MICA: Ultrasound-responsive agents for non-invasive fracture healing

MICA：用于无创骨折愈合的超声响应剂

• 批准号: MR/X009793/1
• 负责人: Nicholas Evans
• 金额: $ 123.72万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX009793%2F1
• 关键词: MICA; Ultrasound; responsive; agents; non

About one in three of us will break a bone in our lifetime. Although painful, usually the bone will heal naturally. However, in about 1/20 cases the bone heals poorly or not at all. These are called delayed union or non-union bone fractures. They can be terrible for the person affected, sometimes taking many years of major surgery and rehabilitation to fix. They also cost a lot as well - about £40-50,000/patient, with the total cost in the UK at ~£350m every year.These fractures may be treated by implantation of bone harvested from other parts of the body or from donors, or with surgery and fixation of the bone using metal plates. Many research groups are investigating the use of drugs, materials and cells implanted at the bone fracture site to help speed up healing, but there is no drug that you can take to speed up or improve bone healing. Development of such an approach would improve the lives of thousands of patients each year.We think we can achieve this by using 'ultrasound responsive agents', including microbubbles and nanodroplets.Microbubbles have been used for a long time to help doctors see inside our bodies more clearly. They are filled with a gas and, because they are smaller than the smallest of our blood vessels, they can be safely injected into the bloodstream. Ultrasound waves are reflected by them much more than by surrounding tissues, and this makes it possible to use them to build up an image of organs and tissues much more clearly than without them. However, microbubbles can also be 'activated' by the right frequency of ultrasound from outside the body. This is somewhat similar to the way in which an opera singer might induce vibrations in a wine glass. By this method, energy can be transferred into the body to a site where microbubbles are present, a process that promotes drug uptake and physical stimulation. This has been used in cancer medicine to enhance delivery of chemotherapy to kill cancers. In this project we want to try to develop this method to see if we can deliver drugs to bone. Our vision is that in future a patient might visit a clinic, receive an injection of an ultrasound responsive agent, and subsequently receive ultrasound stimulation in their bone fracture to speed up bone healing. In recent work, we have found that we can detect microbubbles in human bone fractures and that we can make them resonate close to the bones of mice. This, combined with the work done in cancer medicine, gives us the confidence this idea might work.In the project we plan to find out when during human and mouse bone fractures that ultrasound responsive agents can be measured. To achieve this, we will do a small pilot study in patients who have had a bone fracture, and a controlled study in mice that have either a healing or non-healing bone defect. To do this we will inject and image or detect contrast agents at various stages using ultrasound imaging and detection. In parallel we will develop new formulations of ultrasound responsive agents, including microbubbles and their smaller cousins, nanodroplets, and do experiments in small 'acoustofluidic' devices containing mock bone fractures, or fractures created in real pieces of bone tissue to work out the right ultrasound and formulations to use. Finally, we will use information we learn from these 'in vitro' and 'ex vivo' models to test the idea that we can induce local delivery of molecules in real bone defects in experimental mice. Only by doing this work we will work out the right formulations and ultrasound methods to enable us to test this method as a way of delivering drugs in patients to help their bones heal faster and better. Our project involves close interaction with colleagues in the NHS, who are helping us run the clinical pilot study, and with a big healthcare device manufacturer, GE Healthcare, which will help us get this idea to the clinic as fast as possible.

我们一生中大约三分之一会折断骨头。虽然很痛苦，但通常骨骼会自然健康。但是，在大约1/20情况下，骨骼愈合较差或根本无法愈合。这些称为延迟联合或非工会骨断裂。对于受影响的人来说，他们可能会很糟糕，有时需要进行多年的大手术和康复进行修复。它们的成本也很多 - 大约40-50,000英镑/患者，英国的总费用为约3.5亿英镑。这些骨折可以通过从身体的其他部位或捐助者或捐助者收获的骨骼，或使用金属板进行手术和骨骼固定来治疗这些骨折。许多研究小组正在研究植入骨折部位植入的药物，材料和细胞的使用，以帮助加快愈合的速度，但是您没有药物可以加快或改善骨骼愈合。这种方法的发展每年将改善数千名患者的生活。我们认为，我们可以使用“超声反应剂”（包括微泡和纳米动物）来实现这一目标。Microbubbles已长时间使用，以帮助医生更清楚地看到我们体内的医生。它们充满了气体，因为它们比我们最小的血管小，因此可以安全地注入血液中。超声波的反射远比周围的组织反射得多，这使得可以使用它们来建立器官和组织的图像比没有它们的图像更为清晰。但是，微泡也可以通过体外外部的正确频率“激活”。这与歌剧歌手可能在酒杯中引起振动的方式相似。通过这种方法，可以将能量转移到存在微泡的位置中，这是促进药物摄取和物理刺激的过程。这是我们在癌症医学中被用来增强化学疗法杀死癌症的。在这个项目中，我们想尝试开发这种方法，以查看是否可以将药物输送到骨骼。我们的愿景是，将来患者可能会去诊所，注射超声反应剂，然后在骨折中接受超声刺激以加快骨骼愈合。在最近的工作中，我们发现我们可以检测到人骨骨折中的微泡，并且我们可以使它们与小鼠的骨骼近乎共鸣。这与在癌症医学中所做的工作相结合，使我们有信心。在项目中，我们计划找出何时可以测量超声响应剂的人体和小鼠骨折。为了实现这一目标，我们将对患有骨骼骨折的患者进行一项小型试点研究，以及在具有愈合或非愈合骨缺损的小鼠中进行的对照研究。使用超声成像和检测，在各个阶段对比剂。同时，我们将开发超声响应剂的新公式，包括微泡及其较小的堂兄，纳米光，并在小的“大声液体”设备中进行实验，这些设备包含模拟骨碎片，或在骨骼组织中创建的分数，以便使用右手组织，以便使用右超声和配方。最后，我们将使用我们从这些“体外”和“离体”模型中学习的信息来测试我们可以在实验小鼠中诱导实际骨缺损中局部分子递送的想法。只有通过这项工作，我们才能制定正确的公式和超声波方法，使我们能够测试这种方法，作为一种在患者中输送药物以帮助他们的骨骼更快，更好的方法。我们的项目涉及与NHS中的同事进行密切互动，他们正在帮助我们进行临床试点研究，以及与大型医疗保健设备制造商GE Healthcare，这将帮助我们尽快将此想法带到诊所。