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10 | JULY 2016 | GENengnews.com | Genetic Engineering & Biotechnology News Gail Dutton InSphero, a developer of three-dimensional (3D) cell culture technology, offers micro- tissue platforms derived from liver, pan- creas, tumor, heart, brain, and skin. These platforms constitute the company's 3D In- sight™ line, which was expanded recently to include what the company calls Multi- donor Human Liver Microtissues. The new platform incorporates pooled hepatocytes from multiple donors and offers a more pre- dictive model for drug-induced liver injury (DILI). The new platform, like each of the other 3D Insight platforms, supports 3D spheroids while eschewing scaffolds. According to InS- phero, a scaffold-free approach is attractive because it allows microtissue formation to be driven by completely native cell-cell interac- tions. Also, the absence of scaffold material facilitates a greater number of downstream assays and imaging options. The new platform is the logical exten- sion of InSphero's core philosophy of creat- ing assay-ready tissues for the life sciences industry. By incorporating hepatocytes from fve male and fve female donors, the new platform manifests genetic diversity, a quality that enables researchers to study the effects of compounds of interest on the general population, distinguishing between known hepatotoxicants and related non- toxic analogs. Benefts of Assay-Ready Microtissue "For cell-based assays to be more effcient and biologically relevant, it helps for research- ers to use standardized 3D models," asserts Jan Lichtenberg, Ph.D., InSphero's CEO and co-founder. Standardization enables scientists to conduct benchmark studies that are mean- ingful to other researchers without the error- inducing need to convert home brews to standard references. "Optimizing cell-based knowledge," adds Dr. Lichtenberg, "yields a cost-to-beneft ratio that enables researchers everywhere to generate data that can be pub- lished and easily compared." 3D Hanging Drop Culture Many types of cells form the tissues that make up the liver, heart, and other structures in the body. To understand drug interactions with those tissues, scientists need to assay compounds not just in a single cell type, but in models that mimic tissue in vivo. The 2D monolayer and traditional 3D scaffolding techniques used to create tissue models, however, have limitations that af- fect their value to scientists. For example, 2D monolayers fail to replicate gradients in nutrients, oxygenation, metabolites, and proliferation. Another issue is waning func- tionality. "Hepatic cells grown in a 2D en- vironment lose functionality in two to four days," observes Dr. Lichtenberg. "Therefore, any toxic effects that appear 7 to 10 days af- ter treatment are beyond the scope of what is seen in the lab." With 3D scaffolding techniques, "spher- oid sizes may vary, and matrix materials may interfere with downstream analyses. "The hydrogels and other scaffolding materials introduce artifcial material into the cell tis- sue," explains Dr. Lichtenberg. "Many scaf- folds are porous, making tissue less dense and allowing drug molecules to stick to the scaffold, which makes them less available to the tissue." To overcome these challenges and add scalability, InSphero uses ultra-low attach- ment (ULA) and hanging-drop production technologies. For example, the GravityP- LUS™ platform, which exploits the hanging- drop approach, relies on gravity to form 3D structures within automation-compatible 96-well plates. "With GravityPLUS," says Dr. Lichtenberg, "we create a dense, tissue- like structure that is morphologically and functionally very similar to native tissue." InSphero's hepatic tissues, for instance, are still functional after fve weeks. Lab reports suggest that functionality continues for 60 to 70 days. Broad Applications InSphero's 3D InSight microtissues are based on the company's proprietary cell selection and preconditioning techniques. At present, InSphero offers models for the liver, pancreas, tumor, heart, brain, and skin. "But we can form tissues with nearly every cell type in the body," insists Dr. Lichtenberg. "Ours is a true umbrella patent." The GravityPLUS platform lets scientists use a small number of cells to produce a lot of data points at a price that allows easy technological integration into their work- fow. Once researchers integrate the micro- tissues into their work and deploy the req- uisite downstream processes, they can scale operations easily. "It's a matter of ordering product, taking off the lid, and starting test- ing," states Dr. Lichtenberg. That accessibility and relatively low cost encourages the use of microtissues not only during late-stage work, but also during early- stage discovery and validation of potential lead candidates, Dr. Lichtenberg tells GEN. Growth and Development InSphero's position as a privately held company allows it the freedom to innovate without the pressures of producing quarterly reports for shareholders. As Dr. Lichtenberg recounts, "When we worked on our fnanc- ing round last year, we considered our op- tions and opportunities to capitalize the company. We decided that being a private company had helped us develop quickly dur- ing the past few years." "We're at an exciting stage," Dr. Lichten- berg continues. "We see the adoption of 3D microtissue technology globally, and we have extended our sales force and customer sup- port in the United States and worldwide." InSphero also recently completed a new pro- duction facility in the United States., enabling product to reach American customers faster. The company is also focusing on devel- oping integrated solutions and enhancing compatibility. "We're interested in offering a full solution for our customers," comments Dr. Lichtenberg. To that end, InSphero works closely with assay and imaging tech- nology providers and is considering possible acquisitions. Microtissues for Diagnostics The company also is expanding its pipe- line to include disease models though its new division, InSphero Diagnostics. It has used its technology to generate microtissues that are based on patient biopsies and that mimic patients' tumors. Drugs can be tested against Getting the Hang of 3D Liver Microtissues CORPORATE PROFILE Hanging-Drop Technology Permits Scafoldless Modeling of Drug-Induced Liver Injury InSphero Location Wagistrasse 27 CH-8952 Schlieren, Switzerland Phone +41 44 515 04 90 Website www.insphero.com Principal Jan Lichtenberg, Ph.D. CEO and Co-founder Number of Employees 70 Focus InSphero develops scalable, assay-ready 3D microtissues using its patented hanging-drop technology, which eliminates the need for scafolds. Vital Signs InSphero aims to improve in vitro testing by facilitating the development and use of organotypic 3D cell culture models. Top left image: InSphero's patented GravityPLUS™ Hanging Drop System. Subsequent images (in clockwise order): assay-ready 3D liver, islet, tumor, skin, and brain microtissues. The GravityPLUS can manufacture all these microtissues for safety and efcacy testing.