Although both the science and technology of polymer had advanced remarkably by the early 1950s, formidable challenges remained to be surmounted


Nov 01 - 07, 2004





Most people are probably more familiar with polymers in the form of the plastics that make up such everyday products as plastic food containers, bubble wrap packing, and videotape. But polymers also are found everywhere in nature. Wood, animal and vegetable fibers, bone, and horn are polymers, for example, as is the deoxyribonucleic acid (DNA) inside the cell nucleus and the membrane that separates one cell from another. Indeed, when the polymer industry began in the nineteenth century, it made materials that were derived from natural polymers artificial celluloid from plant cellulose. Eventually the industry began synthesizing new materials, such as nylon, that replaced natural materials and were made without natural precursors. Today products that straddle the boundary between living and non-living like artificial skin are beginning to suggest exciting possibilities for improving human health.

Humanity has a long history of trying to understand the substance and structure of the physical world around us, whether by simple observation or experimental manipulation. In ancient Greece, for example, Aristotle concluded that all materials were made up of combinations of only four elements: air, earth, fire, and water. During the middle ages, chemists tried in vain to convert common metals into gold. By the late eighteenth century, chemists had begun synthesizing and breaking down chemicals in an effort to determine their fundamental components. Nineteenth-century chemists also resolute that it was possible to synthesize organic compound, once believed to be made only in living organisms, from inorganic chemicals. In 1839, American inventor Charles Goodyear discovered a technique, which he called vulcanization, for manipulating the properties of the sap from rubber trees by treating it with heat and sulphur. The process converted a gummy, springy material into a dry, tough, elastic material that makes manufacture of rubber tyres possible and eventually a transportation revolution.

In 1870, American inventor John Wesley Hyatt won a contest to find a material for billiard balls to replace ivory. Hyatt's prize-winning contribution was celluloid, based on cellulose a polymer that is the basic structural material of plant cell walls. It was the start of the polymer industry. Hyatt treated cellulose nitrate, or guncotton, an explosive material made by exposing cotton plant fibers to nitric and sulphuric acids, with alcohol and camphor to get a hard, shiny material that could be molded when hot. Cheap and uniform in consistency, this new material replaced ivory in billiard balls. Occasionally though, when the celluloid billiard balls collided, they created a small detonation like a firecracker because of the explosive nature of cellulose nitrate. In 1887, Count Hilaire de Chardonnet created a related product by spinning cellulose nitrate into Chardonnet silk, the first synthetic fiber to enter production and a forerunner of rayon, nylon, and Dacron.

Both celluloid and Chardonnet silk were polymers created by altering natural polymers. The first truly synthetic polymer come in 1909, when American inventor Leo Baekelan treated phenol, or carbolic acid, another derivative of coal tar, with the preservative formaldehyde under heat and pressure. His product, Bakelite, was hard, immune to harsh chemicals, electrically insulating, and heat resistant characteristics that made it useful for a myriad of household goods and electrical parts. Soon Bakelite was being used to make tools, machines, and cooking ware.

In 1920, the German chemist Hermann Staudinger research suggested that polymers are composed of long chain molecules of many identical or closely related chemical units. The word polymer literally means "many units" and concisely describes the fact that these giant molecules are built up from one, or many types of, single units (monomers). Moreover, their unusual tensile strength and elasticity are a result of that great length or, in chemical terms, of their high molecular weight. Staudinger's key insights that polymers are long chains of many small chemical units and that chain length plays a crucial role in determining physical properties and behavior, pointed up the need for tools to assess molecular weight and thus chain length. One of the first tools was the ultracentrifuge, invented by the Swedish chemist Theodor Svedberg. The ultracentrifuge spins samples at very high speeds and can separate molecules according to their size. It is be used to estimate both the size of the molecules and the distribution of sizes in a given polymer sample.

In 1928, the DuPont Corporation hired chemist Wallace Hume Carothers to build new kinds of polymers. To test Staudinger's theory, Carothers carefully joined small organic compounds into long chains and examined the properties of his products. He found that collections of very long chain molecules produced stiffer, stronger, and denser materials. By 1930, he came up with a new class of polymers called polyamides, or "nylons." These polymers could be melted and drawn into a remarkably strong fiber.



When nylon was introduced as a substitute for silk in stockings in 1937, the new material, strong, cheap, and easy to work with, became an unqualified commercial hit. The instant success of nylon fibers and neoprene, the first synthetic rubber, taught the polymer industry an important lesson, that basic research can lead to products that can replace natural materials. It can also eventually lead to Nobel prizes. Paul Flory of Stanford University received one for his career contributions to polymer science while working in both academic and industrial laboratories. Flory was instrumental in developing the theory of how polymer molecules behave, especially through mathematical and statistical analysis of the shape and properties of polymer chains.

The 1930s were the glory years for the development of new synthetic polymers, producing polyvinyl chloride (PVC), polyurethane, polytetrafluoroethylene (Teflon), and polystyrene, which together would revolutionize the fabric, coating, house ware, packaging, and insulation industries. These new materials bore no resemblance to their raw materials (which were commonly oil or natural gas) and were celebrated for their very artificiality. Because many of these polymers became malleable when heated, they came to be called "plastics" from the Greek word meaning "able to be molded."

Another important development beginning in the late 1930s and 1940s was the large-scale production of artificial rubber, spurred by the booming automobile industry and the military demands of World War II. By 1930, two new forms of artificial rubber had been developed in Germany, both based on the petroleum byproduct butadiene. As tensions grew in Europe, the U.S. government recognized the vulnerability of the nation's rubber supply and in 1941 established the Rubber Reserve Company to produce 10,000 tons of rubber annually. By the middle of 1942 the production goal had soared to 850,000 tons annually in response to the Japanese occupation of the East Indies, whose vast rubber tree plantations had supplied the world with the raw material for rubber. Polymer scientists and engineers worked together to develop a variety of new processes to meet wartime demands.

Although both the science and technology of polymer had advanced remarkably by the early 1950s, formidable challenges remained to be surmounted. Because of the abundant supply and low cost of their component petroleum-derived building blocks or "monomers," hydrocarbon polymers containing only carbon (C) and hydrogen (H) atoms represented a potentially highly useful class of substances. Particularly attractive targets were polymers of the smallest and most abundant such monomers, ethylene and propylene (containing two and three carbon atoms, respectively). The general ability of such molecules, containing pairs of carbon atoms connected by "double bonds," to join together to form long chains had long been recognized (a familiar example being polystyrene). However, in the javascript:ShowCloseup(1538);case of ethylene and propylene this presented a formidable challenge. The "polymerization" of ethylene had been accomplished, but only at undesirably high temperatures and pressures, yielding polymers whose properties left much to be desired. The polymerization of propylene remained to be achieved.

In 1953, while engaged in basic research on the reactions of compounds containing aluminum-carbon bonds, the German chemist Karl Ziegler, discovered that adding salts of certain other metals such as titanium or zirconium to these compounds resulted in highly active "catalysts" for the polymerization of ethylene under relatively mild conditions. Furthermore, the polymers formed in this way, because the chains were longer and more linear, had greatly superior properties such as strength, hardness, and chemical inertness, making them very useful for many applications.

Building on Ziegler's discovery, Italian chemist Giulio Natta, demonstrated that similar catalysts were effective for the polymerization of propylene. Furthermore, with such "Ziegler-Natta catalysts" it was possible to achieve beautiful control of the chain length and structures of the resulting polypropylene polymers and, thereby, of their properties. Among other remarkable achievements of this class of catalysts was the synthesis of a polymer that is identical to natural rubber.

Industrial applications of "Ziegler-Natta catalysts" were realized almost immediately and with various subsequent refinements continue to expand. Today, polyethylene produced with such catalysts is the largest volume plastic material and, together with polypropylene, accounts for about half of the U.S.'s current annual 80 billion pound production of plastics and resins. The uses of polyethylene and polypropylene extend to virtually every facet of industry and daily life, including building and construction materials, containers, toys, sporting goods, electronic appliances, textiles, carpets and medical products. In many of these applications polymers replace other substances, such as glass and metals, but their distinctive properties also have given rise to entirely new applications, including medical uses. In 1963, the Nobel Prize in Chemistry was awarded to Ziegler and Natta "for their discoveries in the field of the chemistry and technology of high polymers.

As new applications for polymer were being found, some researchers wondered whether they could also play a role in the human body, perhaps in repairing or replacing body tissues and cartilage. The natural polymer collagen, found in animal connective tissue, had been used as surgeon's thread for more than 2,500 years. And as early as the 1860s, an artificial polymer called collodion was used as a liquid dressing for minor wounds. Collodion, made from a solution of cellulose nitrate in alcohol and ether, formed a solid film that could be peeled off after the wound healed.

Scientists were beginning to recognize that many diseases of the heart, liver, and kidney actually involved failures of these organs, and they were initiating efforts to replace damaged organs with healthy ones. However, the body's immune cells, which are designed to seek out and destroy any foreign tissue, are unable, to distinguish between an unwanted bacterial infection and a much-desired transplanted kidney. Some early drugs, such as corticosteroids, azathioprine, and 6-mercaptopurine, helped in combating rejection, the problem began to fade only after 1969, when Swiss microbiologist Jean Borel discovered that a soil fungus, cyclosporin A, would selectively interfere with the specific immune cells that drive the rejection reaction. The 1983 approval of cyclosporin A by the U.S. Food and Drug Administration (FDA) gave transplant surgeons a tool that has since saved the lives of thousands of patients with heart, liver, or kidney failure.

Cyclosporin A encouraged a wave of transplants and also helped set the stage for the current rise in "tissue engineering" as scientists call the construction of whole artificial organs. Transplant surgeons, who no longer lost patients because of the rejection of their transplants, now were faced with a new frustration losing patients for lack of donor organs. In 1983, Robert Langer, a chemical engineer at the Massachusetts Institute of Technology, worked on the feasibility of making an artificial liver and possible other artificial tissues to save the lives of his young patients.

In the mid-1970s, Langer had developed some polymer systems for M. Judah Folkman of Harvard University, who was then investigating the role of new blood vessels in promoting the growth of cancerous tumors, and was looking for a slow-release mechanism to release compounds that block the chemical messengers that control angiogenesis, the formation of new blood vessels. Langer discovered that polymers such as ethylene-vinyl acetate, which absorb very little water, could slowly deliver these chemical messages. Langer focused on was polyglycolic acid, or PGA, which was also used in synthetic degradable sutures and had reached the market in 1970. When the sutures reached the market seven years later, they were rapidly adopted as a strong, reliable, and workable replacement for the traditional collagen-based absorbable sutures that surgeons had used until then.

Using PGA and similar polymers, Langer crafted degradable and non-degradable polymer pellets into an intricate porous structure that allowed the slow diffusion of large molecules. (This finding is the foundation of much of today's controlled drug delivery technology.) Loaded with chemical messengers, the pellets played a key role in Langer and Folkman's 1975 discovery in cartilage of the first compound that blocks the formation of new blood vessels, thereby halting tumor growth. In 1984, Langer teamed up with Henry Brem, a brain cancer surgeon at Johns Hopkins Medical Institutions, to test his new techniques using polymers against brain cancer. Although there were new tools for finding tumors, including computed tomography and magnetic resonance scanners, the most malignant brain cancers remained largely untreatable. Cancer cells remaining after the tumor's removal were protected from chemotherapy drugs by the so-called blood-brain barrier, which prevents a variety of blood borne chemicals from penetrating the brain. Brem wondered if polymers could slowly release cancer-killing drugs right where they were needed, in the brain itself. javascript:ShowCloseup(1556);Langer responded by designing surface-degrading polymers that released medicines at a controlled rate. In 1992, Brem and Michael Colvin, now director of the Duke Cancer Center, implanted drug-bearing polymer wafers after brain surgery. The wafers prolonged the lives of both experimental animals and human patients. Since the chemicals were released locally, they did not result in the systemic toxicity typical of anticancer drugs. With FDA approval in 1996, the wafers represent the first new treatment for brain cancer in 25 years. Similar slow-delivery systems are now being used to treat prostate cancer, endometriosis, and severe bone infections.

All these efforts laid the groundwork for researchers continuing search for a framework for growing replacement body parts and organs, such as livers. By now scientists had learned that human cells grown on flat plates did not produce the normal array of proteins, while cells grown on three-dimensional scaffolds had relatively normal biochemistry. At first the best results were obtained from PGA, but since the best source of fibrous PGA in 1984 was degradable sutures, hours were spent unwinding sutures to transform the fibers into meshlike plastic scaffolds to support liver cells. Still, by 1986, liver cells on plastic frameworks were surviving and functioning after transplantation into animals, laying the groundwork for using polymer scaffolds to create a variety of tissues, from bone to cartilage to skin.



javascript:ShowCloseup(1559);The polymer scaffolds, made with non-woven fabric techniques borrowed from the textile industry, have now been used to grow at least 25 types of cells in animals or people and have thus become a kind of generic framework for artificial organs. Biotechnology firms are using the scaffolds to make artificial skin for treating diabetic ulcers and severe burns. They multiply living cells in culture (from tissue that is normally discarded during surgery), and then "seed" the cells on the polymer scaffold. Applied to the patient's wound, the material protects against deadly infection and fluid loss. More important, the cells it carries release chemical growth factors, signals that stimulate normal cellular growth at the wound site. These chemicals account for the roughly 60 percent improvement in healing that diabetics like Frank Baker experience with artificial skin. As tissue engineers look to the future, they are talking about using polymer scaffolds to grow nerve cells for use in spinal cord repairs, bone or cartilage cells for joint repairs, pancreatic cells to make insulin for diabetics, and liver cells to make livers for transplantation.

Through all of these efforts by many kinds of scientists, several facts stand out. The path from need to benefit travels through many areas of science and technology and depends crucially on the insights provided by basic research. The first polymer inventors made progress by transforming natural materials in hit-or-miss fashion, but their work greatly accelerated after basic researchers clarified the fundamental characteristics, such as the relation between size or molecular weight and physical properties that govern the behavior of polymers. Similarly, the progress in medicine and biology that gave birth to organ transplantation still relies on basic research into the role of chemical messengers, genetic codes, and cellular function. As polymer science and materials engineering join forces with biology and medicine to produce these modern miracles, we again see how interdisciplinary collaboration and essential basic and applied research remain the true source of benefits as simple and profound as a living tissue that can be created in the laboratory.