Bubbles for bone: acoustic stimulation for drug delivery in fracture repair.

优先协调：跨学科骨折及其相关并发症是一个主要的社会问题，随着人口老龄化，这个问题会变得越来越严重。延迟的骨愈合和延长的康复每年给欧洲经济造成390亿欧元的骨损伤成本，而英国每年约有15万例手腕、椎体和髋部骨折造成21亿英镑的损失。目前的临床干预措施，包括机械固定或更罕见的生物材料和/或生物活性药物，有一部分骨折不能适当愈合。因此，迫切需要新的治疗方法。到目前为止，还没有临床批准的全身治疗骨折的方法。我们正在开发这样一种方法。在初步工作中，我们发现已知大小的纳米颗粒（NPs）在骨折后的特定窗口内积聚在损伤部位。我们已经使用这种方法在骨折愈合的不同阶段选择性地将治疗分子输送到损伤部位，而不会破坏愈合组织，而愈合组织的完整性通常是令人满意的结果的关键。除了使药物在骨折部位被动释放之外，这些观察结果现在为远程和主动控制骨修复中的药物释放和组织刺激提供了令人兴奋的机会。在本研究中，我们建议通过将超声响应气泡输送到骨折部位来尝试这一点。超声波刺激气泡使它们产生共振。在我们的初步数据中，我们已经表明，这导致气泡相关药物的释放，改善附近细胞对化合物的吸收，以及通过直接膜相互作用或通过细胞外介质剪切对细胞的机械刺激。最近，我们发现可以在纳米尺寸范围内制造声响应气泡，并且它们在裂缝处积聚。这意味着我们将能够在骨折部位定位含有药物的纳米气泡，然后用超声波远程刺激它们，释放它们的货物，并对周围组织产生机械刺激。在本次学习中，学生将首先开发和优化纳米气泡和超声响应纳米液滴配方（在超声刺激下形成微泡），以证明这些制剂可以同时用于输送药物和机械刺激干细胞，诱导其在体外模型中的分化。然后，学生将确定损伤后导致气泡定位到骨折骨痂的尺寸和化学特征。最后，学生将在体内测试声刺激骨折骨痂局部气泡是否会影响骨折愈合的速度和质量。该学生将与南安普顿大学的干细胞生物学、机械生物学、纳米技术和超声波专家一起接受培训

Priority Alignment: InterdisciplinaryBone fractures and their associated complications are a major societal problem that is set to get significantly worse as our population ages. Delayed bone healing and extended rehabilitation contribute to the 39 billion Euros per year cost of bone injuries to the European economy, and approximately 150,000 wrist, vertebral and hip fractures cost the UK £2.1 billion annually. A proportion of bone fractures fail to heal appropriately with current clinical interventions, which include mechanical fixation or, more rarely, biomaterials and/or bioactive agents. New therapies are therefore urgently required. As yet, there is no clinically approved, systemic therapy for bone fracture. We are developing such an approach. In preliminary work, we have found that nanoparticles (NPs) of known size accumulate at injury sites during specific windows post-fracture. We have used this approach to deliver therapeutic molecules to the injury site selectively at different phases of fracture healing without disrupting the healing tissue, the integrity of which is often critical to satisfactory outcomes. Aside from enabling the passive release of drugs at fracture sites, these observations now provide the exciting opportunity to remotely and actively control drug release and tissue stimulation in bone repair. In this studentship, we propose to attempt this by delivering ultrasound-responsive bubbles to the fracture site. Ultrasound stimulation of bubbles causes them to resonate. In our preliminary data, we have shown that this results in the release of bubble-associated drugs, improved uptake of compounds in nearby cells, and mechanostimulation of cells through either direct membrane interaction or via shear of extracellular media. More recently we have found that acoustically-responsive bubbles can be fabricated in the nanometre size range and that they accumulate at fracture sites. This means we will be able to localise drug-containing nanobubbles at bone fracture sites, before remotely stimulating them with ultrasound to both release their cargo and mechanostimulate the surrounding tissue.In this studentship, the student will first develop and optimise nanobubbles and ultrasound-responsive nanodroplet formulations (which cavitate to form microbubbles upon ultrasound stimulation) to demonstrate that these agents can simultaneously be used to deliver drugs and to mechanostimulate stem cells, inducing their differentiation in in vitro models. The student will then determine which size and chemical characteristics lead to localisation of bubbles to the fracture callus post-injury. Finally, the student will test in vivo whether acoustic stimulation of fracture callus-localised bubbles affects the rate and quality of bone fracture healing. The student will train with experts in stem cell biology, mechanobiology, nanotechnology and ultrasonics from established experts at University of Southampton