Monodisperse microbubbles produce ultra-clear ultrasound images

Traditional imaging techniques used to be a bane to patients concerned about their long-term health and finances. With the patented microfluidic technique introduced by Tide Microfluidics in medical imaging, such issues may finally be a thing of the past.

Modern imaging techniques have propelled advancements in the medical field. Diagnosing the causes of symptomatic conditions, screening people for illnesses or injuries, and monitoring patients’ response to treatments have become easier with medical images of the human anatomy.

However, the advances made by these imaging techniques can be a double-edged sword for patients. X-rays, computed tomography (CT) scans, and positron emission tomography (PET) all involve
exposure to ionising radiation that can increase a person’s lifetime risk for cancer. While a fourth option—magnetic resonance imaging (MRI)—does not use radiation, the financial cost of availing it is stillprohibitive for most patients.

Enter Tide Microfluidics, a Netherlands-based medical device company that is using a new microfluidic technology to make ultrasound images 20 times better than they used to be. The technology, which is based on the efficient production of monodisperse medical microbubbles, is changing the market by providing a safer and cheaper option for medical imaging.

‘The world population is ever increasing and people have longer life expectancies, meaning the demands on the healthcare sector continue to grow,’ says Wim van Hoeve, Managing Director of Tide Microfluidics. ‘Tide’s microfluidic technology enables advanced manufacturing of much needed pharmaceutical products for both diagnostic and therapeutic imaging procedures.’

Tide Microfluidics was founded in 2011 as a spinoff of the MESA+ Institute of Nanotechnology of the University of Twente. It was established to develop, manufacture and commercialize the patented microfluidic technology that was developed within the University of Twente in The Netherlands and the University of Sevilla in Spain. ‘Everybody should have access to high quality and affordable healthcare through easy-to-use and accurate medical imaging procedures,’ Tide Microfluidics declares as its vision.

Uniform bubbles

Making superior medical imaging more accessible and affordable is crucial in building a sustainable healthcare sector. According to the European Science Foundation, medical imaging contributes to improved outcomes for patients and cost-efficient healthcare for all major diseases, Van Hoeve says.

Of all the medical imaging techniques being used today, he says ultrasound is the safest because it is non-invasive; it is also the most-cost effective as it is available in almost every hospital in the world.

Furthermore, ultrasound is not subject to factors such as calcified body areas (bones and hardened arteries), body size, and the skill of the person performing the scan.

The only downside to ultrasound is the low contrast of the images produced, making medical diagnoses more difficult. Tide Microfluidics is changing this. The new technique used by the company can magnify the smallest structures and organs in the human body so that the quality of ultrasound images is improved by 20 times.

This allows ultrasound to compete with other imaging modalities, such as MRI or CT scan. ‘With Tide’s products, the diagnostic capabilities of ultrasound can be drastically improved, resulting in more accurate and earlier diagnosis,’ Van Hoeve says.

Tide’s microfluidic technology enhances ultrasound images by producing superior quality ultrasound contrast agents (UCA) in the form of microbubbles and microdroplets smaller than red blood cells.

These UCAs, composed of billions of microbubbles, are not even as big as the thickness of human hair. They can be safely injected in the body to improve image contrast and allow better visualization of the soft tissue structures of organs of interest within the human anatomy.

In the spotlight

PhD thesis becomes a product

The microfluidic technology was discovered when Tide Microfluidics founder Wim van Hoeve investigated the principles underlying microbubble formation as part of his PhD-thesis
at the University in Twente in The Netherlands. The technology works by enabling the controlled creation of microparticles—either bubbles or droplets—in a highly controlled environment.

Such an environment ensures that the UCA’s gas bubbles are produced one at a time and in the same repeatable manner, giving same-sized bubbles each time.

The University of Twente and the University of Sevilla jointly own the patent protecting this technology, with an exclusive license granted to Tide Microfluidics to develop such technology
into commercial products.

Microfluids IIWhile commercially available UCAs are able to enhance ultrasound images in more than three million annual ultrasound procedures worldwide, they do so with limited success. At present, available UCAs are composed of microbubbles in different sizes which cannot guarantee the production of images that are optimal for ultrasound procedures. ‘For the UCAs to provide a significant improvement to image quality, the microbubbles are required to be of a uniform size,” Van Hoeve explains.

In order to work as contrast agents, microbubbles are made to resonate by the high frequency sound wave of the ultrasound equipment. The size of each microbubble plays a crucial role as resonance is only accomplished when the size precisely matches the operating frequency of the ultrasound equipment.

‘This uniformity, or monodisperse nature, is something that our patented technology is able to produce,’ says Van Hoeve. To efficiently apply the microfluidic technology, Tide Microfluidics created an innovative laboratory apparatus called the Microsphere Creator.

The apparatus, launched in January 2015, can manufacture UCAs at the bedside of patients. The Microsphere Creator enables ultrasound researchers to produce their own UCAs on demand. It also
allows them to familiarise with microfluidic technology and develop new products based on monodisperse microbubbles.

Awards and grants

Tide Microfluidics has received numerous accolades for its work. It proved to be the strongest contender during the Young Technology Award at the Commercialization of Micro- and Nanotechnology conference in Salt Lake City, Utah in the United States.

At the conference, young companies such as Tide Microfluidics presented a 3-minute pitch to an expert jury. Tide Microfluidics won both the first prize of US$5000 and the public prize of US$500. ‘The jury was unanimous in its decision, stating that Tide not only showed an innovative technology but also had clear real world relevance in helping solve pressing needs within the healthcare system,’ Van Hoeve says.

Tide showed an innovative technology with a clear real world relevance in helping solve pressing needs within the healthcare system.

Tide Microfluidics won another award in February 2015, the AXON Innovation for Health Award 2015. Innovation for Health is a premier Dutch healthcare innovation event held annually in Amsterdam. Tide Microfluidics received the €2500 AXON voucher for its pitch highlighting its innovative technology. The company has also received a European Union Horizon 2020 SME Instrument Phase 1 Grant, a subsidy consisting of a 70% contribution of €50000 from the EU.

According to Van Hoeve, the company will use this grant to further develop its business model for a bedside UCA production apparatus and continue to grow its company. Van Hoeve points out that the product is highly scalable, and can be used for targeted drug delivery by applying medicines to the microbubbles’ outer shell.

The ultrasound is then used to monitor the patient until the contrast agent reaches the site being targeted, such as tumorous growths or lesions. Once the contrast agent reaches the site, the ultrasound field is used to burst the microbubbles, releasing the drug where it is most needed and where it can work most effectively.

Food and drugs

The advantages of this technique include the continuous visualisation of the target area as the medicine is delivered; the reduction in the dose required as drugs are only released at the affected site; and the reduction in side effects, as drugs are not circulating and affecting other areas of the body but are focused on the site where they are needed.

‘Ultimately, this leads to a next generation in medicine where treatments are personalised and the patient is treated as an individual (and not merely as a disease),’ Tide Microfluidics explains in its company website.

Microfluidic technology can also be useful to the pharmaceutical, food and cosmetics industries by dramatically boosting the stability of dispersions and emulsions. By increasing monodispersity, the technology enables the creation of more uniform foams and emulsified structures. ‘The uses of these emulsions and dispersions are varied from flavour and fragrance enhancers to food production and even solgels,’ Tide says.

Van Hoeve says that Tide Microfluidics has been able to continue the development of the microfluidic technology into commercial products with the support of the University of Twente and the University of Sevilla. ‘This successful transfer has also meant Tide is considered a valuable research and development partner to related research groups, with the continued exchange of students and ideas, which will hopefully lead to further IP transfer possibilities,’ he adds.