Having recently completed its first human clinical trial for fluorescence-assisted resection and exploration (FLARE), a near infrared (NIR) imaging system that allows surgeons to see tumours in real time and in contrasting colours, researchers at the Frangioni Laboratory in Boston, MA, US, are optimistic about the outcome. But perhaps the potential stars of the system are really the new contrast agents currently under development, which attach to virtually any kind of tissue and emit NIR light. This means that surgeons can precisely target an area and operate safely, thereby reducing the need to excise healthy tissue during the course of surgery.
"At present, surgery is performed relatively blindly," explains John Frangioni of the Beth Israel Deaconess Medical Center in Boston, US. "Other than the surgeon's eyes and brain there is really no other imaging system that can provide information about what might be hiding in the surgical field – either things that need to be resected or that need to be preserved."
Frangioni Laboratory has spent the better part of a decade developing the FLARE cart-based imaging system. Designed to work with NIR fluorescent contrast agents, called fluorophores, the development of robust methods to process 800nm NIR fluorophores that use existing contrasts such as heptamethine indocyanine is underway in earnest.
"The basic concept is fluorescence," says Frangioni. "This simply means that we illuminate an object with one wavelength of light and a chemical, the fluorophore, converts it to a different wavelength of light. The advantage of this is that if the surgeon illuminates with one wavelength and is only looking for what comes back at the second wavelength, only the fluorophore will be seen. Everything else will be black because reflected light of the excitation wavelength is what is visible to the system.
“So, fluorescence gives you the ability to highlight things in high visibility and high contrast."
According to Frangioni, FLARE uses LEDs instead of lasers for excitation, thereby eliminating the need for the imaging system to make direct contact with the patient. "The articulating arm has six degrees of freedom, with optics that can be positioned over the patient anywhere the surgeon may require," he adds.
"It can be fully sterilised and comes with a sterile drape and shield, so it's ready to be used in any type of surgery at the present time. Our interest in this has been the use of invisible light, NIR, a wavelength that is between 700nm and 900nm. They are redder than our eye can see so they are invisible to the human eye, but the wavelengths can penetrate relatively deeply into the tissue. And if we are able to launch photons into tissue it means we can retrieve them and in that process be able to see things that might be hiding deeper in tissue than our eye could see."
The human eye is limited to seeing only a few hundred microns or less into tissue under visible light. However, NIR light can go millimetres or even centimetres into tissue. Frangioni believes the use of this light has key advantages:
- it doesn't change the look of the surgical field, thereby eliminating the need to retrain surgeons
- this particular light has properties of high penetrance into tissue and low background auto-fluorescence.
"Wherever we have a condition of low auto-fluorescence, meaning low background, it means we can add a bright star to that black sky and see it easily," says Frangioni. "That is the idea of the contrast agent. The contrast agents are the lightbulb or the bright star on what would otherwise be a black background. That gives us the ability to see things with high sensitivity and, if our agents target well, with high specificity."
Frangioni Laboratory has already completed its first human clinical trial and it went extremely well. The trial was a pilot, used to gauge the ergonomics of the hardware and to ensure that the design of the FLARE imaging system does not interfere with surgery. "It wasn't powered to answer questions about the utility of NIR compared with conventional sentinel lymph node mapping," says Frangioni. "That is something coming up in a large study we are about to start. But we learned quite a bit and we've already taken away a few ideas on how to improve the technology."
The system provides real-time, highly sensitive visualisation of structures. In this pilot trial, a fluorophore was used that is currently available – already FDA approved for other indications. But in this study, its off-label use let Frangioni highlight sentinel lymph nodes, and unlike conventional radioactive substances that are currently used, the lymph node could be seen in real time and in the context of the rest of the surgical field.
"One of the powers of the technology is the ability to overlay two independent channels of this invisible near fluorescent light with the colour video image," says Frangioni. "We've worked many years to perfect this because by acquiring those three images – colour video, NIR channels 1 and 2 – simultaneously, we are now giving the surgeon the ability to know exactly where they are cutting. And they have two independent channels to work with."
In the future those channels can be applied to anything the surgeon needs. So for cancer surgery, one channel might be used to highlight the tumour, the second channel to highlight nerves, and therefore resect all of one wavelength of light and leave behind the second wavelength of light.
One of the tricks used is to take the black and white greyscale image from the NIR channels because the brain doesn't perceive a colour, so the computer is creating an image from a greyscale. That is then changed to an unnatural colour not present in the body, such as fluorescent orange or lime green, and then these are overlayed onto the colour video. What the surgeon sees in real-time is not just the three windows but a fourth window – a merged window – whereas in real-time two invisible wavelengths of light superimposed on the visible light can be seen.
"That's really where the power of the technology is because those two independent channels can be used for anything the surgeon desires," explains Frangioni. "We're only limited now in the field by the existing contrast agents."
Viability and safety factors
In terms of costs, Frangioni believes FLARE technology will be much less expensive than what is currently available. "Operating room time in the US costs in the realm of $40 per minute," he says. "So if this technology is able to cut OR time significantly and along the way provide better care for the patient, I think no matter how you do the calculus this becomes a very cost-effective technology.
Not only that, but the hardware and the chemicals are not expensive. It's the regulatory process that creates an expensive system, not the inherent technology. Unlike an MRI machine, which is expensive because of the parts, or a CT machine or PET machine, these systems are less complicated and therefore less costly."
Safety has been a high priority in the development of the FLARE imaging system and Frangioni believes one of the important features engineered into the system is that there is "absolutely no patient contact". The machine stands 1.5ft away from the patient at all times.
"The NIR light that we use is in the room you're in right now," says Frangioni. "It's just that we're applying the light in a way that isolates the colour video image from the NIR. But the fluence rates that we use – the amount of light used – are not much different from a bright sunny day. They are also a part of the electromagnetic spectrum and are very low energy. In terms of patient safety, from the hardware standpoint, I'm not sure you could
develop a system much safer, because it's no-contact and uses light we are exposed to every day. It meets all 60601 requirements and as an electronic piece of equipment it meets all the standard safety requirements."
From the chemistry side, human safety remains to be proven, only because the industry is now entering a phase of developing new contrast agents.
"We have history on our side though," says Frangioni. "All of the contrast agents that I envision being developed over the next five to ten years will be chemically similar to a molecule called indocyanine green, which has been FDA approved since 1958. It has one of the strongest safety records of any drug ever given to humans. Now, that doesn't necessarily mean that the new derivatives will be as safe but at least we're starting with a chemical where we have 50 years
of experience and an unbelievably good track record."
With the imaging hardware clinically validated and GE developing the system for commercialisation, Frangioni believes there will be plenty of incentive for contrast agent companies to start considering optical imaging in clinic.
"People will be looking for applications because there will be a clinical need and high demand," he says. "Like any new technology, in order to pay for the expense of development, companies will be focusing on things like breast cancer and prostate cancer – high prevalence diseases where there is going to be a need during the surgery for precise incisions."
The hardware will most likely enter the market in the next 12–24 months as it is anticipated that FLARE will be eligible for a 510(k) exemption. However, the contrast agents currently under development may be delayed by as much as three to five years, which is the standard development time for a new entity being used in humans.
Organic fluorophores are just the beginning. Frangioni Laboratory has been collaborating with Bawendi Laboratory at MIT and Beth Israel Deaconess Medical Center to develop NIR quantum dots, fluorescent semiconductor nanocrystals, specifically for cancer-imaging applications such as targeting tumours. But for the interim, between the hardware and contrast agent release dates, Frangioni and his team have been exploring the use of two FDA-approved agents that are not currently used for NIR
fluorescence but are NIR fluorophores. They have published papers on the off-label use of these contrast agents and designed individual channels for each.
"There are many clever things one can do with those existing agents," says Frangioni. "For the two to four year period between the release of the hardware and the release of the new contrast agents, there is a bit of utility in the agents we have right now. They're not perfect and they're not magic; they're all we've got but that we're lucky as a field that we have two agents that have utility in many different cases and that will hopefully bide the time until the targeted agents are available.
“It is important to remember that it is a hypothesis that this technology is going to improve patient care."
Many believe that it will, but it needs to be proven in multicentre trials and it needs to be proven by different surgeons under different conditions. "While we're excited by the possibility, we also temper our enthusiasm because a lot of new technology doesn't work out. We're really just going to have to wait and see."