Blockade of adrenergic β-receptor activation through local delivery of propranolol from a 3D collagen/polyvinyl alcohol/hydroxyapatite scaffold promotes bone repair in vivo.

Hao Wu,Junqin Li,Yi Gao,Yue Song,Shuaishuai Zhang,Long Bi,Liu Yang,Bin Liu,Pengzhen Cheng,Sheng Miao,Guoxian Pei,Xing Lei

doi:10.1111/cpr.12725

Abstract

ObjectivesActivation of the sympathetic system and adrenergic β‐receptors following traumatic bone defects negatively impairs bone regeneration. Whether preventing β‐receptor activation could potentially improve bone defect repair is unknown. In this study, we investigated the effect of systematic administration and local delivery of propranolol through composite scaffolds on bone healing.Materials and methodsCollagen/PVA/propranolol/hydroxyapatite（CPPH）composite scaffolds were fabricated with 3D printing technique and characterized by scanning electron microscope (SEM). Micro‐CT analysis and bone formation histology were performed to detect new bone formation. Osteogenic differentiation of bone marrow stromal cells (BMSCs) and osteoclastogenesis of bone marrow monocytes cultured with scaffolds extract were performed for further verification.ResultsIntraperitoneal injection of propranolol did not significantly improve bone repair, as indicated by micro‐CT analysis and bone formation histology. However, CPPH scaffolds exhibited sustained release of propranolol in vitro and significantly enhanced bone regeneration compared with vehicle collagen/PVA/hydroxyapatite (CPH) scaffolds in vivo. Moreover, in vitro experiments indicated the scaffolds containing propranolol promoted the osteogenic differentiation and migration of rat BMSCs and inhibited osteoclastogenesis by preventing β‐receptor activation.ConclusionsThis study demonstrates that local adrenergic β‐receptor blockade can effectively enhance the treatment of bone defects by stimulating osteogenic differentiation, inhibiting osteoclastogenesis and enhancing BMSCs migration.

Highlights

The incidence of high-energy injuries continues to increase, and large bone defect cases are becoming more common in orthopaedic hospital.[1]
Major trauma and severe injury result in post-trauma stress disorder, which activates the sympathetic system and induces a catecholamine surge.[3,4,5,6]. This pathophysiologic reaction leads to host damage by activating adrenergic β-receptors. 7,8 Recently, a growing body of research has revealed that activation of β-receptors negatively modulates bone remodelling under physiological conditions 9,10 and impairs bone metabolism and bone fracture healing after trauma. 11,12 β-receptors are expressed on osteoblastic cells and osteoclast-like cells, and stimulation of β-receptors using agonists inhibits alkaline phosphatase (ALP) activity and increases osteoclastic activity in vitro.[13,14]
bone marrow stromal cells (BMSCs) were cultured in scaffold-conditioned osteogenic media with or without isoproterenol (1 μM), and the Alkaline Phosphatase Color Development Kit (Beyotime Institute of Biotechnology) was used to measure ALP activity on day 7

Summary

Introduction

The incidence of high-energy injuries continues to increase, and large bone defect cases are becoming more common in orthopaedic hospital.[1] Bone defects exceeding a critical size do not possess self-regeneration capacity and result in bone non-union. 2 the development of novel biomaterials and identification of potential therapeutic targets are urgently required to improve bone regeneration. 11,12 β-receptors are expressed on osteoblastic cells and osteoclast-like cells, and stimulation of β-receptors using agonists inhibits alkaline phosphatase (ALP) activity and increases osteoclastic activity in vitro.[13,14] This evidence indicates that the high levels of catecholamines induced by traumatic bone injury may activate adrenergic β-receptors and negatively impact bone healing process. Adrenergic β-receptors represent a potential therapeutic target to improve the treatment of bone defects

Objectives

Results

Conclusion