The focus of this project has been collection of proof of concept data for a new first-in-class bone graft substitute targeting the repair of significant fractures (e.g. non-union and critical fractures). The tasks within the project have focussed on initial demonstration of efficacy and safety of the system for both human and veterinary purposes. The bone graft material is being developed from an underpinning biomaterial based technology for the efficient, low dose, delivery of growth factors, such as the clinically relevant bone morphogenetic protein 2 (BMP-2), a potent stimulator of stem cell osteogenesis, and new bone formation clinically. Currently there are a number of commercial BMP-2 products available for clinical bone repair which utilise supraphysiological doses of BMP-2 (1.5 mg/ml). These products stimulate bone formation for the purposes of fracture repair and spinal fusion procedures, although have been linked to significant off-target effects such as ectopic bone formation and even cancer highlighted by an FDA warning. These off-target effects are related to the burst release of implanted BMP-2 and the high doses which are needed to maintain a localised stimulatory effect.
The underpinning technology we have developed, HealiOst, is an implant coating which localises growth factors (e.g. BMP-2) to the implant surface and increases the stimulatory efficiency of the growth factor through synergistic integrin and growth factor cellular signalling. The relevancy being that much lower doses are required (e.g. 50 ug/ml for veterinary cases) and therefore risk of clinical complications is expected to be reduced. HealiOst relies on the bioactive properties of poly(ethyl acrylate) (PEA), which spontaneously stimulates fibrillogenesis of the extracellular matrix protein fibronectin (FN) when adsorbed from solution onto the polymer. FN fibrillogenesis increases availability of both the cell and growth factor binding sites on the molecule (FNIII9-10 and FNIII12-14 respectively) allowing a secondary adsorption of growth factor to the surface. This tripartite coating technology (PEA, FN and BMP-2) could be applied to a variety of surfaces and implant materials. In this project we have applied the HealiOst coating to commercial ceramic (hydroxyapatite, HA and β-tricalcium phosphate, β-TCP) granules for the purposes of bone grafting, augmented by low dose, high efficiency, BMP-2.
This proof of concept project has largely been developed due to an initial veterinary fracture case (humeral fracture, Münsterlander dog) which was successfully treated with HealiOst coated granules in 2017 at the Glasgow Small Animal Hospital. This case was treated with the experimental treatment on compassionate grounds, i.e. to avoid amputation or euthanasia of the patient. In its current format HealiOst coated granules are likely to constitute a Class III medical device with two ancillary medicinal products (FN and BMP-2) when considered for human use. The regulatory pathway for such devices is lengthy and as such strong data supporting efficacy is required at the outset to support further clinical and commercial translation of the product. In this project we have focussed on three key topics of development.
Firstly, we have examined the product formulation and production methodology. We have tested a new synthetic granular substrate for the HealiOst coating and defined appropriate sterilisation procedures which will maintain bioactivity (ability to stimulate osteogenesis and bone formation).
Efficacy for the new granular bone graft was assessed through an in vivo murine model and also through a series of veterinary fracture cases. Data produced in these studies has provided initial demonstration of the product’s potential for bone repair, stimulating new bone formation in challenging clinical scenarios. In addition, no safety issues have been seen in either study as a result of the use of HealiOst although further studies will need to be carried out to confirm this. The results of these studies support the application of the product for both veterinary and human orthopaedic use.
The final area of work has been translational and commercial planning. An externally produced market report, funded by BBSRC, has provided guidance on placement of the product within the veterinary market whilst a health economics assessment has examined room for innovation within the human orthopaedic market. We have also partnered with a medical device manufacturer to produce the polymer coated granules for future pre-clinical and clinical studies (Histocell, Spain). Sufficient planning has now been made to present the opportunity to investors with the goal of securing funds to form a new university spin-out.
Impact is currently early stage and the regulatory and funding requirements for this technology to reach market are significant. However, the HealiOst granular graft material surpasses current bone graft products on the market (or could be used to augment them). It exceeds the capability of synthetic ceramic graft through the addition of growth factors and it provides increased safety over existing growth factor products due to the low doses used. The expected impact of this product is primarily clinical with the expectation that safer fracture repair be achieved and that larger non-union defects could be repaired. Currently clinicians rely on autograft but this has limitations of supply. By providing an efficacious, off-the-shelf, alternative we expect significant disruption in the treatment of major bone defects as we move through clinical trials. Commercially we expect to derive impact through the formation of a university spin-out and are considering options for raising investment.
