Additive Manufacturing Creating Functional Organs Using Sustainable Printing Inks

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Fraunhofer-Institut für Silicatforschung

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3D bioprinting can be used to produce organs and tissues. However, the bio-inks do not adequately replicate the physiological structure and composition of tissues. Fraunhofer researchers have developed bio-printing inks made from the most common tissue proteins to address this issue.

Every year in Germany alone, 8,000 people are on a waiting list for an organ donation, and about 10 percent of them wait in vain. 3D bioprinting is seen as a potential solution to the global shortage of donor organs. It is intended to enable the automated production of implantable organs or parts of organs, individually tailored to the patient, “at the push of a button.”
The technology could also allow for the printing of pathological—that is, diseased—tissue models for disease research as well as for the testing and development of active ingredients. However, one challenge of 3D bioprinting that remains unresolved is the choice of printing inks: some have good printing properties but cannot reproduce the natural tissue structure, while others can reproduce the tissue structure but lack sufficient printability. 
The Fraunhofer Institutes for Silicate Research ISC, for Applied Polymer Research IAP, for Microstructure of Materials and Systems IMWS, and for Cell Therapy and Immunology, Division of Bioanalytics and Bioprocesses IZI-BB, aim to overcome this hurdle. In the PhysioINK project, they aim to develop sustainable, process-optimized bio-printing inks that enable the precise replication of physiological human organ structures and can be used effectively in various 3D printing processes. The plan is to implement two applications: standardized intestinal tumor models for drug development and physiological heart tissue as a step toward functional implants for personalized, regenerative medicine.

Highly Concentrated Printing Inks Based on Collagen and Elastin

Human soft tissue contains fibrous, structure-forming proteins: collagen and elastin. Depending on the type of tissue, they account for 60 to 100 percent of its composition. “Until now, completely synthetic or heavily chemically modified materials have been used for printing inks. We, on the other hand, use physiological material—that is, the same material that makes up organs,” says Dr. Tobias Weigel, project coordinator and researcher at Fraunhofer ISC in Würzburg (Germany). As a first step, the project team is developing highly concentrated printing inks based on proteins—specifically type I collagen, type IV collagen, and elastin—which are characterized by a neutral pH, physiological properties, and high compatibility with human cells. To achieve this, the consortium combines cellulose sulfates that are molecularly tailored to the specific collagens or structural proteins, which initially stabilize the proteins in their dissolved and printable state. A temperature trigger then reverses this stabilization, allowing the structural proteins to self-assemble into their physiological fibrous or network-like structure.

Encapsulate Positively Charged Collagen Molecules with Negatively Charged Cellulose Sulfates

As part of the PhysioINK project, researchers are encapsulating positively charged collagen and elastin molecules with corresponding negatively charged macromolecules based on sustainable cellulose derivatives (CS). “Cellulose sulfate is very similar to large human sugar molecules and is able to bind to the collagen, initially preventing its reorganization. This reorganization occurs spontaneously, during which the protein chains coil around each other to form so-called fibrils—very small, thread-like fibers—and provide high strength, so that the collagen can no longer be used for shaping,” explains Weigel. “Cellulose sulfate temporarily slows down the reorganization and stabilizes the proteins in their dissolved or printable state. After printing, we can trigger the natural reorganization process again by raising the temperature, allowing the structural proteins to spontaneously reorganize into their physiological fibrous or network-like structure, thereby yielding a tissue with a fibrillar structure.” The researchers have already filed a patent application for this key principle. Based on this, the partners in the PhysioINK project are developing three different printing inks (based on type I collagen, type IV collagen, and elastin). In the long term, however, the key principle is also intended to be applied to other proteins. To achieve this, the cellulose sulfate must be adapted accordingly.

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First Skin Tissue Successfully Printed

For initial printing trials, the researchers printed the type I collagen ink at concentrations of three, five, and seven percent using various print heads, while examining structural stability and cell viability. While the ink still bled after printing or during gelation at a three percent collagen concentration, the two higher concentrations demonstrated that freestanding printing is possible. Initial skin tissue models have already been successfully printed, demonstrating the applicability of the type I collagen ink. Real-time monitoring of human cell metabolism also enables continuous control of the nutrient supply to the cell tissue. In this way, the quality of the printed tissue structures can be evaluated and their architecture specifically optimized.This new technology represents a major leap forward, as—for cost reasons—nearly all printing inks currently are produced using animal-derived and heavily modified collagens, which can only partially mimic human physiology. In contrast, PhysioINK printing inks will consist of physiological and, ideally, human components—promising prerequisites for drug discovery and the printing of customized, viable, implantable organs.

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