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

在本研究中，我们建议通过向骨折部位输送超声响应气泡来尝试这一点。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，附近细胞中化合物的吸收改善，以及通过直接膜相互作用或通过细胞外介质的剪切对细胞进行机械刺激。最近，我们发现可以在纳米尺寸范围内制造声响应气泡，并且它们在断裂部位积聚（图2）。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以释放它们的货物并机械刺激周围组织。在这个实习中，学生将首先开发和优化纳米气泡和超声响应纳米液滴制剂（在超声刺激下空化形成微泡），以证明这些药物可以同时用于递送药物和机械刺激干细胞，诱导它们在体外模型中分化。然后，他或她将确定哪些尺寸和化学特性导致气泡定位到损伤后的骨折骨痂。最后，学生将在体内测试骨折胼胝局部气泡的声学刺激是否会影响骨折愈合的速度和质量。学生将与来自UoS的专家的干细胞生物学，机械生物学，纳米技术和超声波专家一起培训，并与牛津大学（生物医学超声波，生物治疗和生物制药实验室）合作。

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 (Figure 2). 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. He or she 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 UoS, and with a collaboration with the University of Oxford (biomedical ultrasonics, biotherapy and biopharmaceuticals laboratory).