Stroke remains a leading cause of disability and mortality worldwide. The main treatment options are (i) mechanical removal of blood clots using a specially designed catheter or (ii) the clot-busting drug, tissue plasminogen activator (tPA). Unfortunately, due to its potentially severe side effects, only a small fraction of patients is eligible for treatment with tPA. Ultrasound and microbubbles have been shown to enhance the efficacy of thrombolytic drugs and hence reduce the doses required, but delivering sufficient quantities of microbubbles to occluded vessels presents a significant challenge.
To address this challenge, we have created microbubbles containing magnetic nanoparticles that can be localised to a target area of the body using an externally applied magnetic field. We have shown that by magnetically targeting the microbubbles we can produce a significant enhancement in the concentration of microbubbles at the site of a clot and in the rate of clot dissolution. Using this system we have also demonstrated intracellular delivery of conventional small molecule drugs and small interfering RNA.
A further challenge for clinical applications, is generating a sufficient magnetic force at relevant tissue depths in humans. We have therefore also developed arrays of permanent magnets capable of producing high field gradients without the need for large electromagnetic or superconducting systems. These enable targeting at tissue depths of several centimetres and under physiologically relevant flow conditions. We have also combined these arrays into hybrid probes incorporating both single element and array ultrasound transducers to enable simultaneous targeting, imaging and activation of microbubbles for treatment delivery.
Magnetic microbubbles targeted in a vessel-mimicking phantom using a Halbach array
The use of minimally invasive procedures to treat heart and artery problems has increased over the years. These procedures require the insertion of needle(s) in the groin artery to create a so-called “keyhole,” which then provides access for instruments to other locations in the body (such as the heart and the arteries). At the end of these procedures, the keyhole is closed to stop bleeding.
A complication of such minimally invasive surgeries may occur when the hole in the artery is not sealed completely, resulting in bleeding from the hole. The flowing blood is initially contained by the surrounding tissue which is called a pseudoaneurysm (as compared to a true aneurysm which is formed as part of a natural disease process). If left untreated, a pseudoaneurysm can become bigger as the bleeding continues, resulting in gross swelling, pain, and sometimes skin ulcers due to the pressure built up within the pseudoaneurysm.
The standard treatment for pseudoaneurysms is to perform open surgery and directly repair the bleeding hole. However, open surgery is associated with increased risks such as wound infection and those resulting from the requirement for general anaesthesia. An accepted alternative method of treating pseudoaneurysms is to directly inject medication (thrombin) to induce clotting of the pseudoaneurysm, thereby indirectly sealing the keyhole as blood will no longer flow though the cavity of the pseudoaneurysm as it is occupied by clots. Unfortunately, because thrombin is a very potent medication that rapidly induces clotting, a potential complication of thrombin injection is the outflow of thrombin from the pseudoaneurysm through the keyhole and back into the artery. This free thrombin may then cause clotting within the native artery and impede blood flow. To avoid this, thrombin injection is only administered in cases where the shape and size of the pseudoaneurysm are considered favourable.
We have developed a magnetic microbubble formulation to which thrombin can be directly attached. This allows injected thrombin to be trapped and held in the pseudoaneurysm by the application of a focused magnetic field while simultaneously imaging the location of the microbubbles using ultrasound. This enables a much larger proportion of patients to be treated safely without the need for open surgery.