A revolution in medical diagnostics and treatment has often been proclaimed because of recent advances like genetic screening and “lab-on-a-chip” technology. But this revolution, often referred to as personalized medicine, won’t take place without a new generation of diagnostic devices that fundamentally change the way diseases are detected and treated.
And that technology is being developed, put into clinical trials, and in some cases commercialized by Beckman Institute researchers in work that could contribute to a truly different experience for patients in the near future.
Some of this technology includes electronic biosensor monitors that conform to skin or the heart, tissue assessment technology that eliminates the need for laboratory work, and handheld digital devices that can be used in the clinic or the operating room for a variety of purposes. Diseases will be detected much earlier at the cellular and even molecular scales, surgical procedures will be much more precise and less damaging, and patients won’t have to wait days to hear whether a tumor is cancerous or benign.
One of the Beckman researchers working toward this new future in diagnostics is Stephen Boppart, Co-chair of the Integrative Imaging research theme. Boppart has already taken technology for non-invasive or minimally invasive breast cancer assessments and real-time surgical probes to the clinical trial stage. Boppart said revolution is not too strong a word to describe what is happening when it comes to technology advances in medical diagnostics and treatment.
“I think it’s going to dramatically change things,” Boppart said. “What we hope is that diagnosis is going to get shifted closer and closer to the point of care.”
Those involved in this area of research at Beckman are taking a variety of paths toward that goal.
Taking Diagnostics out of the Lab and into the Operating Room and Doctor's Office
Boppart is using optical coherence tomography (OCT) as the imaging basis for technologies like handheld devices that produce immediate diagnostic images that are easy to read for medical personnel and time-saving for all involved. OCT uses a beam of near-infrared light and the tissue’s light-scattering properties to provide high-resolution, micron-scale subsurface images.
Boppart and his collaborators developed an OCT-based system that proved successful in clinical trials for assessing tumor margins in breast tissue. These “optical biopsies” give immediate results and require no invasive, or perhaps only minimally invasive, procedures. Their viability as a diagnostic device has already been demonstrated in clinical trials at Carle Foundation Hospital in Urbana.
They are also developing an OCT-based handheld probe with multiple applications in the clinic and operating room. Beckman researcher Scott Carney collaborated on research that advanced the technology to provide a microscopy technique where computational image-formation renders high-resolution, three-dimensional images from blurry data.
The handheld optical imaging surgical probe — enabling what the developers are calling computed histology — will give physicians performing procedures on cancer patients the ability to image tissue in situ, meaning it provides information on a patient’s tumor during surgery. The technology can also be used as a versatile diagnostic tool through integration with current instruments such as the otoscope and ophthalmoscope used, respectively, for ear and eye exams. Clinical trials using this device recently began at Carle Foundation Hospital and The Eye Center in Champaign.
Those methods, and others being developed by Beckman researchers, will play a role in reducing the reliance on time-consuming and expensive laboratory work, as well as the subjective judgments of medical personnel.
Boppart said diagnostic technology such as the ones he, as well as fellow researchers like Rohit Bhargava and Gabriel Popescu, are developing are based on biological changes that take place at the cellular and even molecular level, where disease first begins.
“We’re developing techniques to get at molecular changes,” Boppart said. “So much of medicine and pathology are based on structural changes. If we think of a pathologist looking at a slide, he or she looks at the cells and tissue structures. A radiologist will look at how organs and these anatomical structures are arranged.
“But with a lot of these techniques, we can get the molecular changes where disease starts. So a pathologist that has molecular information, not just structural, will perhaps catch disease earlier. The same is true for Rohit’s work and Gabi’s work.”
Stain-free Tissue Analysis
Bhargava has a research focus on integrating chemical information into imaging and other diagnostic applications, while Popescu combines different imaging modalities to both visualize and quantify the structure and dynamics of cells and tissues. Both are working on stain-free imaging techniques that would either complement or in some cases eliminate the need for laboratory work, especially the time-consuming, labor intensive method of staining that has undergirded tissue assessment for more than a century.
Popescu said the different approaches taken by Bhargava and himself are in fact working toward the same goal of assessing biological information without staining tissue for examination.
“They provide two facets of the same thing,” Popescu said. “One is giving chemical information while we’re looking at morphology information in great detail, more of the structural information.”
Popescu used an imaging technique he developed called Spatial Light Interference Microscopy (SLIM) to create a method for stain-free assessments of tissue for cancer diagnosis. SLIM uses phase contrast microscopy and holography to combine multiple light waves that enable visualization of nanoscale structures, as well as providing quantitative information.
Using the method Popescu and his collaborators imaged more than 1,200 biopsies and were able to visualize unstained cells with high-resolution, high-contrast images and derive information about the molecular scale organization of tissue, revealing prostate tumors and breast calcifications. In addition, the technique is automated, and it provides quantitative data on structures at the cellular level.
Bhargava has a five-year grant from the National Institutes of Health to create a new diagnostic method for assessing prostate cancer, and is working on projects related to breast cancer detection and treatment. He uses infrared spectroscopic imaging to measure chemical changes, such as those associated with tumor-stromal cell interactions.
These label-free spectroscopic imaging methods elucidate biochemical events that correlate with aggressive disease through chemical changes in different parts of the tissue; they then use differential equations to predict the behavior of tumors. This type of method not only doesn’t require tissue staining, but also is novel for combining important chemical information with structural information about cells.
Bhargava said that current methods provide, at best, a correct diagnosis about 50 percent of the time while an automated technology using chemical imaging techniques could provide more accurate diagnoses, for example, for prostate cancer and prevent unneeded surgery.
“The key question now is how do we determine who those people are who are going to get the truly risky kind of prostate cancer versus those who have incidental and age-related prostate cancer,” Bhargava said. “It’s a very powerful technique to look at
Biosensors for Patient Monitoring
John Rogers has gained worldwide attention going back more than a decade for his pioneering work with flexible and stretchable electronics. More recently, Rogers has applied the technology to biomedical purposes such as health monitoring.
In one project Rogers and his collaborators created an ultrathin flexible patch, or “electronic tattoo” as it was dubbed, for, among other applications, use as an epidermal monitor. The patches could be used to monitor brain or muscle activity – as is done with, respectively, EEG and EMG methods – but using a thin sheet of water-soluble plastic that, unlike those methods, is unobtrusive to the person wearing it.
Rogers led a project that also uses stretchable electronics for integration with standard endocardial balloon catheters. They first created an ultrathin sheet of electronic sensors that was successfully laminated to the heart in an animal model. Later they applied the technology to common endocardial balloon catheters, which are one of the least invasive methods used for angioplasty and other cardiac procedures.
Currently, cardiologists use rigid catheters sporting electrodes for applications like detecting arrhythmias. But the device created by Rogers and his collaborators can perform the same functions simultaneously, while softly pressing against heart tissue.
The stretchable electronics technology was created with the manufacturing methods of the semiconductor industry in mind, so it will easily fit into current manufacturing methods. Rogers’ start-up company is already working to commercialize the technology.
Kenneth Watkin’s research includes components that could impact diagnostics, such as developing contrast agents used in cancer diagnosis methods. Watkin is also working to create a battlefield helmet that uses biosensors embedded in the helmet pads to record data on trauma such as blast injuries to the head. Nanoscale computers power the biosensors for recording and analyzing real-time information on the extent of a head injury.
Rashid Bashir’s research focus is on developing new technologies such as micro- and nanoscale structures that have biomedical applications. One project that is now to the commercialization stage involves a portable CD4 cell counting system for rapid detection of white blood cells. It’s a small system that Bashir says could easily be used throughout the world, including in developing countries.
“It’s coming out of our technology for global health applications for detection of HIV AIDS,” Bashir said. “The idea is you put blood in a cartridge and in a matter of 10 minutes and for less than 10 dollars you can count the CD4 cells of white blood cells, the number of which corresponds to the level of HIV infection that someone has.
“This is an electrically-based method. It’s a cartridge that is fully self-contained. All you need is a drop of blood. Essentially there is a handheld reader that is the size of a small toaster, so it’s truly portable.”
Turning Research into Diagnostic Devicess
Bashir has a start-up company, Daktari Diagnostics, that creates diagnostic products specifically for what it terms “resource-poor markets.” Its first product will be the Daktari CD4, which the company says is as easy to use as a glucose meter and “robust enough to be used anywhere, from a doctor’s office to the most remote settings.” Bashir said they expect the product to be on the market within a year.
Boppart also has a start-up, Diagnostic Photonics, Inc., which was created to advance medical imaging technology. Andrew Cittadine, CEO of Diagnostic Photonics, said they have received approval to start a small pilot study and enrolled their first patient in April for evaluation of the handheld probe. The next steps will include publishing results of the clinical trials, win regulatory approval, and then partner with a firm to develop the manufacturing infrastructure.
“We plan to be in large-scale clinical trials, for example a 400-plus patient study, in 2013 and 2014,” Cittadine said. “I believe we could begin to see significant clinical use starting in 2015.”
For most of these diagnostic devices being developed by Beckman researchers, the future is sooner rather than later.
“I think the technologies that are out there are wonderful and are proven and exciting,” Boppart said. “They’re proven from the physics point of view. They have to be proven now from the clinical point of view.
“I think we have done well at the technology point and have been successful, but there’s going to be three or four other steps before this is going to be used. I think between five and ten years, we’re going to see a lot of medicine changing in terms of how we practice it.”
