3D-printed titanium implant combined with interleukin 4 regulates ordered macrophage polarization to promote bone regeneration and angiogenesis

Da-Wang Zhao; Bing Ren; Hong-Wei Wang; Xiao Zhang; Ming-Zhi Yu; Lei Cheng; Yuan-Hua Sang; Shuai-Shuai Cao; Florian M Thieringer; Dong Zhang; Yi Wan; Chao Liu

doi:10.1302/2046-3758.107.BJR-2020-0334.R4

3D-printed titanium implant combined with interleukin 4 regulates ordered macrophage polarization to promote bone regeneration and angiogenesis

Bone Joint Res. 2021 Jul;10(7):411-424. doi: 10.1302/2046-3758.107.BJR-2020-0334.R4.

Authors

Da-Wang Zhao^{1

2

3}, Bing Ren^{4

5

6}, Hong-Wei Wang^{4

5}, Xiao Zhang^{4

5}, Ming-Zhi Yu^{4

5}, Lei Cheng¹, Yuan-Hua Sang⁷, Shuai-Shuai Cao^{8

9}, Florian M Thieringer^{8

9}, Dong Zhang^{3

10}, Yi Wan^{4

5}, Chao Liu^{3

10}

Affiliations

¹ Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, China.
² Cheeloo College of Medicine, Shandong University, Jinan, China.
³ Institute of Stomatology, Shandong University, Jinan, Shandong, China.
⁴ Key Laboratory of High Efficiency and Clean Manufacturing, School of Mechanical Engineering, Shandong University, Jinan, China.
⁵ National Demonstration Center for Experimental Mechanical Engineering Education, School of Mechanical Engineering, Shandong University, Jinan, China.
⁶ Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, Florida, USA.
⁷ State Key Laboratory of Crystal Materials, Shandong University, Jinan, Shandong, China.
⁸ Medical Additive Manufacturing Research Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland.
⁹ Department of Oral and Cranio-Maxillofacial Surgery, University Hospital Basel, Basel, Switzerland.
¹⁰ Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Jinan, China.

PMID: 34259564
PMCID: PMC8333031
DOI: 10.1302/2046-3758.107.BJR-2020-0334.R4

Abstract

Aims: The use of 3D-printed titanium implant (DT) can effectively guide bone regeneration. DT triggers a continuous host immune reaction, including macrophage type 1 polarization, that resists osseointegration. Interleukin 4 (IL4) is a specific cytokine modulating osteogenic capability that switches macrophage polarization type 1 to type 2, and this switch favours bone regeneration.

Methods: IL4 at concentrations of 0, 30, and 100 ng/ml was used at day 3 to create a biomimetic environment for bone marrow mesenchymal stromal cell (BMMSC) osteogenesis and macrophage polarization on the DT. The osteogenic and immune responses of BMMSCs and macrophages were evaluated respectively.

Results: DT plus 30 ng/ml of IL4 (DT + 30 IL4) from day 3 to day 7 significantly (p < 0.01) enhanced macrophage type 2 polarization and BMMSC osteogenesis compared with the other groups. Local injection of IL4 enhanced new bone formation surrounding the DT.

Conclusion: DT + 30 IL4 may switch macrophage polarization at the appropriate timepoints to promote bone regeneration. Cite this article: Bone Joint Res 2021;10(7):411-424.

Keywords: 3D-printed titanium implant; Interleukin 4; macrophage polarization.