S P E C I A L R E P O RT TISSUE ENGINEERING The obstacles to building new organs from cells and synthetic polymers are daunting but surmountable A s the other articles in this special report indicate tissue engineering has emerged as a thriving new field of medical science Just a few years ago most scientists believed that human tissue could be replaced only with direct transplants from donors or with fully artificial parts made of plastic metal and computer chips Many thought that whole bioartificial organs hybrids created from a combination of living cells and natural or artificial polymers could never be built and that the shortage of human organs for transplantation could only be met by somehow using organs from animals Now however innovative and imaginative work in laboratories around the world is demonstrating called progenitor cells from tissues Such progenitors have taken some of the steps toward becoming specialized but because they are not yet fully differentiated they stay flexible enough to replenish several different cell types Arnold I Caplan of the Cleveland Clinic and his colleagues for instance have isolated progenitor cells from human bone marrow that can be prompted in the laboratory to form either the osteoblasts that make bone or the chondrocytes that compose cartilage Similarly Lola Reid of the University of North Carolina at Chapel Hill has identified small oval shaped progenitor cells in adult human livers that can be manipulated in culture to form either mature hepatocytes cells that produce bile and break down toxins or the epithelial cells that line bile ducts Generating universal donor cell lines would be another approach To make such cells scientists would remove or use other molecules to mask proteins on the surfaces of cells that normally identify the donor cells as nonself This strategy is now being used by Diacrin in Charlestown Mass to make some types of pig cells acceptable for transplantation in humans Diacrin also plans to use the masking technology to allow cell transplants between unmatched human donors It has received regulatory approval in the U S to begin human trials of masked human liver cells for some cases of liver failure In principle such universal donor cells would not be expected to be rejected by the recipient they could be generated for various types of cells from many different tissues and kept growing in culture until needed But it is not yet clear how universal donor cells will perform in large scale clinical trials Someday equipping patients with tissueengineered organs and tissues may be as routine as coronary bypasses are today that creation of biohybrid organs is entirely feasible Biotechnology companies that develop tissue engineered products have a market worth of nearly 4 billion and they are spending 22 5 percent more every year But before this investment will begin to pay off in terms of reliably relieving human suffering caused by defects in a wide range of tissues tissue engineering must surmount some important hurdles Off the Shelf Cells Establishing a reliable source of cells is a paramount priority for tissue engineers Animal cells are a possibility but ensuring that they are safe remains a concern as does the high likelihood of their rejection by the immune system For those reasons human cells are favored The recent identification of human embryonic stem cells cells that can give rise to a wide array of tissues that make up a person offers one approach to the problem see Embryonic Stem Cells for Medicine by Roger A Pedersen on page 68 But researchers are a long way from being able to manipulate embryonic stem cells in culture to produce fully differentiated cells that can be used to create or repair specific organs A more immediate goal would be to isolate so86 Scientific American Parts Factories Finding the best ways to produce cells and tissues has been far from straightforward Scientists have identified only a handful of the biochemical signals that dictate the differentiation of embryonic stem cells and progenitor cells into specialized cell types and we cannot yet isolate cultures of stem cells and progenitor cells from bone marrow without having connective tissue cells such as fibroblasts mixed in Fibroblasts are undesirable because they divide quickly and can overgrow cultures of stem cells In addition scientists need to develop more advanced procedures for growing cells in large quantiTissue Engineering The Challenges Ahead April 1999 Copyright 1999 Scientific American Inc THE CHALLENGES AHEAD PHOTOGRAPHS BY SAM OGDEN by Robert S Langer and Joseph P Vacanti ties in so called bioreactors growth chambers equipped with stirrers and sensors that regulate the appropriate amounts of nutrients gases such as oxygen and carbon dioxide and waste products Existing methods often yield too few cells or sheets of tissue that are thinner than desired New solutions are beginning to appear however For several years researchers struggled to grow segments of cartilage that were thick enough for medical uses such as replacing worn out cartilage in the knee But once the cartilage grew beyond a certain thickness the chondrocytes in the center were too far away from the growth medium to take up nutrients and gases respond to growth regulating chemical and physical signals or expel wastes Gordana Vunjak Novakovic and Lisa Freed of the Massachusetts Institute of Technology solved the problem by culturing chondrocytes on a three dimensional polymer scaffold in a bioreactor see photograph below The relatively loose weave of the scaffold and the stirring action of the bioreactor ensured that all the cells became attached uniformly throughout the scaffold material and were bathed in culture medium Maximizing the mechanical properties of tissues as they grow in bioreactors will be crucial because many tissues remodel or change their overall organization in response to being stretched pulled or compressed Tissue engineered cartilage for example becomes larger and contains more collagen and other proteins that form a suitable extracellular matrix if it is cultured in rotating vessels that expose the developing tissue to variations in fluid forces Extracellular matrix is a weblike network that serves as a support for cells to grow on and organize into tissues Cartilage cultured in this way contains extracellular matrix proteins that make it stiffer more durable and more responsive physiologically to external forces Likewise John A
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