MICA: Ultrasound-responsive agents for non-invasive fracture healing
Lead Research Organisation:
University of Southampton
Department Name: Human Development and Health
Abstract
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.
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.
Technical Summary
Bone fractures and their complications are a societal challenge with an estimated cost to the UK economy of more than £5 billion every year. Around 5% of bone fractures fail to heal properly and can be devastating for the patient affected. This risk increases with ageing and with underlying disease. Current interventions require surgery and have the associated risk of disease transmission or donor site morbidity.
We are exploring ultrasound responsive agents (USAs), including microbubbles and nanodroplets, as a means of minimally invasive drug delivery for promoting bone fracture healing. USAs can be induced to cavitate energetically in tissues by remote ultrasound excitation. We and others have found this improves vascular permeability and molecular delivery in applications including oncology, and several formulations are in clinical development. Our new preliminary data indicate that (1) microbubbles can be detected in human bone fractures; (2) ultrasound responsive agents can be manipulated in bone defects in rodent models; and (3) osteogenic molecules can be incorporated in USAs and release their payload on remote ultrasound activation. In order to develop this approach to clinical application in this project we propose:
- to quantify the perfusion of healing and non-healing bone fractures by ultrasound responsive agents with respect to time in human subjects and mouse models;
- to determine ultrasound and formulation parameters necessary for inducing local tissue penetrance of fluorophores and signalling activity of putative anabolic agents in organotypic and mouse models of bone repair.
In achieving these aims, we will determine the ultrasound and formulation parameters necessary to induce biological activity in bone fractures, paving the way for development of this technology to the clinic.
We are exploring ultrasound responsive agents (USAs), including microbubbles and nanodroplets, as a means of minimally invasive drug delivery for promoting bone fracture healing. USAs can be induced to cavitate energetically in tissues by remote ultrasound excitation. We and others have found this improves vascular permeability and molecular delivery in applications including oncology, and several formulations are in clinical development. Our new preliminary data indicate that (1) microbubbles can be detected in human bone fractures; (2) ultrasound responsive agents can be manipulated in bone defects in rodent models; and (3) osteogenic molecules can be incorporated in USAs and release their payload on remote ultrasound activation. In order to develop this approach to clinical application in this project we propose:
- to quantify the perfusion of healing and non-healing bone fractures by ultrasound responsive agents with respect to time in human subjects and mouse models;
- to determine ultrasound and formulation parameters necessary for inducing local tissue penetrance of fluorophores and signalling activity of putative anabolic agents in organotypic and mouse models of bone repair.
In achieving these aims, we will determine the ultrasound and formulation parameters necessary to induce biological activity in bone fractures, paving the way for development of this technology to the clinic.
