Abstract
Bone morphogenetic protein-2 (BMP-2) is considered a promising adjuvant for the treatment of skeletal non-union and spinal fusion. However, BMP-2 delivery in a conventional collagen scaffold necessitates a high dose to achieve an efficacious outcome. To lower its effective dose, we precomplexed BMP-2 with the glycosaminoglycans (GAGs) dermatan sulfate (DS) or heparin (HP), prior to loading it into a hyaluronic acid (HA) hydrogel. In vitro release studies showed that BMP-2 precomplexed with DS or HP had a prolonged delivery compared to without GAG. BMP-2-DS complexes achieved a slightly faster release in the first 24 h than HP; however, both delivered BMP-2 for an equal duration. Analysis of the kinetic interaction between BMP-2 and DS or HP showed that HP had approximately 10 times higher affinity for BMP-2 than DS, yet it equally stabilized the protein, as determined by alkaline phosphatase activity. Ectopic bone formation assays at subcutaneous sites in rats demonstrated that HA hydrogel-delivered BMP-2 precomplexed with GAG induced twice the volume of bone compared with BMP-2 delivered uncomplexed to GAG.
Highlights
Worldwide, patients continue to suffer from bone non-unions
The hydrogel components in lyophilized form were purchased from TERMIRATM (Auxigel; Stockholm, Sweden) and prepared as follows: component A was prepared by dissolving aldehyde-modified hyaluronic acid (HAA) at a concentration of 15 mg/mL in PBS and passing it through a 0.45-μm sterile filter, and component B was prepared by dissolving polyvinyl alcohol with 5% hydrazide functionality (PVAH) at a concentration of 5 mg/mL in deionized water, filtering it through a 0.22-μm sterile filter, and mixing it with Bone morphogenetic protein-2 (BMP-2) that was earlier precomplexed with dermatan sulfate (DS) or HP
First we investigated the ability of DS and HP to protect bone morphogenetic proteins (BMPs)-2 and control its release from a hydrogel scaffold in vitro
Summary
Patients continue to suffer from bone non-unions. Gold standard treatment relies on the continued use of autologous bone graft obtained from the patient’s own iliac crest [1]. This bone source has a limited quantity and the quality is dependent on the individual patient, which reduces its therapeutic potential [2]. Despite the continuing development of hormones and other bonestimulating molecules, bone morphogenetic proteins (BMPs) remain the most potent inducers of bone formation in vivo [3]. Human recombinant BMP-2 [7], has proven to be highly efficient as a bone-inducing adjuvant in animals
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