Title: Controlled Strontium Release from Resorbable Devices to Improve Osteoporotic Fracture Fixation
Funder: Dunhill Medical Trust

Abstract: A fracture fixation device designed specifically for the older, osteoporotic population is urgently needed. We aim to address this, thereby generating transformational impact that can improve quality and extent of life for millions of osteoporotic patients. We target clinical launch within a 10-year time scale, by which point the UK population over 50 will be in excess of 26 million(6). Clinically, strontium, in the form of strontium ranelate used systemically (Protelos®), has been shown to reduce the risk of osteoporotic fractures in older women(2). However, the increased risk of myocardial infarction, and other reported side-effects(3) has led to the withdrawal of this drug (2017). Our new approach is timely in that we propose a locally delivered alternative, incorporated within bioresorbable fracture fixation devices. Bioresorbable devices have seen significant clinical success in fracture fixation and are a promising alternative for metallic devices. We have developed a surface-modifying technology which can be applied to bioresorbable polymer fixation devices, resulting in enhanced release of incorporated bioactives(10, 11). We now propose to use this technology to address the unmet need of osteoporotic fracture in older patients by incorporating Strontium (Sr) into a bioresorbable fixation device. Aim: To develop and test a strontium-doped bioresorbable polymer device in vitro and in vivo. Study Objectives: 1. Demonstrate controlled release of incorporated strontium ions from bioresorbable polymers 2. Validate that this is an effective means of enhancing bone quality using an osteoporotic animal model 3. Use in vitro systems to understand dose response of relevant primary cells to strontium; 4. Investigate differences in response of cells from osteoporotic patients to strontium, compared to healthy donors. Sr will be incorporated into poly(lactic-co-glycolic acid), PLGA, at a range of concentrations. Electron beam surface modified and non-treated specimens will be compared in cell free dissolution studies to determine Sr release rates. In vitro studies using hMSC cells derived from “healthy” and osteoporotic donors will estimate the therapeutic dose of Sr through investigating cell response. Finally, the ability of Sr-doped and surface modified resorbable PLGA pins to aid osteoporotic fracture repair will be assessed in vivo using an osteoporotic rat model. Due to the multidisciplinary nature of this investigation, the results will have significant broad academic impact, be of relevance to clinicians and industry and, most importantly, if this technology can be developed into an effective clinical product, it would address an unmet need relating to fracture treatment for older, osteoporotic patients.

Lay abstract: Osteoporosis leads to nearly 9 million fractures annually worldwide and these mainly effect the older population. The patient's bone quality is poor meaning that fractures don't heal well or not at all. Strontium has been shown to increase new bone and prevent bone loss in human and animal studies but when given to patients orally (as a pill) it increases the risk of heart attack, as well as causing other side-effects. We are seeking to develop a clinical treatment that delivers strontium directly to broken bones, therefore avoiding side-effects caused by the oral drug. Bone fractures often require a fixation device such as a plate or screw to stabilise the bones until healing can occur. In patients with frail bones- osteoporosis- the bone is so poor that the plates and screws (fixators) don't hold. A bit like trying to get a screw to hold in cardboard! Strontium is a metal similar to calcium which has been shown to encourage new bone to form. We plan to put strontium into a 'bioresorbable' fixator, so that new bone is encouraged while the fracture heals. Bioresorbable polymers (plastic materials that are degraded by the body over time and replaced with normal tissue) have been used to make screws and pins for fracture repair for some time. It is possible to include a "bioactive agent" within these polymers to make them more effective and we have developed a method of treating the surface of the polymer to control release of the "bioactive agent". The questions we would like to answer are: (1) can we control strontium release from a polymer to achieve good local therapeutic doses (2) will these improve local bone quality enough to improve fracture repair. Our experimental plan will involve loading a bioresorbable polymer with different levels of strontium and treat the surface with low energy electron beam irradiation to optimise the delivery rate. We will then measure the strontium released over time. From this, an ideal concentration of strontium will be chosen and pins made with this formulation will be implanted into an osteoporotic rat model. These animals have features similar to humans. The strontium-loaded polymer will be implanted into the shin bone and, at various time points, the amount of bone around the implant and the strength of the bone will be measured.

Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL;INJURIES AND ACCIDENTS