Genetic Engineering & Biotechnology News

DEC 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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GENengnews.com | Genetic Engineering & Biotechnology News | DECEMBER 2018 | 21 to be used to print replacement tissues for use in humans. While no 3D printed tissue has yet received FDA approval, Gatenholm thinks one of the earliest types to be approved may be cartilage or skin, which are relatively homogenous and should be less complex to manufacture. In the meantime, Cellink is focused on offering more user friendly yet more advanced systems as well as better bioinks and biomaterials. 3D Printing, but with Lasers While the prospect of 3D bioprinting new tissues to re- place worn out ones has driven much of the interest in the technology, in the near term most of the advances in the field will come from printing miniature copies of different tissues for drug testing and improving our understanding of basic cell biology. And, if Doug Chrisey, Ph.D., professor, Jung Chair of Materials Engineering, Tulane University, has his way, those tiny replicas will imitate the cel- lular heterogeneity of, and reside in the same microenvironments as, the full-size versions in our bodies. "Conventional cell cultures often com- prise a single cell type," Dr. Chrisey said. "What we're trying to do is mimic an en- tire tissue construct, which is made up of biochemicals, scaffolding, and a great deal of heterogeneous cells that are present in a specific combination." Dr. Chrisey and his team have pioneered the use of a technology called laser direct-write (LDW) printing to create structures on the order of a few cubic millimeters on a cell- by-cell basis. This technique gives the researchers the ability to precisely deposit a variety of different cell types with near single-cell spatial resolution. The team starts by culturing cells that it wants to de- posit. Because most cells in the body are adherent, they cut off the cells' pseudopod binding sites, leaving the cells in a temporary balled-up, nonadherent state. The cells are then loaded into a biopolymer film that is placed above a receiv- ing substrate such as a petri dish or glass slide. A computer then triggers a precise pattern of 248-nanometer excimer la- ser bursts that produce tiny gas bubbles in the biopolymer. These bubbles propel cells forward and deposit them direct- ly onto the receiving substrate in layers that can be stacked up to form 3D tissues. Dr. Chrisey and his team have used LDW printing to cre- ate many types of complex tissues, including collagen fibers, muscle fibers, and neural circuits. They also found that de- posited cells rapidly organize into physiologically functional tissues and that metastatic cancer cells tend to migrate more toward vasculature than non-metastatic cells. Building Modular Units Advances in 3D printing are benefitting biology not only through the prospect of printing biological tissues, but also in making it cheaper and more efficient to design tools that biologists use in the lab. One such biologist making the most of modern 3D bioprinting technology is Noah Malmstadt, Ph.D., associate professor of chemical engineering and ma- terials science, biomedical engineering, and chemistry at the University of Southern California. Dr. Malmstadt and his colleagues use 3D bioprinting tech- niques to build modular microfluidic systems utilizing stan- dardized parts without having to rely on costly clean room fabrication methods. They primarily use their microfluidics systems to simplify fluid mixing underlying miniature diag- nostic tests and high-throughput microbioreactor processes. Routing fluids through 3D assemblies of microfluidic modules allows for rapid and more precise fluid mixing. One such assembly his research team has designed is a de- vice with a parallel network of four 250-micron-wide tubes. Forcing nonmixing fluids, such as oil and water, through the tubes allows the team to produce an endless stream of nearly identical microdroplets. Each droplet acts as a micro-scale chemical reactor in which chemicals can be mixed with high- levels of precision. The team has used the device to develop a reliable method for producing gold nanoparticles, which have been shown to be an ideal medium for delivering drugs to individual cells. This method has the potential to greatly reduce the cost of generating gold nanoparticles, which cur- rently run $80,000 per gram. Going forward, Dr. Malmstadt is experimenting with us- ing materials in his printing process that minimize adhesion, and therefore don't gum up the 150-micron-wide channels he is trying to create. "That'll really allow us to increase the density of channels on a device and minimize overall device size," he prediated. The next big step, though, for Dr. Malmstadt will be in- tegrating off-the-shelf components—including photodiodes, heaters, and sensors—into his devices. "That would really bring our costs down," Dr. Malmstadt explained. "We're inspired by the microelectronics industry and their cost-min- imization procedures. That's really what's driving us and our technology forward." Taking 3D Printing to the Next Level While many researchers are expanding the potential of 3D bioprinting by focusing on characteristics such as spatial resolution and embedded vasculature, others are looking at a more literal expansion of the technology—moving it from three dimensions to four. 4D bioprinting—the printing in 3D of an object with the engineered capability to respond over time to its environ- ment and change in shape (e.g., deforming, twist- ing, or growing in size) or function (e.g., cellular differentiation, change in cell polarity, or even organ development)—is just one of the many av- enues of 3D bioprinting that GE Healthcare is pursuing. Like many companies involved in the 3D bio- printing field, GE Healthcare also supports the development of novel bioink materials and bio- printing instrumentation. But, according to Wil- liam Whitford, strategic solutions leader for bioprocesses at GE Healthcare Life Sciences, the healthcare conglomerate is quite interested in peripheral technologies aimed at improv- ing and streamlining the 3D bioprinting process, including imaging analysis and data management tools. "Imagine you've printed a series of organoids and want to see how they respond to certain chemical or biological challenges," Whitford suggested. "We support the devel- opment of high-power microscopes that will let you track those responses in fine detail." In addition, GE Healthcare has long been interested in the storage, processing, and transfer of medical images in a digital format. This expertise extends to the digital de- sign models that direct the 3D bioprinting process itself. "Many 3D bioprinted objects are very basic, but they're becoming much more complicated because we're moving into multi-material, multi-mode bioprinting that requires sophisticated model construction and control of the print- er," Whitford noted. "GE Healthcare is supporting the 3D bioprinting field in the development of digital model- ing and data management tools." Translational Medicine Producing synthetic scaolds with adequate physical, chemical, and biological proper ties remains a challenge for tissue engineering. Internal architecture, surface chemistry, and material properties have strong impact on the cell's biological behavior. This requires sophisticated systems not only able to process multiple materials with different characteristics—creating fully interconnected, 3D porous structures with high reproducibility and accuracy—but also able to modify their properties during the fabrication process. A study ("Hybrid Additive Manufacturing System for Zonal Plasma-Treated Scaolds") by Liu et al. which appeared in 3D Printing and Additive Manufac- turing, Vol. 5, No. 3 (published by Mary Ann Liebert, Inc.), introduced a novel additive manufacturing sys- tem comprising a multiprinting unit (screw-assisted and pressure-assisted printing heads) together with a plasma unit that enables the surface modi•cation of printed scaolds. Poly(ε-caprolactone) scaolds with a lay-down pattern of 0/90° were fabricated using the screw-assisted printing head, and a plasma jet unit was used to uniformly modify each layer (either a speci•c region of each layer during the printing process or the external surface of the printed scaolds). Scaolds were produced using dierent plasma exposure times and dierent distances between the plasma head and the printed layer while using •xed printing conditions. Produced scaolds were morphologically, mechanically, chemically, and bio- logically characterized. Results show that the distance between the plasma head and the printed material has no signi•cant eect on the mechanical properties, whereas the increase of the plasma deposition velocity improves the mechanical properties. As expected, plasma treatment increases hydrophi- licity and consequently the biological performance of the scaolds. Results also show the potential of the proposed fabrication system to create functional gradient or scaolds with tailored properties. Q The journal article can be found at: www.liebertpub.com/doi/10.1089/3dp.2018.0056 Hybrid Additive Manufacturing Many researchers are focusing on 3D characteristics such as spatial resolution and embedded vasculature; others are moving from three dimensions to four.

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