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

在我们的有生之年，大约三分之一的人会骨折。虽然疼痛，但通常情况下，骨骼会自然愈合。然而，在大约1/20的病例中，骨愈合很差或根本不愈合。这些骨折称为延迟愈合或不愈合骨折。对受影响的人来说，它们可能是可怕的，有时需要多年的大手术和康复才能修复。这些骨折的费用也很高--每个患者大约40-50,000 GB，英国每年的总费用约为3.5亿GB。这些骨折可以通过植入从身体其他部位或捐赠者那里获取的骨来治疗，或者通过手术和使用金属钢板进行骨固定来治疗。许多研究小组正在研究使用在骨折部位植入的药物、材料和细胞来帮助加速愈合，但没有任何药物可以加速或改善骨骼愈合。这种方法的发展每年将改善数以千计的患者的生活。我们认为我们可以通过使用包括微泡和纳米液滴在内的“超声响应剂”来实现这一点。微泡已经被使用了很长时间，以帮助医生更清楚地看到我们体内的情况。它们充满了一种气体，因为它们比我们最小的血管还小，可以安全地注入血液中。与周围组织相比，超声波被它们反射得更多，这使得使用它们来建立器官和组织的图像比没有它们要清晰得多。然而，微泡也可以被来自体外的合适频率的超声波“激活”。这有点类似于歌剧演员在酒杯中诱发振动的方式。通过这种方法，能量可以转移到体内存在微泡的地方，这是一个促进药物摄取和物理刺激的过程。它已被用于癌症药物，以增强化疗的传递，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上。我们的设想是，未来患者可能会去诊所，接受超声波响应剂的注射，然后在他们的骨折处接受超声波刺激，以加速骨骼愈合。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，我们可以让它们与小鼠的骨骼产生共鸣。这一点，再加上在癌症医学上所做的工作，给了我们这个想法可能奏效的信心。在这个项目中，我们计划找出在人类和小鼠骨折期间，什么时候可以测量超声波响应剂。为了实现这一目标，我们将在骨折患者中进行一项小型先导性研究，并在骨缺损愈合或未愈合的小鼠身上进行对照研究。为了做到这一点，我们将在不同阶段使用超声成像和检测来注射和成像或检测造影剂。与此同时，我们将开发超声响应剂的新配方，包括微泡及其较小的近亲纳米液滴，并在包含模拟骨折或在真实骨组织中造成的骨折的小型“声流控”设备中进行实验，以确定正确的超声波和配方。最后，我们将使用我们从这些‘体外’和‘体外’模型中学到的信息来测试我们可以在实验小鼠的真实骨缺损中诱导分子局部传递的想法。只有做了这项工作，我们才能制定出正确的配方和超声波方法，使我们能够测试这种方法，将其作为一种在患者体内传递药物的方式，帮助他们的骨骼更快更好地愈合。我们的项目涉及与帮助我们进行临床试点研究的NHS的同事以及大型医疗设备制造商GE Healthcare的密切互动，GE Healthcare将帮助我们尽快将这个想法带到临床上。

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.