Optimisation of nanoclay delivery of an osteoinductive growth factor for bone tissue engineering

Abstract

Bone is the most abundant connective tissue in the body and continues to regenerate throughout adult life. Although bone has an exceptional capacity to heal and remodel, nevertheless, tumour, infection, trauma and revision surgery can all lead to significant bone loss requiring skeletal augmentation or repair. The capacity for bone to regenerate is influenced by the biological and mechanical environment in which the bone defect resides. Impaired local soft tissues, patient co-morbidities and mechanical instability can significantly affect the clinical outcome. Bone loss in the lower limb poses a complex clinical problem, requiring reconstructive techniques to enable restitution of form and function. Failed reconstruction leads to significant patient morbidity and even loss of a limb. Today, there is an array of reconstructive possibilities available including distraction osteogenesis, Masquelet techniques and cellular manipulations or “biologics”, to name a few, that can be used to attempt to salvage a limb.

The pathway to generate vascularised bone includes four essential domains: i) osteogenic cells, ii) stimulatory growth factors, iii) osteoconductive/inductive scaffolds and iv) a supportive mechanical environment. This work aims to evaluate and investigate these components, osteoinductive growth factors and scaffolds, utilising in vivo models to induce bone formation.

A nanoclay hydrogel, LAPONITE® has previously been used as a scaffold and to successfully deliver bone morphogenic protein-2 (BMP-2) in low doses to induce bone formation in murine models. On commencing this work, an ovine condylar defect model was underway that investigated the ability of LAPONITE® to deliver BMP-2 in low doses in a large animal bone defect model. Following the analysis of this study, and based on further unpublished in vitro studies, it transpired that further investigation was required to elucidate the optimum LAPONITE® concentration, the optimum gel formulation and most efficacious BMP-2 dose.

The optimum LAPONITE® concentration, formulation and BMP-2 dose was established through investigation in a series of murine subcutaneous implant studies, in which bone formation was evaluated using micro-computed tomography (micro-CT) and histological assessment. Following this, the appropriate LAPONITE® gel and BMP-2 dose was investigated in a rat posterior lumbar fusion to assess a clinically relevant in vivo model to progress the development of LAPONITE® with BMP-2 products towards clinical translation.

The ability of LAPONITE® to deliver a physiological dose of BMP-2 to induce bone induction has exciting implications for clinical translation in limb reconstruction. This work has discovered the optimum concentration of LAPONITE® to deliver BMP-2 to induce bone formation in vivo; that LAPONITE® can be used effectively without an additional collagen scaffold; and that LAPONITE® pregelling steps are not beneficial to bone formation. LAPONITE® delivery of BMP-2 can be administered through both open and percutaneous techniques. Optimising the delivery and efficacy of BMP-2 treatment has huge potential as a clinical adjunct in limb reconstruction surgery. A safeand effective technique to deliver BMP-2 to promote bony union could be the difference between an unsalvageable limb requiring amputation and a successful limb reconstruction. Ultimately, LAPONITE® delivery of BMP-2 could save limbs.

More information

Identifiers

ORCID for Richard Oreffo: orcid.org/0000-0001-5995-6726

Catalogue record

Export record