A few centuries ago, if a patient complained of general maladies such as “fever” or “chest pain,” the physician could only guess at what was wrong and provide symptomatic relief (such as sponging down the fever and ensuring that the patient is eating and ambulating). We should not be too quick to dismiss the “guesses” of experienced physicians who are so attuned to their 5 senses that they can often diagnose a medical condition accurately even without modern conveniences.
However, it must have crossed their minds how wonderful it would be if they were able to just look inside a patient to see what’s going on. Today, that once-unlikely dream is an everyday reality, with a whole host of medical imaging technologies available to us.
Cast your mind to the future for a moment and imagine our current medical imaging tools being looked on as archaic by future physicians. What could substitute the medical imaging tools at our disposal today?
One possible imaging tool that fits the bill is the 3D visualization and reconstruction of lumenized structures in the body. Scientists are racing to improve this technology, testing out a few different methods simultaneously, to discover the best 3D imaging techniques that can later be expanded and utilized on a massive scale.
Unique Biliary Abnormalities
Now we turn our attention to a study conducted by Hankeova and colleagues on the architectural mechanisms that contribute to bile duct recovery in an Alagille syndrome mouse model.
But before getting ahead of ourselves, we need to ask an important question: do we have a safe and effective method to visualize lumenized structures in the body? Many pathologies are directly or indirectly impacted by changes in tubular structures, such as the heart, kidney, and lungs, so possessing such a technology would be invaluable.
Hankeova and colleagues readily admitted this is a problem: “Visualizing biological tubes in three dimensions is challenging. One major roadblock is the difficulty in seeing several tubular structures at once. Traditional microscopic imaging of anatomy is in two dimensions, using slices of tissue. This approach shows the cross-sections of tubes, but not how the ducts connect and interact.”
Read more about Alagille syndrome etiology
Hankeova and colleagues developed a technique, which they called double resin casting micro computed tomography (DUCT), to address this problem. This method makes casts of tube systems using 2 types of resin that show up differently under X-rays. To test the feasibility of this method, the researchers injected 1 resin into the bile duct and another into the blood vessels of a mouse model of Alagille syndrome. This allowed them to reconstruct both trees digitally, showing them in stunning detail.
“In order to define and quantify the adaptive process resulting in a de novo generated biliary system in adult Jag1Ndr/Ndr mice, we investigated the spatial relationship of portal venous and biliary systems in normal and diseased liver in 3D,” the researchers explained.
The researchers compared double carbon ink injection with whole mount immunofluorescence staining combined with tissue clearing to assess the 3D liver architecture. The research team discovered that “DUCT outperformed ink injection and immunofluorescence in most aspects, from 3D analysis (not possible with ink) to analysis of lumenization (not possible with immunofluorescence).”
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Hankeova et al devote much of their study to the subtle advantages that DUCT has over other methods of bile duct visualization. Through DUCT, the researchers were able to identify 6 unique features of biliary abnormalities of Alagille syndrome in de novo generated bile ducts:
- Increased branching in region 1 (with the liver divided into 3 regions)
- Increased branching independent of the portal vein
- An increased distance between the bile ducts and the portal vein
- Blunt/abrupt endings facing the hilum in the bile ducts
- Peripheral tortuosity exhibited by the bile ducts
- Bridging of the bile ducts between two portal veins.
From 3D Visualization to 3D Printing
Hamada and colleagues, in their study on bile duct reconstruction, successfully performed the “reconstruction of the extrahepatic bile duct with a scaffold-free tubular construct created from pig fibroblasts using a novel Bio-3D Printer.” They wrote, “This construct could provide a novel regenerative treatment for patients with hepatobiliary diseases.”
The Bio-3D Printer has been in use to produce a variety of tissues and organs using human cells. Hamada et al commented, “The most notable and potentially beneficial features of this model are that it does not incorporate any artificial components or require donors.” In other words, no human tissues were needed.
What is exciting here is that medical imaging is well on the pathway towards 3D visualization, using increasingly sophisticated technology. In the case of Alagille syndrome, 3D visualization allows us to delve further into the pathological features of the disease, thus opening the door to newer and better therapeutics. Opening doors, one after another, in search of a cure or a new gold standard: that is medicine at its very best.
Hankeova S, Salplachta J, Zikmund T, et al. DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for Alagille syndrome. Elife. 2021;10:e60916. doi:10.7554/eLife.60916
Hamada T, Nakamura A, Soyama A, et al. Bile duct reconstruction using scaffold-free tubular constructs created by Bio-3D printer. Regen Ther. 2021;16:81-89. doi:10.1016/j.reth.2021.02.001