SonoLysis

When a blood clot or thrombus is formed, strands of fibrin anchor one red blood cell to another. It is these fibrin strands that form the lattice or structural matrix of the blood clot. tPA works by converting plasminogen in the blood stream to plasmin, the active enzyme that dissolves fibrin². Clinical studies have demonstrated that when ultrasound energy is applied during conventional intravenous tPA thrombolytic therapy, there is a dramatic improvement in the ability to dissolve blood clots and restore blood flow to the ischemic regions of the brain^3-6. SonoLysis is the result of ultrasound pressure waves traveling through tissue that induce a mechanical force, which in turn causes the tissues to displace or strain.

When the tissue contains fluid compartments (such as blood), the energy of the ultrasound beam is transformed into energy of fluid motion. This is called acoustic streaming. At very low pressures this streaming inside the confined areas of complex tissues such as the brain will cause a mild “stirring” action. Acoustic streaming is believed to be the primary means of ultrasound-potentiated fibrinolysis in which additional fibrin binding sites are exposed to plasmin at the site of the clot⁷. SonoLysis, therefore represents a fundamentally different approach to the treatment of ischemic stroke in which externally applied ultrasound energy can significantly enhance the clot lysis potential of conventional thrombolytic therapy.

CLOTBUST^TM-ER

Cerevast has developed a novel operator independent SonoLysis Headframe System called the ClotBust^TM-ER. This device employs multiple transducers operating at 2 MHz (the same frequency used in FDA-cleared TCD instruments). However, rather than being used as a diagnostic instrument for measuring blood flow velocity in the brain, the ClotBust^TM-ER. is designed to deliver therapeutic ultrasound energy to the region of the occluded vessel in the brain as a treatment for ischemic stroke in those patients eligible to receive intravenous thrombolytic therapy.

The device is comprised of multiple ultrasound transducers. These transducers are mounted on an adjustable head frame, which allows the transducers to be fixed in place to administer therapeutic ultrasound in the principal regions in which the majority of vessel occlusions in the brain are known to occur. The transducers do not need to be aimed as the device contains external features, which self-align the transducers based on known anthropometric landmarks. Proprietary firmware controls the ultrasound parameters, which in turn allows the device to deliver therapeutic levels of ultrasound energy necessary to achieve acoustic streaming and enhanced clot lysis within the occluded vessel of the brain without the need for a trained sonographer.

By employing this approach, Cerevast can significantly reduce the technical challenges associated with the administration of transcranial ultrasound as a new treatment for ischemic stroke, thus extending this therapy beyond dedicated stroke centers. Sonographers capable of detecting occluded cerebral artery segments are normally staffed in the larger, more sophisticated, stroke treatment capable emergency departments (EDs) or hospitals. The smaller EDs frequently administer tPA to stroke patients but generally do not have sonographers with the necessary training or expertise to conduct ultrasound exams with conventional diagnostic TCD instruments. The ClotBust^TM-ER. has therefore been designed to overcome this rate-limiting component of establishing a viable ultrasound enhanced thrombolytic solution in those EDs capable of administering tPA.

By incorporating these operator independent features into the device, it is Cerevast’s objective to enable emergency room personnel, paramedics and other health care professionals to readily employ this technology, thus providing ease of use and broad market update within the stroke treatment community.

Future Applications

Spectral Doppler Add-on Module:

The CLOTBUST^TM-ER is being developed initially as a therapeutic-only device. As such, the device will not have monitoring capability during the period in which therapeutic ultrasound energy is being administered during stroke treatment. Monitoring of blood flow in the brain with conventional single probe TCD devices is difficult to perform and typically requires a trained sonographer. Having the ability to monitor intracranial blood flow during SonoLysis treatment is an attractive add-on feature because it provides the clinician with the ability to assess recanalization of the occluded vessel on a real-time basis. The only way this can currently be performed is with conventional TCD. In the absence of a trained sonographer, hospitals typically perform CT angiography (CTA) or an MRI to assess recanalization. It should be noted, however; that both CTA and MRI only provide a point-in-time “snapshot” assessment of blood flow and do not provide the clinician with the ability to monitor blood flow on a continuous, real time basis. It is believed that the unique configuration of the CLOTBUST^TM-ER has the potential to drastically simplify this procedure and provide clinicians with the ability to not only deliver therapeutic ultrasound energy to stroke patients, but monitor recanalization at the same time.

Microspheres:

Through the acquisition of the assets of ImaRx Therapeutics, Cerevast gained title to an extensive IP estate. Many of the patents now owned by Cerevast pertain to the combination of microspheres and ultrasound as a treatment for blood clot disorders. Cerevast’s microspheres have an average diameter of 1.2 microns and are sufficiently small that they can penetrate and pass through the fibrin matrix of blood clots. Furthermore, these microspheres have the unique physical characteristic of undergoing cavitation (expansion and contraction) when subjected to the appropriate ultrasound energy levels. When Cerevast’s microspheres are cavitated by ultrasound at the site of a blood clot, mechanical energy is transferred to the surrounding fluid, further enhancing the acoustic streaming effect associated with ultrasound alone, thus enhancing dissolution of the clot.

Several clinical studies have been conducted in stroke patients combining microspheres with ultrasound and tPA^8-11. In aggregate, these studies have provided encouraging clinical results demonstrating that microspheres have the potential to further enhance the therapeutic effect of the CLOTBUST^TM-ER as a treatment for ischemic stroke.