Heparinized chitosan stabilizes the bioactivity of BMP-2 and potentiates the osteogenic efficacy of demineralized bone matrix

Soyon Kim,Jiabing Fan,Ksenia Bubukina,Chen Chen,Chung-Sung Lee,Min Lee

doi:10.1186/s13036-020-0231-y

Soyon Kim, Jiabing Fan + Show 4 more

Open Access

https://doi.org/10.1186/s13036-020-0231-y

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Abstract

BackgroundDemineralized bone matrix (DBM), an allograft bone processed to better expose osteoinductive factors such as bone morphogenetic proteins (BMPs), is increasingly used for clinical bone repair. However, more extensive use of DBM is limited by its unpredictable osteoinductivity and low bone formation capacity. Commercial DBM products often employ polymeric carriers to enhance handling properties but such carriers generally do not possess bioactive functions. Heparin is a highly sulfated polysaccharide and is shown to form a stable complex with growth factors to enhance their bioactivities. In this study, a new heparinized synthetic carrier for DBM is developed based on photocrosslinking of methacrylated glycol chitosan and heparin conjugation.ResultsHeparinized chitosan exerts protective effects on BMP bioactivity against physiological stressors related to bone fracture healing. It also enhances the potency of BMPs by inhibiting the activity of BMP antagonist, noggin. Moreover, heparinized chitosan is effective to deliver bone marrow stromal cells and DBM for enhanced osteogenesis by sequestering and localizing the cell-produced or DBM-released BMPs.ConclusionsThis research suggests an essential approach of developing a new hydrogel carrier to stabilize the bioactivity of BMPs and improve the clinical efficacy of current bone graft therapeutics for accelerated bone repair.

Highlights

Demineralized bone matrix (DBM), an allograft bone processed to better expose osteoinductive factors such as bone morphogenetic proteins (BMPs), is increasingly used for clinical bone repair
Characterization of heparinized chitosan Hep-methacrylated glycol chitosan (MeGC) was prepared by conjugation of heparin into MeGC via EDC chemistry and a hydrogel was fabricated by visible blue light crosslinking with a riboflavin initiator (Fig. 1a)
The ability of heparinized chitosan to sequester endogenous BMP-2 secreted by the encapsulated Bone marrow stromal cells (BMSCs) was further detected by immunofluorescence staining (Fig. 1e)

Summary

Introduction

Demineralized bone matrix (DBM), an allograft bone processed to better expose osteoinductive factors such as bone morphogenetic proteins (BMPs), is increasingly used for clinical bone repair. More extensive use of DBM is limited by its unpredictable osteoinductivity and low bone formation capacity. Demineralized bone matrix (DBM) is processed to reduce immunogenicity and has been used widely in the orthopedic industry [2, 3]. The mineral content of DBM is removed to better expose the osteoinductive factors present in DBM bone morphogenetic proteins (BMPs), powerful regulators for bone formation [4]. The processing eliminates stem cells and the osteoinductivity of DBM can be variable, and clinical failure in orthopedic applications is reported high compared to autograft bone [5].

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