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Sep 15, 2011 (Vol. 31, No. 16)

3-D Cell Culture Takes Research Deeper

In Vivo-Like Environment Paves Way toward Fresh Insights and Whole-Organ Generation

  • Engineering a Transplantable Liver

    Click Image To Enlarge +
    Scientists at Massachusetts General Hospital are developing transplantable liver grafts. Decellularized liver retains both venous (blue) and portal (red) network of blood vessels.

    Basak Uygun, Ph.D., an instructor at the Center for Engineering and Medicine at Massachusetts General Hospital, leads a project aimed at developing transplantable liver grafts. This approach involves the portal perfusion of rat livers with SDS, an anionic detergent that lyses cells and solubilizes cytoplasmic components, leaving a translucent scaffold, which retained the shape of the liver.

    While no viable cells remain, the matrix consists of a variety of extracellular matrix proteins, including collagen and glycosaminoglycans. The scaffold contains an intact microvasculature and can serve as a construct for rebuilding an artificial liver.

    Dr. Uygun’s team determined that the scaffolds can be reseeded with primary rat hepatocytes at high efficiency; they used as few as 50 million cells (or 5% of the normal liver population), which was previously shown to be sufficient to restore liver function in the rat model. This number could be further increased up to 200 million or 20% of the original mass.

    Hepatocyte viability and metabolic function were maintained in perfusion culture, including albumin production and gene expression equivalent to 20% and 30% of in vivo levels, respectively.

    Previous attempts have failed in creating complex tissue-engineered constructs for liver transplantation, Dr. Uygun said. While these latest results are quite encouraging, she cautioned that there are still many problems that need to be resolved before a fully functional artificial liver is available.

  • Challenges in Creating Whole Organs

    Despite years of investigation, the successful development of 3-D matrix scaffolds that will successfully support a recellularized, functional organ has many barriers to overcome, according to Stephen Badylak, M.D., Ph.D., a professor in the department of surgery at the University of Pittsburgh.

    Dr. Badylak believes that the extracellular matrix (ECM) represents an ideal support scaffold for regenerative medicine applications. “Recent advancements in decellularization and recellularization techniques and promising preclinical studies suggest that organ engineering is a very real possibility in the foreseeable future,” he stated.

    Yet Dr. Badylak enumerated many formidable challenges, including the appropriate choice of candidate species from which the donor organ can be harvested, optimal methods of removing and reintroducing cells into the ECM, and selection of the most appropriate cell populations.

    He cautioned that none of the whole-organ grafts produced to date have been used to replace or support function in vivo for more than a few hours, aside from skin grafts.

    The formation of fibrotic tissue and scarring is a significant problem in the engineering of artificial organs. In the case of skin, in which vascularization has not sufficiently occurred, extensive scarring can profoundly compromise the quality of life for patients.

    For this reason, Dr. Badylak suggests that protocols in which vascularization is promoted would improve the outlook for all types of whole-organ engineering. Sounding a cautionary note, Dr. Badylak stated, “it is important not to claim victory prematurely and create overly optimistic expectations until indisputable success in animal models of organ failure is demonstrated.”

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