VisualSonics

VisualSonics is a Canadian preclinical imaging systems company. It is currently the world’s sole manufacturer of high-frequency ultrasound systems designed specifically for scientific research, with a wide portfolio of products catering towards oncology, cardiovascular research, neurobiology, gene delivery, and clinical applications of high resolution ultrasound. In addition, it is seen in the industry as a constant innovator of novel technologies, including fibered fluorescence microscopy and photoacoustic tomography.

VisualSonics is a global organization with presence in more than 30 countries. Its global headquarters are based in Toronto, Canada and the European headquarters are based in Amsterdam, Netherlands.

History

VisualSonics was founded in 1999 by medical physicist Dr. Stuart Foster, who has been involved in the development of high-frequency ultrasonic systems since 1983. The company was started with support from the Canadian Institutes of Health Research (CIHR), Ontario R&D Challenge Fund (ORDCF), National Cancer Institute of Canada (NCIC), and venture capital investment.

VisualSonics launched its Vevo^® 660 micro-ultrasound system in 2003. By 2005, the company had sold over 200 systems and experienced a 145% compounded annual growth rate. The company also launched its Vevo^® 770 system that year, which drastically improved upon the system’s user-friendliness and stability, in addition to a multitude of functionality enhancements.

In September 2005, VisualSonics opened its European sales operations headquarters in Science Park, Amsterdam. This is a significant landmark for the company because it represents the tremendous growth the company has enjoyed in just 2 years. Ever since then, VisualSonics has been actively expanding its markets and is now considered the world leader in small animal in vivo imaging.

In October 2008, VisualSonics released the world’s first high frequency linear array transducers in its Vevo^® 2100 system. The launch of this system marked a jump over previous products in the image quality, speed and functionality available.

In November 2008, VisualSonics announced an exclusive partnership with Seno Medical to develop a pre-clinical research system involving [...] edge photoacoustic tomography technology. Scheduled to be released in late 2010, the system will be the first commercially available photoacoustic imaging system in the world.

In May 2009, VisualSonics introduced the [...] edge Cellvizio^® LAB in vivo Fluorescence Imaging System in collaboration with Mauna Kea Technologies. The technology revolves around fiber optic fluorescence microscopy, in which a tiny probe (as small as 300 μm in diameter) is inserted into living animals (eg. a mouse brain) to visualize biochemistry and biological processes in real-time. VisualSonics soon announced an add on technology named NeuroPak^TM which allows the probe to be attached to brains of freely-moving, conscious mice to enable a novel approach to the observation of neurochemistry and neurological processes in behavioral studies.

The number of exciting new technologies brought by VisualSonics in the past few years demonstrates the company’s dedication towards continuous improvement and innovation in the field of pre-clinical and clinical, non-invasive, high-resolution imaging.

Technology

The cornerstone of VisualSonics technology is the ability to produce ultra-high frequency ultrasonic transducers. VisualSonics proprietary technology is used in the fabrication of both single element mechanically sweeping probes and the linear array probes used in the Vevo^® 2100.

Normal clinical ultrasound systems operate at frequencies below 15 MHz. The high VisualSonics scanning probes utilize frequencies as high as 80Mhz, and provide resolution as low as 30 μm. Contrast this to the more common clinical systems, with resolutions in the 100’s of μm.

The Vevo^® family of instruments provides functionality similar to that found on a clinical ultrasound instrument, but at much higher resolution. Imaging a murine heart with a clinical instrument provides a low resolution picture of the organ, whereas with the high frequency capabilities of the Vevo systems, the murine heart is visible in great detail, with enough clarity to make important measurements of cardiopulmonary function. For the cancer researcher, the resolution afforded allows very precise measurements of tumor volume and vascularity, important factors in the study of oncogenesis, treatment efficacy and disease pathology.

The Cellvizio^® LAB Fluorescence Imaging System utilizes a bundle containing 10’s of thousands of parallel optical fibers to transmit an image from the tip of the probe to the complex optics of the instrument. A laser is scanned across every individual fiber 12 times per second, and the fluorescent signal from the tissue at the distal tip of the probe is detected back along each individual fiber by a sensitive detector. Each complete sweep of the laser across the proximal end of the fiber bundle creates a single frame of the image. The instrument is technically a confocal microscope, as the excitation light (scanning laser optics) and detector optics are focused on the same points during the construction of the image.

Products

VS40

The VS40 was produced by VisualSonics between 2000-2003. It represented the first time that a high-frequency ultrasound system was ever designed specifically for animal research. The system was more of a prototype device than a first-generation product, and it was sold primarily to research institutions. Even so, the VS40 was hailed by the scientific community as producing far superior images than clinical systems. The VS40 system involved a single element mechanical transducer that could emit ultrasound waves in the range of 20 to 55 MHz. Imaging resolution was between 60 μm to 100 μm, compared to about 300 μm for clinical systems. Only 2 dimensional image acquisition was possible, of up to 4 frames per second. Thus, the Doppler function was only suitable for imaging low velocity blood flow in veins, small arteries, arterioles, or in the embryonic vasculature.

Vevo^® 660

With much supporting interest from the scientific community, VisualSonics released its second-generation system in 2003, named the Vevo^® 660. This was the company’s first truly commercial product. The ultrasound transducers were optimized to 30 to 55 MHz. Image resolution was significantly improved to 30 μm, and the system was able to construct 3D images based on a compilation of 2D images. Image acquisition was as fast as 30 frames per second, which is significantly better for imaging fast events such as heartbeats and blood flow in small animals. Different software enhancements such as Power Doppler gave researchers more flexibility in studying blood flow and other functional information.

The Vevo^® 660 system was made by researchers, and thus was constructed with researchers' needs in mind. The whole system was made much more user-friendly with an integrated anesthesia system, and image guided injection system. This allowed researchers to reduce the need for invasive surgeries when specific substances such as drugs and stem cells needed to be injected at an exact location in the animal body to allow for the most accurate results.

Vevo^® 770

The Vevo^® 770 micro-ultrasound system was released in 2006 to further improve upon and cater to the needs raised by the research community after using the Vevo^® 660. Specifically, frame rates were enhanced to 100 frames per second, compared with 30 in the Vevo^® 660. This allowed researchers to visualize very quick events in small animals (mice heartbeat etc) better. Furthermore, improved electronics and signal detection allowed image penetration depth to increase by about 25%. Although data collection is typically very fast for ultrasound, data analysis could take significant time depending on the experiences of the user and software used. As such, VisualSonics developed many additional software options to be integrated with the Vevo^® 770 system, in order to further improve upon throughput speed, for which ultrasound is known for. For example, new features on the Vevo^® 770 include Power Doppler, a mode that allows for the visualization and quantification of relative microvascularity in vivo for anti-angiogenic studies. In addition, Advanced Cardiovascular Functionality provides Tissue Doppler Imaging (TDI), Integrated Blood Pressure Measurement, Anatomical M-Mode, Automated Left Ventricular Quantification, and Advanced Measurements and Annotation Functionality.

The system continues to be improved upon for user-friendliness. The Vevo^® 770 was designed to be more ergonomic and upgradable. In addition, an integrated animal platform was also released, allowing the researcher to monitor in real time animal physiology such as heart rate, temperature rate, respiration rate, and blood pressure while they are being imaged by ultrasound.

Vevo^® 2100

The fourth-generation Vevo^® 2100 released in 2008 is a large technological improvement over previous products. One of the biggest changes is that single-element mechanical transducers offered on previous systems were upgraded to 256-element solid state transducers. This is not only the world's first array transducer technology to be released for preclinical imaging, but also significantly increased transducer reliability, and the quality of images produced. Frame rates are also drastically improved to 300-400 frames per second, and up to 1000 frames per second in a narrow field of view. Many software enhancements were also offered, such as Color Doppler for visualizing direction of blood flow, and VevoStrain to quantify advanced myocardial functions. The Vevo^® 2100 continues to become more user-friendly to the average researcher. Datasets collected from experiments can now be exported in various open formats for management and analysis.

The release of the Vevo^® 2100 was accompanied by many novel software and hardware enhancements designed specifically for cancer imaging, as the company began its aggressive campaign towards research in this area. This was accompanied by the support of over 100 recent publications in top journals such as Cancer Research, Science, PNAS, Clinical Cancer Research, etc with applications of the Vevo^®. With microbubble contrast agents (2 μm diameter) that can be biotinated to endothelial molecular markers, events such as neoangiogenesis of tumors can now be observed and quantified in real-time. The system also offers a high-throughput way of quickly quantifying tumor size (>50 μm) before they are palpable.

SoniGene™

The Vevo^® SoniGene™ is an ultra-low frequency ultrasound device that is integrated with the Vevo^® systems. The SoniGene™ delivers a low frequency/high-powered ultrasound pulse sequence. When used in conjunction with the contrast agents, SoniGene™ will cause a sonoporation of the targeted cells and allow the gene or [...] to transfect to the cellular level. This concept has been demonstrated in many scientific journals. Contrast agents can also act as a carrier agent for the gene or [...] to the targeted site. Research has yet to yield a conclusive theory on the mechanism of transfer and so the debate continues. The current theory for microbubble-enhanced transfection is the destruction of each microbubble causes a chain reaction of cavitation events. This cavitation opens transient pores in cell membranes, allowing the entry of foreign DNA into the cell.

Cellvizio^® LAB

The Cellvizio^® LAB is a [...] edge fibered fluorescence microscopy device released by VisualSonics in collaboration with Mauna Kea Technologies. The system revolves around a high speed fluorescence microscope with miniaturized microprobes capable of high resolution (up to 1.4 μm), real-time endoscopic imaging of fluorescent tissues, cells and markers at a micron level. The system is composed of 300 µm probes attached to optical fibers, which are inserted into the tissue of interest. Minimally invasive because of their diameter size, the microprobes have applications for surface, internal and deep imaging of any organ, including brain. Furthermore, image acquisition happens in real-time.

The Cellvizio^® LAB System is applicable to many neurobiology researchers because of the similarity of its operation to microdialysis systems in terms of its probe size and insertion.

The revolutionary product NeuroPak™ was also released as a complement to the Cellvizio^® LAB system. This allows the secure attachment of microprobes in small animal brains, so that their brain activities can actually be visualized and quantified when the animals are conscious and freely moving. This technology signifies a huge breakthrough in the area of functional brain imaging.

Photoacoustic Tomography System

VisualSonics announced in 2008 that it was partnering up with Seno Medical to produce a photoacoustic tomography system designed specifically for preclinical research. The system is scheduled to be released in 2010, but no name for the product has been announced yet.

Applications

Preclinical small animal studies are a key part of medical and biological research. The non-invasive high resolution ultrasound technology represented in the VisualSonics product line represents a significant improvement in the quality and speed with which information about disease models may be obtained. Furthermore, the use of non-invasive imaging has the potential to significantly reduce the number of animals required for research, by eliminating the need for histological approaches in some longitudinal animal studies.

Ultrasound has been a common imaging modality in cardiovascular research and the availability of high resolution has meant that murine models of cardiovascular disease may be imaged with some of the same techniques used in larger animals and humans. This access to high quality cardiovascular data in mice has facilitated better research into human cardiovascular disease, medical and surgical treatments, and improved the lives of millions of people. Ultrasound is less common in cancer research. However, the advent of high resolution ultrasound provides the opportunity to image both subcutaneous and orthotopic tumors easily, quickly and with higher accuracy and precision than other modalities in small animal disease models.

The application of high resolution ultrasound in preclinical development opens the possibility of using ultrasound more frequently as a component of clinical trials by translating the techniques developed in the animal models directly into the clinic. The key areas of high-frequency ultrasound include:

• Molecular Imaging
• Cardiovascular Research
• Neurobiology
• Developmental Biology
• Cancer Research
• Nephrology
• Toxicology
• Gene Delivery
• Image Guided Injections

The wide range of uses for Vevo systems makes them arguably the most versatile preclinical imaging modalities available.

Major Customers

The company's major customers include:

• Harvard University
• Stanford University
• Cornell University
• University of California, Berkeley
• University of California, San Diego

• University of Pennsylvania
• University of Texas
• Indiana University
• University of Edinburgh
• University of Notre Dame

• University of Toronto
• Columbia University
• New York University
• University of Michigan
• Washington University in St. Louis

• Duke University
• John Hopkins University
• SickKids Hospital
• Children’s Hospital Boston
• National Cancer Institute

Awards and Recognitions

In 2005, VisualSonics’ President and CEO, Mr. Tom Little, received Ernst & Young’s “Entrepreneur of the Year^TM 2005 Ontario Region Health Science Award” based on the large growth he brought to VisualSonics in a few short years.

In 2006, VisualSonic’s Founder and CSO, Dr. Stuart Foster, received the 2006 Ernest C. Manning Award Foundation’s “Award of Distinction” in recognition of his innovative concept of micro-ultrasound and its contribution to the field of pre-clinical imaging.

In 2007, VisualSonics was awarded the “Best Customer Value” Award by Frost & Sullivan for its Vevo^® 770 system. Frost & Sullivan is a global growth consulting company conducting extensive primary and secondary research including hundreds of customer and subject matter expert interviews. This was compiled in the “North American Preclinical Small Animal Imaging Markets” report, which recognized the Vevo^® systems by VisualSonics as having an extremely satisfied and rapidly growing customer base in both academic research and industry.

Corporate Governance

Current members of the board of directors at VisualSonics are:

• Anil Amlani (President and CEO, VisualSonics)
• Dr. Doug Armstrong (Managing Director, Dawson James Securities)
• Dr. William Clarke (CEO, Cellectar, LLC)
• Jeff Courtney (Partner, VenGrowth Capital Partners)
• Sam Ifergan (President and CEO, Hargan-Global Ventures)
• Riccardo Pigliucci (Former Chairman and CEO, Discovery Partners International)
• Harold Wodlinger (President, Wodlinger Consulting)

See also

• Preclinical imaging
• Ultrasound
• Photoacoustic tomography