As the other articles in this special report in-dicate, tissue engineering has emerged as athriving new field of medical science. Justa few years ago most scientists believed that hu-man tissue could be replaced only with directtransplants from donors or with fully artificialparts made of plastic, metal and computer chips.Many thought that whole bioartificial organs—hy-brids created from a combination of living cellsand natural or artificial polymers—could never bebuilt and that the shortage of human organs fortransplantation could only be met by somehow us-ing organs from animals.Now, however, innovative and imaginative workin laboratories around the world is demonstratingthat creation of biohybrid organs is entirely feasible.Biotechnology companies that develop tissue-engi-neered products have a market worth of nearly $4billion, and they are spending 22.5 percent more ev-ery year. But before this investment will begin to payoff in terms of reliably relieving human sufferingcaused by defects in a wide range of tissues, tissueengineering must surmount some important hurdles.Off-the-Shelf CellsEstablishing a reliable source of cells is a para-mount priority for tissue engineers. Animal cells area possibility, but ensuring that they are safe remainsa concern, as does the high likelihood of their rejec-tion by the immune system. For those reasons, hu-man cells are favored.The recent identification of human embryonicstem cells—cells that can give rise to a wide array oftissues that make up a person—offers one approachto the problem [see “Embryonic Stem Cells forMedicine,” by Roger A. Pedersen, on page 68]. Butresearchers are a long way from being able to ma-nipulate embryonic stem cells in culture to producefully differentiated cells that can be used to create orrepair specific organs.A more immediate goal would be to isolate so-called progenitor cells from tissues. Such progenitorshave taken some of the steps toward becoming spe-cialized, but because they are not yet fully differenti-ated they stay flexible enough to replenish severaldifferent cell types. Arnold I. Caplan of the Cleve-land Clinic and his colleagues, for instance, have iso-lated progenitor cells from human bone marrowthat can be prompted in the laboratory to form ei-ther the osteoblasts that make bone or the chondro-cytes that compose cartilage. Similarly, Lola Reid ofthe University of North Carolina at Chapel Hill hasidentified small, oval-shaped progenitor cells in adulthuman livers that can be manipulated in culture toform either mature hepatocytes—cells that producebile and break down toxins—or the epithelial cellsthat line bile ducts.Generating “universal donor” cell lineswould be another approach. To make suchcells, scientists would remove, or use othermolecules to mask, proteins on the surfaces ofcells that normally identify the donor cells as“nonself.” This strategy is now being used byDiacrin in Charlestown, Mass., to make sometypes of pig cells acceptable for transplantation inhumans. Diacrin also plans to use the “masking”technology to allow cell transplants between un-matched human donors. It has received regulatoryapproval in the U.S. to begin human trials of maskedhuman liver cells for some cases of liver failure. In principle, such universal donor cells would notbe expected to be rejected by the recipient; theycould be generated for various types of cells frommany different tissues and kept growing in cultureuntil needed. But it is not yet clear how universaldonor cells will perform in large-scale clinical trials.Parts FactoriesFinding the best ways to produce cells and tissueshas been far from straightforward. Scientists haveidentified only a handful of the biochemical signalsthat dictate the differentiation of embryonic stemcells and progenitor cells into specialized cell types,and we cannot yet isolate cultures of stem cells andprogenitor cells from bone marrow without havingconnective tissue cells such as fibroblasts mixed in.(Fibroblasts are undesirable because they dividequickly and can overgrow cultures of stem cells.)In addition, scientists need to develop more ad-vanced procedures for growing cells in large quanti-Tissue Engineering: The Challenges Ahead86Scientific American April 1999TISSUE ENGINEERING: The obstacles to building new organs from cells andsynthetic polymers are daunting but surmountableSomeday equipping patients with tissue-engineered organs and tissues may be asroutine as coronary bypasses are today. SPECIAL REPORTCopyright 1999 Scientific American, Inc.ties in so-called bioreactors, growth chambersequipped with stirrers and sensors that regulate theappropriate amounts of nutrients, gases such as oxy-gen and carbon dioxide, and waste products. Exist-ing methods often yield too few cells or sheets of tis-sue that are thinner than desired. New solutions are beginning to appear, however.For several years, researchers struggled to grow seg-ments of cartilage that were thick enough for medicaluses such as replacing worn-out cartilage in the knee.But once the cartilage grew beyond a certain thick-ness, the chondrocytes in the center were too faraway from the growth medium to take up nutrientsand gases, respond to growth-regulating chemicaland physical signals, or expel wastes. Gordana Vun-jak-Novakovic and Lisa Freed of the MassachusettsInstitute of Technology solved the problem by cul-turing chondrocytes on a three-dimensional polymerscaffold in a bioreactor [see photograph below]. Therelatively loose weave of the scaffold and the stirringaction of the bioreactor ensured that all the cells be-came attached uniformly throughout the scaffoldmaterial and were bathed in culture medium.Maximizing the mechanical properties of tissuesas they grow in bioreactors will be crucial becausemany tissues remodel, or change their overall organi-zation, in response to being stretched, pulled or com-pressed. Tissue-engineered cartilage, for example,becomes larger and contains more collagen and oth-er proteins that form a suitable extracellular matrixif it is cultured in rotating vessels that expose the de-veloping tissue to variations in fluid forces. (Extra-cellular matrix is a weblike network that serves as asupport for cells to grow on and organize into tis-sues.) Cartilage cultured in this way contains extra-cellular matrix proteins that make it stiffer, moredurable and more responsive physiologically to ex-ternal forces.Likewise, John A. Frangos of the University
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