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.

我们中大约有三分之一的人在一生中会骨折。虽然疼痛，但通常骨头会自然愈合。然而，在约1/20的病例中，骨愈合不良或根本不愈合。这些被称为延迟愈合或不愈合骨折。它们对受影响的人来说可能很可怕，有时需要多年的大手术和康复才能修复。他们也花费很多-约£40- 50，000/病人，与总成本在英国约£ 3.5亿每年。这些骨折可以通过植入从身体的其他部位或捐赠者收获的骨，或与手术和使用金属板固定骨治疗。许多研究小组正在研究使用药物，材料和细胞植入骨折部位，以帮助加速愈合，但没有药物可以加速或改善骨愈合。这种方法的发展每年将改善数千名患者的生活。我们认为我们可以通过使用“超声响应剂”来实现这一目标，包括微泡和纳米液滴。微泡已经被用于帮助医生更清楚地看到我们的身体内部。它们充满了气体，因为它们比我们最小的血管小，所以它们可以安全地注射到血液中。超声波被它们反射的比周围组织多得多，这使得使用它们来建立器官和组织的图像比没有它们更清晰。然而，微泡也可以被体外正确频率的超声波“激活”。这有点类似于歌剧演唱者可能引起酒杯振动的方式。通过这种方法，能量可以转移到体内存在微泡的部位，这是一个促进药物吸收和物理刺激的过程。这已被用于癌症医学，以增强化疗的输送，以杀死癌症。在这个项目中，我们想尝试开发这种方法，看看我们是否可以将药物输送到骨骼。我们的愿景是，在未来，患者可能会访问诊所，接受超声响应剂的注射，随后在骨折处接受超声刺激，以加速骨愈合。在最近的工作中，我们发现我们可以检测到人类骨折中的微泡，并且我们可以使它们在小鼠骨骼附近产生共振。这一点，结合在癌症医学方面所做的工作，给了我们信心，这个想法可能会工作。在该项目中，我们计划找出在人类和小鼠骨折时，超声响应剂可以测量。为了实现这一目标，我们将在骨折患者中进行小型试点研究，并在具有愈合或未愈合骨缺损的小鼠中进行对照研究。为此，我们将使用超声成像和检测在各个阶段注射和成像或检测造影剂。与此同时，我们将开发新的超声响应剂配方，包括微泡及其较小的表亲，纳米液滴，并在含有模拟骨折或在真实的骨组织中产生的骨折的小型“声流体”装置中进行实验，以确定正确的超声和配方。最后，我们将使用我们从这些“体外”和“离体”模型中学到的信息来测试我们可以在实验小鼠的真实的骨缺损中诱导局部分子递送的想法。只有通过这项工作，我们才能找到正确的配方和超声方法，使我们能够测试这种方法，将药物输送到患者体内，帮助他们的骨骼更快更好地愈合。我们的项目包括与NHS的同事密切互动，他们正在帮助我们进行临床试点研究，以及与大型医疗设备制造商GE Healthcare密切互动，这将帮助我们尽快将这个想法带到诊所。