New use for old drug: Local delivery of puerarin facilitates critical-size defect repair in rats by promoting angiogenesis and osteogenesis

Huijuan Cao; Lingli Li; Ling Li; Xiangbo Meng; Yanzhi Liu; Wenxiang Cheng; Peng Zhang; Yongbo Gao; Ling Qin; Xinluan Wang

doi:10.1016/j.jot.2022.05.003

New use for old drug: Local delivery of puerarin facilitates critical-size defect repair in rats by promoting angiogenesis and osteogenesis

J Orthop Translat. 2022 Jul 31:36:52-63. doi: 10.1016/j.jot.2022.05.003. eCollection 2022 Sep.

Authors

Huijuan Cao^{1

2

3

4}, Lingli Li^{1

5}, Ling Li^{1

3

4}, Xiangbo Meng^{1

3

4}, Yanzhi Liu^{1

6}, Wenxiang Cheng^{1

3

4}, Peng Zhang^{1

3

4}, Yongbo Gao⁵, Ling Qin^{1

3

7}, Xinluan Wang^{1

2

3

4}

Affiliations

¹ Centre for Translational Medicine Research & Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, PR China.
² University of Chinese Academy of Sciences, Beijing, PR China.
³ Joint Laboratory of Chinese Academic of Science and Hong Kong for Biomaterials of the Chinese University of Hong Kong, PR China.
⁴ Key Laboratory of Health Informatics, Chinese Academy of Sciences, Shenzhen, PR China.
⁵ Shenzhen Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, PR China.
⁶ Guangdong Key Laboratory for Research and Development of Natural Drugs, Department of Pharmacology, Guangdong Medical University, Zhanjiang, PR, China.
⁷ Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.

Abstract

Objectives: Large bone defect repair is a challenging clinical problem due to limited self-repair ability. A well-designed bone filling product should possess the ability to induce tissue in-growth and facilitate neovascularization and new bone formation. Puerarin has been used in clinics for a long time, and recently it was found to be able to promote osteogenesis. This study aimed to investigate a puerarin-based drug/delivery combination implant for promoting large bone defect repair.

Methods: Puerarin was incorporated into the poly (lactic-co-glycolic acid)/β-calcium phosphate (PLGA/TCP, PT) to form a porous PLGA/TCP/Puerarin (PTP) composite scaffold by low-temperature rapid prototyping technology. Its structural and degradation were analyzed in vitro. Then we employed a rat calvarial critical size defect model to assess the potency of the PTP scaffold. MC3T3-E1 cells and EA. hy 926 cells were used to investigate the underlying mechanism.

Results: PTP scaffold inherited all advantages of PT scaffold in structural, mechanical, and biodegradation, meanwhile puerarin stably and continuously released from PTP scaffold and lasted for 5 months in vitro. At 8 weeks after implantation, the PTP scaffold triggered new bone formation in the macro-pores of the scaffold and inside the scaffold accompanied by the degrading materials. The underlying mechanism revealed that the PTP scaffold induced vascular infiltration and recruit repair cells through stimulating vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP-2) expressions to promote angiogenesis and osteogenesis.

Conclusion: Puerarin-enriched porous PTP scaffold was a promising local delivery system with sustained release of puerarin for facilitating defect repair through getting synergistic angiogenic and osteogenic effects.

The translational potential of this article: The PTP scaffold presents a potential drug/device combination medical implant for large bone defect repair, which also provides a new and innovative application for the "old drug" puerarin.

Keywords: ALP, Alkaline phosphatase; Angiogenesis; BMD, Bone mineral density; BMP-2, Bone morphogenetic protein 2; BV/TV, The ratio of bone volume; CPC, Calcium phosphate cement; DXA, Dual-energy X-ray; Drug/device combination implant; FBS, Fetal bovine serum; HIF-1α, Hypoxic induction factor-1 alpha; HPLC, High-performance liquid chromatography; LT-RP, Low-temperature rapid prototyping; MRI, Magnetic resonance imaging; Osteogenesis; PLGA, Poly (lactic-co-glycolic acid); PLGA/TCP; PT, PLGA/TCP; PTP, PLGA/TCP/Puerarin; Puerarin; RSR, Relative survival rate; SEM, Scanning Electron Microscope; TRAP, Tartrate-resistant acid phosphatase; VEGF, Vascular endothelial growth factor; β-TCP, β-calcium phosphate.