Early Disease Detection with Color-Coded X-Rays

Early Disease Detection, Medical imaging is no longer limited to Kansas, Toto, as a team lead by Penn State researchers converts typical black and white diagnostic images of X-rays and CT scans to technicolor. The researchers created novel contrast agents that target two proteins involved in osteoarthritis, a degenerative joint disease often known as wear-and-tear arthritis. By labeling the proteins with contrast agents containing newly designed metal nanoprobes, the researchers can use advanced imaging known as “K-edge” imaging or photon-counting computed tomography (CT) to track separate biological processes in color, revealing more about the disease’s progression than a traditional scan.

The researchers published their findings in Advanced Science. The technique, which was conducted in rats but has ramifications for humans, enables researchers and physicians to view previously obscured processes in color and detect disease signs long before clinical symptoms appear.

“If we can develop a contrast agent -; a metal nanoprobe -; tailored to identify and quantify target particles, there is very little we cannot see with the photon-counting CT scanner,” said first author Nivetha Gunaseelan, doctoral student in biomedical engineering at Penn State.

And that visualization is especially important when it comes to diseases such as osteoarthritis, which can progress unnoticed until clinical presentation, which is often at an advanced and irreversible stage. Early intervention could reduce symptoms and improve lifestyle, if we have the tools to enable early diagnosis and longitudinal disease tracking. We can enhance imaging techniques to detect early cartilage changes at a molecular level, and that could help improve diagnosis and monitoring.”

Nivetha Gunaseelan, Doctoral Student. Biomedical Engineering, Penn State

Study

The technique is based on a relatively new technology, the photon-counting computed tomography (CT) scanner, which displays the same bone, muscle, and fat that traditional CT scanners can detail, but with a far greater ability to separate individual components at a higher resolution and in specific colors. A version of this advanced scanner, manufactured by Siemens, has been approved by the United States Food and Drug Administration for clinical use and is now being used in some hospitals, but its smaller-scale molecular imaging capabilities for clinical applications have remained largely unexplored, according to researchers.

The photon-counting CT scanner detects materials having distinct K-edge identities, which describe how electrons in a material absorb energy. Electrons sit on a K-shell, which is a type of casing that surrounds an atom’s nucleus. As energy is absorbed from photons, or light particles, electrons can move to new exterior shells. The atom can absorb only a limited amount of energy, and when that limit is reached, it emits a burst of light. The researchers may direct the scanner to look for a certain type of light emission known as the K edge. If a substance with a definite K-edge identity targets a certain protein, the researchers can use the scanner to monitor its activity.

“This high-resolution, K-edge-based imaging approach could potentially be used to image multiple biological targets, thus enabling disease progression tracking over time by measuring the ratio of protein expression,” said corresponding author Dipanjan Pan, the Dorothy Foehr Huck & J. Lloyd Huck Chair Professor in Nanomedicine and professor of materials science and engineering and of nuclear engineering at Penn State. “The approach can be particularly beneficial in skeletal disease diagnoses since the progression of cartilage degradation is highly variable among patients and the ratio information from the protein markers could provide crucial information about the stage of the disease.”

The researchers created two K-edge metal nanoprobes composed of praseodymium and hafnium. The probes target two proteins found in cartilage tissue: aggrecan and aggrecanase. Aggrecan, which contributes to cartilage’s structure and ability to bear weight, is plentiful in healthy joints and in the early stages of osteoarthritis. Aggrecanase, which cleaves aggrecan and impairs cartilage function, is abundant in the late stages of osteoarthritis. As the disease advances, the protein ratio shifts, providing metrics for monitoring disease status.

The team utilized a photon-counting CT scanner to monitor how the ratio changed as the disease advanced in an animal model. They employed additional imaging and experimental validation to confirm their findings.

“X-ray imaging has advanced greatly since Röntgen’s first demonstration,” Pan said, referring to Wilhelm Röntgen, the physicist who produced the first radiograph in 1895, with the hand of Anna Bertha, his wife, as the subject. “This technique has the advantage of capturing images quickly, making it a good choice for emergency situations, but it lacks soft tissue contrast and cannot separate the imaging signal from the disease site from that of intrinsic structures, such as bones.”

However, Pan added that improved detector technologies such as photon-counting CT scanning and K-edge imaging, which his lab has been working on for over a decade, have permitted extremely precise and detailed imaging.

“We are now able to count individual photons, and as a result, we can generate ‘hot spot’-like images based on an element’s K-edge energy,” Pan said. “The results of our experiment demonstrate -; for the first time -; that a complementary biological process can be followed in multicolor, with a clinically relevant modality.”

According to Pan, photon-counting CT scanning has various therapeutic uses because of its advantages, such as immunity to electronic noise and high-resolution imaging without sacrificing quantum efficiency.

“We showed the potential of K-edge nanoprobes and photon-counting CT scanning in detecting critical stages of osteoarthritis before symptom development and clinical presentation with advanced stages,” Pan said. “It is anticipated that the synergistic development of these tools will determine the success of this field.”

For more information: Gunaseelan, N., et al. (2024) Targeted K‐Edge Nanoprobes From Praseodymium and Hafnium for Ratiometric Tracking of Dual Biomarkers using Spectral Photon Counting CT. Advanced Science. doi.org/10.1002/advs.202408408.