O3h Hnso3h

represent areas that are demonstrably devoid of both epidermis and dermis, the outer and inner layers of skin, respectively. Such wounds normally close by contraction of wound edges and by synthesis of scar tissue. Previously, collagen and various glycosaminoglycans, each prepared in various forms such as powder and films, had been used to cover such deep wounds without observing a significant modification in the outcome of the wound healing process (compare the historical review of Schmitt, 1985).

Surprisingly, grafting of these wounds with the porous CG copolymer on guinea pig wounds blocked the onset of wound contraction by several days and led to synthesis of new connective tissue within about 3 weeks in the space occupied by the copolymer (Yannas et al., 1981, 1982). The copolymer underwent substantial degradation under the action of tissue collagenases during the 3-week period, at the end of which it had degraded completely at the wound site. Studies of the connective tissue synthesized in place of the degraded copolymer eventually showed that the new tissue was distinctly different from scar and was very similar, though not identical, to physiological dermis. In particular, new hair follicles and new sweat glands had not been synthesized. This marked the first instance where scar synthesis was blocked in a full-thickness skin wound of an adult mammal and, in its place, a physiological dermis had been synthesized. That this result was not confined to guinea pigs was confirmed by grafting the same copoly-

mer on full-thickness skin wounds in other adult mammals, including pigs {Butler et al., 1995) and, most importantly, human victims of massive burns {Burke et al., 1981).

Although a large number of CG copolymers were synthesized and studied as grafts, it was observed that only one possessed the requisite activity to modify dramatically the wound healing process in skin. The structure of the CG copolymer required specification at two scales: at the nanoscale, the average molecular weight of the cross-linked network which was required to induce regeneration of the dermis was described by an average molecular weight between cross-links of 12,500 ± 5,000; at the microscale, the average pore diameter was between 20 and 120 /Am. Relatively small deviations from these structural features, either at the nanoscale or the micro-scale, led to loss of activity (Yannas et al., 1989). In view of the nature of its unique activity this biologically active macro-molecular network has been referred to as skin regeneration template (SRT). (See also Chapter 7.10.)

The regeneration of dermis was followed by regeneration of a quite different organ, the peripheral nerve (Yannas et al., 1987; Chang and Yannas, 1992). This was accomplished using a distinctly different ECM analog, termed nerve regeneration template (NRT). Although the chemical composition of the two templates was identical there were significant differences in other structural features. NRT degrades considerably slower than SRT (about 6 weeks for NRT compared to about 2 weeks for SRT) and is also characterized by a much smaller average pore diameter (about 5 fim compared to 20-120 /um for SRT). A third ECM analog was shown to induce regeneration of the knee meniscus in the dog (Stone et al., 1990). The combined findings showed that the activity of individual ECM analogs was organ specific. It also suggested that other ECM analogs, still to be discovered, could induce regeneration of organs such as a kidney or the pancreas.

Bibliography

Burke, J. F,, Yannas, I. V., Quinby, W. C., Jr., Bondoc, C. C., and Jung, W, K. (1981). Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann. Surg. 194: 413-428.

Butler, C. E., Compton, C. C., Yannas, I. V., and Orgill, D. P. (1995). The effect of keratinocyte seeding of collagen-glycosaminoglycan membranes on the regeneration of skin in a porcine model. 27th Annual Meeting of the American Burn Association, Albuquerque, NM, April 19-21. Chang, A. S., and Yannas, I. V. (1992). Peripheral nerve regeneration, in Encyclopedia of Neuroscience, B. Smith and G. Adelman, eds., Birkhaiiser, Boston. Suppl. 2, pp. 125-126. Chvapil, M. (1979). Industrial uses of collagen, in Fibrous Proteins: Scientific, Industrial and Medical Aspects, D. A. D. Parry and L. K. Creamer, eds., Academic Press, London, vol. 1, pp. 247-269. Davidson, |, M. (1987). Elastin, structure and biology, in Connective Tissue Disease, J. Uitto and A, J. Perejda, eds. Marcel Dekker, New York, Ch. 2 pp. 29-54. Kauzmann, W. (1959). Some factors in the interpretation of protein denaturation, Adv. Protein Chem. 14: 1—63. Nimni, M. E., ed. (1988). Collagen, Vol HI, Biotechnology. CRC

Press, Boca Raton, FL. Piez, K. A. (1985). Collagen, in Encyclopedia of Polymer Science and Technology 3: 699-727.

Schmitt, F. O. (1985). Adventures in molecular biology. Ann. Rev. Biophys. Biophys. Chem. 14: 1-22.

Silbert, J. E. (1987). Advances in the biochemistry of proteoglycans, in Connective Tissue Disease, J. Uitto and A. J. Perejda, eds. Marcel Dekker, New York, Ch. 4, pp. 83-98.

Stenzel, K. I I., Miyata, T., and Rubin, A. L. (1974). Collagen as a biomaterial. in Annual Review of Biophysics and Bioengineering, L. J. Mullins, ed., Annual Reviews Inc., Palo Alto, CA, Vol. 3, pp. 231-252.

Stone, K. R., Rodkey, W. G., Webber, R. J., McKinney, L„ and Stead-man, J. R. (1990). Collagen-based prostheses for meniscal regeneration. Clin. Orth. 252: 129-135.

Yannas, I. V. (1972). Collagen and gelatin in the solid state. J. Macro-mol. Sei.-Revs. Macromoi. Chem., C7(l), 49-104.

Yannas, I. V., Burke, J. F., Gordon, P. L., and Huang, C. (1977). Multilayer membrane useful as synthetic skin. U.S. Patent 4,060,081; Nov. 29.

Yannas, I. V., Burke, J. F., Warpehoski, M., Stasikelis, P., Skrabut, E. M., Orgill, D. P., and Giard, D. J. (1981). Prompt, long-term functional replacement of skin. Trans. Am, Soc. Artif. Intern. Organs 27: 19-22.

Yannas, I. V., Burke, J. F., Orgill, D. P., and Skrabut, E. M. (1982). Wound tissue can utilize a polymeric template to synthesize a functional extension of skin. Science 215: 174—176.

Yannas, I. V., Orgill, D. P., Silver, ]., Norregaard, T. V., Zervas, N. T., and Schoene, W. C. (1987). Regeneration of sciatic nerve across 15 mm gap by use of a polymeric template, in Advances in Biomedical Polymers, C. G. Gebeleim, ed. Plenum, New York, pp. 1-9.

Yannas, I. V., Lee, E., Orgill, D. P., Skrabut, E. M., and Murphy, G. F. (1989). Synthesis and characterization of a model extracellular matrix that induces partial regeneration of adult mammalian skin. Proc, Natl. Acad. Sei. U.S.A. 86: 933-937.

2.8 Composites

Harold Alexander

The word "composite" means "consisting of two or more distinct parts." At the atomic level, materials such as metal alloys and polymeric materials could be called composite materials in that they consist of different and distinct atomic groupings. At the microstructural level (about 10~4 to 10~2 cm), a metal alloy such as a plain-carbon steel containing ferrite and pearlite could be called a composite material since the ferrite and pearlite are distinctly visible constituents as observed in the optical microscope. At the molecular and microstructural level, tissues such as bone and tendon are certainly composites with a number of levels of hierarchy.

In engineering design, a composite material usually refers to a material consisting of constituents in the micro- to macrosize range, favoring the macrosize range. For the purpose of discussion in this chapter, composites can be considered to be materials consisting of two or more chemically distinct constituents, on a macroscale, having a distinct interface separating them. This definition encompasses the fiber and particulate composite materials of primary interest as biomaterials. Such composites consist of one or more discontinuous phases embedded within a continuous phase. The discontinuous phase is usually harder and stronger than the continuous phase and is called the rein-

Composite materials

Fiber—reinforced composites (fibrous composites)

Particle—reinforced composites (particulate composites)

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