 ng, 10 ng, 50 ng and 100 ng) were delivered into rat large cranial bone defects at day 3 post-operation of decellularized bone matrix (DBM) material implantation, and the osteogenesis, angiogenesis and macrophage polarization were meticulously evaluated.Results: Micro-CT analysis showed that immunomodulation with 10 ng IL-4 significantly outperformed the other groups in terms of new bone formation (1.23-5.05 fold) and vascularization (1.29-6.08 fold), achieving successful defect bridging and good vascularization at 12 weeks. Histological analysis at 7 and 14 days showed that the 10 ng group generated the most preferable M1/M2 macrophage polarization profile, resulting in a pro-healing microenvironment with more IL-10 and less TNF-α secretion, a reduced apoptosis level in tissues around the materials, and enhanced mesenchymal stem cell migration and osteogenic differentiation. Moreover, in vitro studies revealed that M1 macrophages facilitated mesenchymal stem cell migration, while M2 macrophages significantly increased cell survival, proliferation and osteogenic differentiation, explaining the in vivo findings.Conclusions: Accurate immunomodulation via IL4 delivery significantly enhanced DBM-mediated osteogenesis and angiogenesis via the coordinated involvement of M1 and M2 macrophages, revealing the promise of this accurate and proactive immunomodulatory strategy for developing new bone substitute materials.

<p>Magnesium-doped Nanostructured Titanium Surface Modulates Macrophage-mediated Inflammatory Response for Ameliorative Osseointegration</p>

“…Thus, systematic studies are required to assess the osteogenic ability and immune system participation of biomaterials of implants. 47 Compared with the NT group, MgN showed a satisfactory effect on switching the macrophage phenotype toward M2 type. After induction by MgN, fewer macrophages expressed CCR7 and more expressed CD206.…”

M2 Macrophages Enhance the Cementoblastic Differentiation of Periodontal Ligament Stem Cells via the Akt and JNK Pathways

“…In summary, by elucidating the influence of different Mφs on the cementoblastic differentiation of PDLSCs, we highlight the role of precise immune modulation in optimizing the outcome of tissue repair for a variety of inflammatory diseases, which provides a foundation for the material design of tissue engineering [74,75]. In addition, these results confirmed by two coculture systems are convincing and valuable for further elucidating the interaction between immune cells and stem cells in vivo, which is a complex regulatory network that balances the process of tissue damage and repair.…”

Interleukin‐4‐loaded hydrogel scaffold regulates macrophages polarization to promote bone mesenchymal stem cells osteogenic differentiation via TGF‐β1/Smad pathway for repair of bone defect

“…And some inflammatory cytokines secreted by M2 macrophages could promote the osteogenic differentiation of BMSCs. 27 In this study, bone-bioactive Ca-GG hydrogel beads were successfully synthesized. Interleukin-4 (IL-4), one of the cytokines that can regulate the transformation of macrophages from the proinflammatory M1 phenotype into the anti-inflammatory M2 phenotype, 28 was incorporated into the hydrogel beads to regulate macrophage polarization and promote bone regeneration.…”