3. Biomedical Materials

One place, where the new face of a functional, nano-engineered materials science should be felt most keenly, is in the hospital. We have, since time immemorial, been able to do little better in effecting mechanical repairs to the body than if it were an inanimate machine. Thus, prostheses of wood or metal have evolved into robotic limbs of immeasurable benefit to the recipient, but nonetheless a tacit submission to the traditional idea that the ways and materials of engineering have little or no overlap with those of biology.

This disjunction becomes all the more stark in the case of artificial organs, and it is perhaps remarkable that a heart imitated by a plastic air-blown pump, or a kidney by a plastic membrane filter, does so well! Such synthetic devices are by no means crude in engineering terms: the Jarvik-7 artificial heart, for example, has complex laminated polymer walls designed to minimize an inflammatory response and to incur low friction and wear as it inflates and deflates. This device has been used to sustain many patients awaiting urgent cardiac transplants. But nothing of the kind will suffice for long-term use.

In biomedicine, "minimal visibility" of materials was long equated with inertness: as long as a material in contact with the bloodstream did not provoke an allergic, toxic or inflammatory response, it was deemed adequate. But to an organism, utter passivity is not at all the same as invisibility. An inert material is typically regarded as a wound, triggering the creation of scar tissue at the interface. To truly look like a biological material, an implant must be active, capable of a kind of communication with the surrounding cells. That is why, for example, artificial blood vessels made from polymers such as polytetrafluoroethylene (in a porous form comparable to the Goretex fabric) may be given a lining of the protein heparin, which prevents blood clotting. The epithelial cells of real blood vessels release heparin to combat thrombosis, and the same end is served by immobilizing heparin at the surface of synthetic vessels.

The same broad principle is being employed in materials that simulate bone. Here, one finds a tidy illustration of the many, sometimes conflicting, demands placed on a biomedical material. Clearly a bone replacement must be strong and lightweight. Metals such as stainless steel and titanium have good fracture-resistance, but are considerably denser than real bone. The material must also be corrosion-resistant, and if, as in hip joints, it is liable to be subjected to movement against another hard surface, wear resistance is crucial. Flexibility similar to that of real bone is also an important attribute. And if the material takes up too much stress in its load-bearing capacity, it can induce dissolution and weakening in surrounding bone.

Small wonder, then, that the best bone replacement materials are composites that derive the right combination of properties from several distinct substances: e.g., fiber-reinforced polymers. A porous microstructure is important both mechanically, and to allow ingrowth of new tissue, e.g., so that the implant can develop an intimate interface with freshly grown bone. Natural coral has been used as a master for making molds with the required porosity.

Yet even this falls short of providing a material that can bind smoothly and securely to real bone, as an implant is commonly required to do. Again, inertness is in this respect a hindrance, not a help. The formation of fresh bone demands a surface that is conducive to the bone-depositing osteoblast cells. Bioactive ceramics are materials that actively encourage this regrowth. These "bioglasses" are typically mixtures of silica with sodium, calcium and phosphorus oxides, which appear to be capable of mimicking the behavior of the calcium phosphate (hydroxyapatite) component of real bone. Osteoblasts will create crystallites of a carbonate-containing variant of hydroxyapatite, a precursor to the deposition of true bone, on the surface of the bioactive ceramic, and this helps to weld together the new bone and the implant. Composites of bioactive ceramics with metals or polymers can achieve an attractive combination of stength, flexibility and compatibility with natural tissue.

If even apparently "mechanical" biological structures like blood vessels and bone display this complexity of interaction with the surrounding tissue and fluid, what are the prospects for developing materials systems that have a more active biological role, like that of the liver, the cornea, the spinal cord or the brain? While some organs have a function that one might hope to mimic crudely in purely artificial devices, there are others whose job can, at present, be conducted only by the living cells themselves. We simply do not know how to make an artificial nerve cell or neuron that interfaces seamlessly with the real thing.

Therefore, the ultimate in biomedical materials engineering is to find ways of growing the biological tissue itself: to grow new organs in culture, seeded by the cells of the intended recipient. This is called tissue engineering.

The process, as yet still hypothetical, is something like the following. Rather than having to await a suitable donor and then run the risk of transplant rejection, a person suffering from kidney failure has a smattering of cells removed from her kidney. These are scattered within a porous polymer material shaped like a kidney, and the cells are stimulated into growth by the right amounts of nutrients. Slowly the cells multiply and colonize the scaffold, which is gradually dissolved away as the tissue forms around it. The cells are provided with the hormones that promote the formation of a network of blood vessels, ensuring that the nutrient-bearing "blood" gets distributed throughout. The final product is a fully grown kidney, complete with blood supply, ready to be implanted in the patient and fully compatible with her immune system.

Some researchers even speculate that, given an appropriately shaped scaffold seeded with cells of the requisite tissue types, an entire artificial arm could be grown in culture to replace one lost in an industrial accident. Once grown, it is simply stitched into place.

Figure 3. Graftskin, Artificial Skin Grown from Cultured Cells
on a Scaffold of Biodegradable Polymer

The key to these advances is a suitable polymer scaffold: the material should be broken down slowly by the cells into non-toxic by-products. A copolymer of lactic and glycolic acid is a favorite material (approved by the US Food and Drugs Administration), which is degraded to carbon dioxide. Liver cells have been cultured in such supports. The formation of blood vessels (angiogenesis) can be encouraged by doping the scaffold with the protein called the angiogenic growth factor, which does just what the name implies. Similarly, bone growth in a biodegradable scaffold may be stimulated using bone morphogenic protein.

Many organs are not, however, just a mass of cells. They might contain several different tissue types interwoven in a complex geometry that is essential to proper cell-to-cell communication. For example, the hepatocyte cells of the liver are mixed in with tissue-forming fibroblasts. Hepatocytes cultured in isolation do not function so efficiently. The right blend might be achieved by growing the two cell types on surfaces treated with a thin layer of cell-adhesion molecules. Techniques of microlithography, discussed in Section 6, may be used to imprint a microscopically patterned film of adhesion molecules on the surface, and hepatocytes will then stick only to the patterned areas. Once growth is underway, the intervening spaces can be made adhesive too, and fibroblasts deposited in these interstices. Studies of this kind have shown that there is an optimal patterning scale at which the hepatocytes function best.

Biomedical materials are therefore moving in two related directions. The first is towards greater biological integrity: synthetic materials are being developed for their ability to interact with cells in beneficial ways, so that the interface of the natural and the artificial is as inobtrusive as possible. The ultimate extension of this approach is then to remove the interface altogether: to grow real biological materials, assisted by supports and scaffolding that direct and stimulate the growth before, in the ideal case, being destroyed by the very tissues whose formation they have promoted.

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