Our team of ultrasound engineers from the Department of Biomedical Engineering at Cornell University developed a platform ultrasound technology in 2007 that reduces the cost and size of ultrasound devices by orders of magnitude (Figure 1). The principles behind the technology are to reduce the output impedance of the ultrasound generator and the input impedance of the ultrasound transducer to zero, to create zero resistance to energy flow and optimize electrical power transfer for battery powered ultrasound devices. This pioneering approach of zero output and input impedance pushes the efficiency of ultrasound systems, and provides ultrasound power in a pocket-sized form. Since our technologys inception, motivations from physicians have driven ultrasonic innovations to improve drug delivery in glioblastoma brain cancer therapy, develop non-invasive varicose vein treatment systems, apply ultrasound over extended periods as a pharmaceutical-free approach to pain management, and improve fetal heart rate monitoring to allow easy and consistent measurements during labor.

Ultrasound-assisted Brain Cancer Therapy (In Vivo Preclinical Studies): Scientists in our laboratory have developed and commenced testing of a new ultrasound-based drug delivery system for pre and post-resection treatment of high-grade malignant gliomas. Surgery and adjuvant radiation are standard treatments for these malignancies. However, invasive malignant cells migrate into surrounding healthy tissue and, as a consequence, are not all removed in surgery, leading to tumor recurrence, usually close to the site of the original tumor. Convection enhanced delivery (CED) has emerged as a leading investigational delivery technique for the treatment of several disorders, including glioblastoma, which presents an especially poor prognosis for patients. CED bypasses the blood-brain barrier by infusing compounds through a needle or microcatheter directly into the brain parenchyma or brain tumor. The clinical trials of CED show mixed results and suggest that the outcome of therapy depends strongly on the extent of penetration of drug into the brain, which is determined by infusion velocity, and the relative rates of convection and elimination during CED. In collaboration with Drs. Susan Pannullo and George Lewis Sr. of the Department of Neurosurgery at Weill Cornell Medical College (WCMC) and Transducer Engineering Incm., respectively, we have developed ultrasound-assisted convection enhanced drug delivery technology (UCED) to improve the penetration and spatial control of pharmaceuticals in the brain (Figure 2).

 

 

We have developed in vitro and in vivo models of UCED brain tumor treatments and have shown that combining ultrasound with traditional CED improves the penetration and distribution of tracer molecules by 4-6 times in vivo. This work involves both the basic science of transport mechanisms as well as the translational science of scaling the UCED brain cancer therapy into a large animal glioblastoma model at Cornell Veterinary Medical Center. If successful, we will transition the technology to human treatment in the next few years.

 

Non-invasive High Intensity Focused Ultrasound Varicose Vein Treatment (In Vivo Preclinical Studies): Varicose veins affect more than 30 million people in the United States each year. They cause emotional distress and discomfort for patients and, if left untreated, can progress to deep venous thrombosis, skin ulceration, limb loss or death. Clinicians perform more than 150,000 varicose vein treatments in the U.S. each year, using methods such as vein stripping, sclerotherapy, and endovenous laser and RF treatment, which together comprise a $450MM market. Because these methods are invasive, they incur added costs in training, equipment, facilities, and staff. In collaboration with Drs. Jason Spector and Peter Henderson from the Department of Surgery at WCMC, we have developed and tested the first battery-powered handheld HIFU system to non-invasively cauterize and occlude varicose veins (Figure 3).

 

By focusing ultrasound energy to a sharp point with the handheld HIFU system, we are able to successfully ablate and occlude veins without damaging surrounding tissue. The handheld device has gone through multiple design iterations with our team, and we have tested the device in both ex vivo and in vivo platforms. We will soon be incorporating low-cost ultrasound image guidance into the system and begin testing on large animal porcine models. The technology has potential to be utilized similar to a Bovie Pen for tissue cauterization in a range of clinical applications.

 

 

Wearable Ultrasound Pain Therapy Patch (Clinical Studies): Ultrasound therapy for pain and healing has been approved by the U.S. FDA and has been in use around the globe for the last 60 years. Diathermy, tissue-regeneration, pain relief and rehabilitation applications of ultrasound are primarily driven by the positive results obtained during treatments. Traditionally, ultrasound-mediated treatment has been limited to short and confined periods of 15-25 min at acoustic intensities from 1-4W/cm² over a course of weeks to months. Over the past decade, research has increasingly focused on lower-intensity ultrasound (30-1000 mW/cm²) delivered over extended 1-8hr periods. Recent studies using low-intensity ultrasound have demonstrated successful muscle rehabilitation, and tendon and facture healing resulting in pain relief. It is believed that using a lower-intensity ultrasonic treatment rgime over extended treatment periods works better with the bodys natural healing process and minimizes acoustic insult as compared to traditional higher intensity, short-term treatments. Working with Drs. Cary Reid and Ralph Ortiz from WCMC and Pain Management Specialists respectively, and the Clinical Translational Science Center, we are testing the first iPod sized ultrasound therapy device on a range of disorders including tennis elbow, arthritis, fibromyalgia, tendon and ligament tears, muscle spasms, and joint inflammation (Figure 4).

 

 

We are currently conducting multiple pilot studies in an effort to reduce pain, increase mobility, and improve quality of life for multiple patients suffering from chronic pain issues. We have further initiated the process of conducting a 50-100 patient clinical trial using the ultrasound device on osteoarthritis of the knee. The patients will receive ultrasound therapy for a minimum of 4 hrs each day during normal activity (no doctors visits required). If successful, this will potentially enable a pharmaceutical free approach to everyday pain relief.

 

Improved Fetal Heart Rate Monitoring for Mothers and Doctors (Clinical Studies): Doppler ultrasound has been used for over 20 years in measuring the fetal heart rate (FHR) during labor and delivery of neonates. However, aside from switching the signal processing from continuous-wave Doppler to pulse-wave Doppler FHR monitoring in the late 1980s, few ultrasound advances have improved the field. Our collaborator from Cayuga Medical Center, Dr. Steven Gelber, found this frustrating and with our Cornell and Transducer Engineering Inc. research team decided to improve FHR monitoring as well as uterine contraction monitoring -- using ultrasound.

 

During labor there is movement from the fetus inside the womb as well as from the mother. Due to a very limited detection range, traditional ultrasound transducers, which are strapped to the mothers belly, lose the heart rate signal. The transducer must then be repositioned by the nurse to redetect the FHR. Wireless telemetry devices for FHR monitoring exist, but FHR detection only works well if the mother and fetus do not move. We have designed a custom transducer that improves fetal tracking and spatial heart rate detection yet works with existing FHR commercially available devices from GE and Philips Healthcare (Figure 5).

 

 

Our team has designed and tested the FHR monitoring transducer in the lab and is now initiating patient testing at Cayuga Medical Center. Additionally, we have begun development of an ultrasound based solution to measure the uterine contraction strength and duration with a signal processing approach using the same ultrasound transducer used for FHR monitoring. The overall goal is to provide the doctor an ultrasound device to perform all heart rate and contraction measurements throughout the labor and delivery and not require repositioning.

 

The future of ultrasound is truly amazing with unbounded possibilities, and it will possibly cover the largest spectrum of medical related applications of any other non-ionizing energy source. Our collaborative team of engineers and clinicians seek to extend and improve ultrasound, and deliver the technology in an easy to use, pocket-sized platform.

 

This research is supported in part by the National Institutes of Health, the National Science Foundation, Weill-Cornell Brain Tumor Project, EBL Products Inc. and Transducer Engineering Inc.