Oct 12, 2016 | By Benedict

Scientists at Harvard have used a 3D bioprinter to 3D print a tubular renal architecture that mimics human kidney function. The research advances the collective goal of 3D printing functional human organs for drug screening, disease modeling, and regenerative medicine.

In recent years, a group of Harvard materials scientists has demonstrated its ability to 3D print tissue constructs made up of several types of living cells patterned alongside a vascular network in an extracellular matrix—one of many techniques currently being used by scientists to “print” tissue structures for various medical and biological applications. The researchers could then scale up these constructs to create thick, vascularized tissue constructs capable of remaining viable for over a month in vitro. The same group of researchers has now taken the project a step further, using similar techniques to create a functional 3D renal architecture containing living human epithelial cells, which line the surface of kidney tubules.

Behind the groundbreaking research is Jennifer A. Lewis, the Hansjörg Wyss Professor of Biologically Inspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and Core Faculty member of Wyss Institute for Biologically Inspired Engineering. After developing the modular Voxel8 Developer’s Kit 3D printer and taking part in a number of 3D printing ventures, Lewis has made a name for herself as one of the most important women in 3D printing. This latest study, which has been published in Scientific Reports, confirms Lewis’ place amongst 3D printing’s elite while advancing the collective effort towards fabricating human organs. “The current work further expands our bioprinting platform to create functional human tissue architectures with both technological and clinical relevance,” Lewis said.

Although other groups of researchers have used 3D printing to advance renal medicine, the Harvard team may have made one of the most important breakthroughs in the field by developing a system which is both scalable and adaptable for future research. Human kidneys, the subject of the study, have over a million nephrons, functional units which perform the vital function of transferring components between blood and urine. Inside a nephron’s proximal tubules (serpentine hollow tubes), 65-80 percent of nutrients are reabsorbed and transported from the renal filtrate back into the bloodstream. The 3D printed renal architecture created by the Harvard scientists mimics the function of a proximal tubule, a small yet critical part of the kidney as a whole, and the consequences of the replication could be huge.

To create the 3D printed renal architecture, Lewis and her team adapted their established technique for bioprinting thick tissues made of living cells. In this case, the scientists use a 3D printed silicone gasket as a mold, casting an engineered extracellular matrix as a base layer. After this layer comes a “fugitive ink” printed in a convoluted, winding tubular shape similar to the structure of renal proximal tubules, before that layer is encapsulated with another layer of extracellular matrix. Afterwards, the entire construct is cooled and the fugitive ink removed, leaving behind an open tubule embedded within extracellular matrix.

Once the scientists have their open tubule structure, they can begin adding live cells. A single inlet and outlet on opposite ends of the tubule are perfused with cell growth medium and then human proximal tubule cells, which quickly begin to adhere to the lining of the open channel. These cells then form into a tightly packed monolayer lining the entire length of the 3D printed renal architecture, acting as a cell barrier between the inner lumen of the tubule and the extracellular matrix outside.

The inlet and outlet of the structure can be used to pass nutrients, nourishing the living cells and keeping them alive and functional for over two months. As the cells mature, the 3D renal architecture begins to perform the same important duties as a natural nephron’s proximal tubule, making it potentially suitable for important medical applications such as drug screening and disease modeling.

According to the researchers behind the project, the 3D printed renal architecture is a credible in vitro model that functions like living kidney tissue, and therefore represents a significant advance over traditional 2D cell culture. The model could be used to assess patient treatment options or diagnose diseases, or as a way to determine how drugs impact the health and function of a kidney’s nephrons.

“The use of functional tissue-like models during pre-clinical studies will provide unprecedented insights into human-relevant drug response prior to clinical development,” said Annie Moisan, an author on the paper and Laboratory Head in Mechanistic Safety at Roche Pharmaceutical Sciences, which collaborated with Harvard on the research.

Human proximal tubule cells adhere to the hollow channel, forming a functional, 3D renal architecture. (Image: Lewis Lab/Wyss Institute at Harvard University)

The scientists believe that their approach is flexible, scalable, and adaptable, and could therefore be used as a foundation for developing other 3D printed organ models besides renal architecture. “We have initially targeted this renal architecture because the kidney represents such a pressing clinical need across the world,” said Lewis. “While thus far we have merely demonstrated a functioning subunit within the kidney, we are actively scaling up the method and its complexity to enable future in vivo applications.”

Authors of the paper included Lewis, Moisan, Kimberly Homan, David Kolesky, Mark Skylar-Scott, Jessica Herrmann, and Humphrey Obuobi.




Posted in 3D Printing Application



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