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

Abstract

Objectives Activation 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 methods Collagen/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. Results Intraperitoneal 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. Conclusions This 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.

Effect and mechanism of propranolol on promoting osteogenic differentiation and early implant osseointegration

“…The present study investigated the effects of β-AR blocker propranolol on osteogenesis in an animal model. The results demonstrated that propranolol promoted osseointegration of implants in rabbits, which is consistent with conclusions of previous studies (7,50), suggesting that propranolol enhances bone regeneration and implant osseointegration.…”

“…MScs serve as a source of osteochondral progenitors that invade bone sites, proliferate and differentiate into cartilage and bones (59). β-AR antagonists promote MSc osteogenesis (50,55). In the present study, propranolol promoted osteogenic differentiation of MScs while inhibiting their proliferation.…”

“…Multiple studies have shown that propranolol inhibits expression of β2-AR (47,48). Previously, the effect of propranolol on bone metabolism has received attention (41,49,50). Minkowitz et al (49) reported that mineral deposition and bone formation increase in a rat model of surgical fracture treated with propranolol for 9 weeks.…”

Review of the Applications of Biomedical Compositions Containing Hydroxyapatite and Collagen Modified by Bioactive Components

“…Li et al [317] also carried out studies on the combination of hydroxyapatite, collagen, and a synthetic polymer, i.e., PLGA. The main objective of their work was to develop a new methodology of homogeneous introduction Among the combinations of collagen/hydroxyapatite/polymer, the polymer components are mainly polycaprolactone (Figure 17) [311], poly(vinyl alcohol) (Figure 18) [312] and poly(lactide-co-glycolide) (Figure 19) copolymer [313]. For example, the research subject of Prosecka et al [314] was to develop a three-dimensional scaffold based on type I collagen and hydroxyapatite enhanced with polycaprolactone nanofibers, autologous mesenchymal stem cells (MSC) in the osteogenic medium, and with a solution containing thrombocytes (TRC).…”

Regulation of bone metabolism mediated by β-adrenergic receptor and its clinical application

“…Similarly, another animal experiment found that propranolol (PRO), a nonselective BB, promoted osteogenic differentiation and migration of rat BMSCs in vitro and inhibited osteoclast formation by inhibiting β-AR activation. The above studies suggest that BB might become an alternative antiosteoporosis drug to prevent osteoporosis and increase bone mass[ 15 ].…”