November 15, 2013

3D Printing May Revolutionize Drug R&D

Genetic Engineering & Biotechnology News

Nov 15, 2013 (Vol. 33, No. 20)

Organovo Offers Design Options for Modeling Diverse Tissue Types

Gail Dutton

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A cross-section of bioprinted human liver tissue that has undergone histological staining demonstrates cell viability and density, as well as compartmentalization between the hepatocytes (shown as blue nuclei), endothelial cells (red), and hepatic stellate cells (green).

    Differences between animal models and human tissues have contributed to approximately one dozen failures of late-stage drugs in 2012 alone. Organovo is remedying the situation with an innovative tissue development technology that produces fully functional human tissue for research and therapeutic applications.

    “We can create a number of tissues,” notes Keith Murphy, president and CEO. “Liver, cancer, and kidney tissues are highest on our list.” Created using 3D printing, the resulting tissue models have greater predicative capacity and are available in unlimited quantities for multiple studies, thus enabling drug candidates to be tested on functional human tissue before entering clinical trials.

    To develop tissue, “We create a bio-ink from cell aggregates and locate them precisely, using the Organovo NovoGen Bioprinter™. These are building blocks,” Murphy says. They are composed of approximately 1,000 cells that maintain tissue-specific geometries. These blocks fuse together naturally and build collagen, creating small pieces of tissue that perform like natural tissue.

    Printed tissue has similar cellular density to native tissue and incorporates multiple cell types and the key architectural and functional features—such as intercellular tight junctions and microvasculature—that are present in native tissue. Unlike traditional tissue engineering, 3D printed tissue is free of scaffolds, and any hydrogel components are temporary. When they are gone, they leave behind 100% cellular tissues. Currently, printed tissues are supplied in multiwell plates, slices, or blocks.

    “There are limitations, however,” Murphy cautions. “Our ability to make tissue thicker than about one millimeter is restricted by our ability to deliver nutrients and oxygen to the cells. Today, nobody can integrate the small vessels and capillaries needed for thicker tissue. Therefore, we’re not making whole organs,” he stresses, although doing so may become possible eventually.

    Organovo is working toward that. Already, it has developed a linear artery from human cells and is working to create branched blood vessels. “We hope this will provide a way to perfuse tissues,” Murphy says. “We’re still a couple steps away.”

    Models for Drug Development

    The ability to print 3D human tissue offers significant benefits in drug development and holds promise for therapeutics. Improving the models used for drug testing reduces the failure rates and can eliminate some surprise failures. 3D printing delivers better models because they use human cells and are highly reproducible. It also has the advantage of providing ample quantities and improved longevity for sometimes scarce tissue.

    Organovo’s liver tissue model, for example, survives approximately six days, while normal liver tissue survives about two days. Organovo is currently testing longer time points and plans to release data on performance at 30 days and beyond.

    Because the tissue can be designed, it offers the potential for knockouts as well as the ability to be patient-specific for various disease models. It also enables predictive modeling based on genetic profiles of multiple people, thus helping drug developers select nonresponders before clinical trials begin.

    Printed tissues’ greater predictive capabilities are based upon the structure that can be designed. “Fibrosis, for example, is difficult to research in animal and cellular models,” Murphy says. That’s partially because, in a co-culture of the best current model, the cells randomly originated in a Petri dish are oriented differently than cells in the human body. Printing the underlying cell type with the epithelial cell type on top delivers tissue more similar to what actually is in the human body, he explains. “That premise works for anything with a multilayered structure.”

    Models for Therapeutics

    3D printed tissues also may be used therapeutically. For example, heart tissue may be printed to repair (rather than replace) a heart, or veins may be printed to eliminate the need to transplant a patient’s vein from the leg to the heart for bypass surgery. Because autologous cells may be used, the risk of transplant rejection and the need for immunosuppressant drugs may be avoided. “The simpler applications are only a few years from clinical studies,” Murphy says.

    Partnerships

    Organovo has partnered with Oregon Health & Science University to study tumors using bioprinted tissue. “Researchers typically don’t have access to a whole tumor,” Murphy explains. But, by placing a bioprinter onsite, researchers can print as much tissue as needed to study multiple drug regimens. Organovo’s researchers work closely with their partners, developing custom tissues for drug discovery, preclinical disease modeling, and ADME-Tox studies.

    In late September, Organovo announced a collaborative research agreement with Roche involving liver toxicity. In addition, the company has an agreement with United Therapeutics for undisclosed work. “We also have agreements for tissue engineering with academic institutions,” Murphy says. “Longer term, we want to partner with pharma to help take drugs through development to the clinic. We also plan to develop some of the tissues alone and with partners, using bioprinters as research tools and for direct manufacture.”

    Organovo

    Location: 6275 Nancy Ridge Drive, Suite 110, San Diego, CA 92121

    Phone: (858) 224-1006

    Website: www.organovo.com

    Principal: Keith Murphy, President and CEO

    Number of Employees: 35

    Focus: Organovo uses 3D printing technology to design and develop structurally and functionally accurate human tissue models with improved properties and predictive capabilities. The tissues have applications in medical research and therapeutic interventions.

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