J. BIOMED. MATER. RES.
VOL. 10, PP. 273-281 (1976)
An in vitro Study of Bacterial Response to Inert and Reactive Metals and to Methyl Methacrylate ANTHONY G. GRISTINA, GEORGE D. ROVERE, HIRUMO SHOJI, and JOSEPH F. NICASTRO, Section on Orthopedic Surgery, Department of Surgery, Bowman Gray School of Medicine of W a k e Forest University, Winston-Salem, North Carolina ,27104
Summary The clinical use of inert materials for internal fixation and joint replacement devices is increasing rapidly; studies on the effect of these materials on bacteria and host resistance to infection have not kept apace. Any substance placed within the body may interfere with host-parasite interaction, either by its physical presence or by physiochemical activity a t its interface with the surrounding tissue. Either mechanism, by altering the normal host defense mechanisms, may promote or retard bacterial growth. Bacterial growth may also be altered if a trace element essential to or inhibitory to the bacteria or an element that antagonizes or potentiates humoral antibacterial systems is leached from the substance. We have tested bacterial growth and inhibition in vitro in the presence of substances used as implant materials: surgical silver, iron, zinc-coated galvanized iron, aluminum alloy, stainless steel, Vitallium, and methyl methacrylate. Our results showed: 1) metals that have low grades of tissue reactivity and little bacteriotoxic effect provided a framework along which bacterial growth and propagation occurred ; 2 ) metals that have higher levels of cellular reactivity, specifically aluminum and galvanized wire, caused selective bacterial toxicity. The in vitro response of bacteria to methyl methacrylate was similar to that of Vitallium and other inert substances, i.e., growth and propagation were abundant adjacent to methyl methacrylate. These studies led us to speculate that, if similar phenomena occur in vivo, bacterial growth and dissemination might be increased when an inert implant material was used and decreased when the implant material was more reactive.
INTRODUCTION As the use of artificial joints becomes more common in orthopedic practice, it has been concluded that the ideal prosthetic material, 273 @ 1976 by John Wiley & Sons, Inc.
274
GRISTINA ET AL.
in addition to being structurally strong and composed only of elements that do not act electrolytically with one another, must be as inert as possible.1-10 Some studies t h a t we have done have made us question whether these criteria are indeed best as far as postoperative sepsis is concerned. I n , 1963, we reported an in vitro study of the effect of various substances on bacterial growth." The substances used were steel, Vitallium, stainless steel, catgut, silk, dermalon, wood, and autoclaved human bone; the bacteria tested were Xtaphylococcus aureus, Staphylococcus albus, and Escherichia coli. A suspension of bacteria was spread over one-half of a n agar plate and a strip of the substance placed so that it lay half on the inoculated and half on the bacteriafree agar. We found that the foreign substance formed a scaffold along which bacteria grew into the previously bacteria-free zone. I n no instance was growth inhibited; in all instances growth was abundant adjacent to the foreign substance. When an antibiotic disc was added to the inoculated side of the agar plate, the usual halo of antibacterial kill appeared around the disc and was not affected by the presence of the foreign substance. However, one year later, we tested a cleansed and sterilized fragment from a steel plate that had been removed from a femur after 17 years' implantation. At the time of the operation, the steel plate had been blackened and fragmented; the adjacent tissue was bluishblack and contained specks of steel. After the fragment had lain on the agar plate for 48 hr, a zone of inhibition of bacterial growth could be seen around it, similar to the zone of inhibition that develops around a n antibiotic sensitivity disc. These findings led us to wonder 1) whether the zone of inhibition was secondary to a bacteriotoxic effect of that particular metal or its corrosion products and 2) whether other metals or implant substances not previously tested might demonstrate in the same in vitro testing system a selective inhibition or enhancement of bacterial grow-th and propagation. We then carried out the following experiments.
MATERIALS AND METHODS Isolates of Staphylococcus aureus (coagulase positive and mannitol positive), Staphylococcus faecalis, Enterobacteriaceae, and Escherichia
INERT MATERIALS
275
coli were incubated overnight in trypticase soy broth at 37°C and then spread over one-half of an agar plate prepared of tryptose blood agar with 5% human blood, one isolate per plate. Two inch strips of surgical silver, iron, galvanized iron (zinc coated*), aluminum alloyt and tantalum (all .003 diameter wire), stainless steel (316 L VM, .045 diameter wire), Vitallium (.045 diameter wire),** and methyl methacrylate, all autoclaved at 121°C for 20 min at 15 lb pressure, were placed on the agar plates so that one-half lay on the bacteria-streaked zone and the other half lay on the bacteria-free zone, one strip per plate. The plates were then incubated for 48 hr at 37°C and examined a t 24 and 48 hr for bacterial growth.
RESULTS Bacterial growth into the previously bacteria-free zone occurred along the strips of stainless steel, iron, tantalum, silver, Vitallium, and methyl methacrylate, being greatest at the end of the stainless steel and Vitallium wires furthest from the inoculated zone (Fig. I), and being least along the methyl methacrylate. No bacterial migration occurred along the strips of galvanized wire and aluminum; in fact, a zone of inhibition was seen in the inoculated area adjacent to strips of these metals (Fig. 2). Results were similar for all bacteria tested.
DISCUSSION These in vitro findings led us to speculate on their in vivo significance. On the one hand, we found that smooth, inert substances such as Vitallium, methyl methacrylate, and stainless steel allowed propagakion of bacteria; on the other hand, we found that less stable substances such as galvanized wire, aluminum, and oxidized steel not only prevented bacterial propagation but actually destroyed bacteria in their immediate vicinity. Several explanations for the spread of bacteria along the inert materials tested are possible. First, propagation along smooth * Pure zinc on 98% iron, less than 1% nickel, less than 1% copper. t 92% aluminum, .3 to .9% manganese, 1.2 to 1.8% magnesium, 3.7 t o 4.997, copper. ** 19-21% chromium, 14-16% tungsten, .05-.15% carbon, 2% manganese, 1%silicone, 3% iron, 9-11% nickel, remainder cobalt.
276
GRISTINA E T AL.
Fig. 1. An example of bacterial propagation along a substance (Vitallium). The inoculated portion of the agar plate is a t the bottom of the illustration. The organism is X.aureus.
substances may be a simple piling up of bacteria as they divide at the interface between the agar and the foreign substance. Bacteria are known to divide and disperse on a plane parallel to the surface on which they are growing."J2 The presence of a second plane perpendicular to that surface (in this instance the foreign-body bridge) may allow division and propagation in that plane also, resulting in a spilling over of bacteria into the previously bacteria-free area.
INERT MATERIALS
277
Fig. 2. An example of the lack of bacterial propagation along a substance (aluminum). The inoculated portion of the agar plate is at the bottom of the illustration; note the area5 of inhibition. The organism is S. aureus. Note corrosion on the surface of the aluminum.
Second, such propagation may also have been caused by the hydrophilic properties of the foreign body which converted the agar in the immediate area into a liquid milieu through which the bacteria could spread more easily.I2 The in vivo traversing of a tissue plane by a foreign body might allow spreading of an infection or a microorganism by the same mechanism. Third, the foreign body might yield, or sequester from the surrounding medium or tissue, a growth-
278
GRISTINA ET AL.
stimulating substance. Fourth, the foreign body might detoxify a normally bacteria-inhibiting substance from the surrounding medium or tissue. There are also several explanations for the antibacterial effect of the less inert substances. 1)The foreign body might yield, or sequester from the surrounding medium or tissue, a growth-inhibiting substance. 2) The foreign body might detoxify a normally bacteriastimulating substance from the surrounding medium or tissue. Heavy metals in trace amounts are essential for all forms of life, including microorganism^.^^ Heavy metals are taken up by the living bacterial cell in the form of cations and their uptake is strictly regulated since most or all of them are toxic in excess. Just as a deficiency in a trace metal causes one sort of injury, an excess of that metal causes another sort of injury, in many cases a lethal injury rather than deficient growth. A remarkable specificity has been found. Seldom can an excess of one essential metal prevent the damage caused by a deficiency of another; in fact, such an excess often increases that damage. This response of bacteria to metals is believed to be related to enzyme ~ y s t e m s . ' ~ - ~ ~ The conclusion that any substance is essentially nonreactive (or noncorrosive) in human physiological systems need not imply that the same substance is equally so for a bacterial physiological system. Even minute amounts of steel, Vitallium, high-density polyethylene, or methyl methacrylate may positively or negatively alter the rate of growth or viability of microbes in their environment. Such an effect, if not due to chemical action on bacterial or host systems, could be caused by surface effects of the multiple particle residua of friction breakdown of implants. Heavier or lighter bacterial growth along implant substances tested may be the result of a combination of all variables. If a substance is completely inert, then only surface effects or particle size, i.e., only physical factors, are affecting bacterial growth. If a substance is even minutely unstable, as probably all substances are in the final analysis, then even the most minute amounts of elements or compounds leached from or worn from their surfaces wilkinteract with the medium or adjacent bacterial systems on a molecular or microenzymatic basis to cause a predictable response. This responsepositive or negative for bacteria in the environment-is of vital importance and must be considered and studied and, if possible, should even be used therapeutically.
I N E R T MATERIALS
279
The suggestion that the bacterial response to metals is important, especially the bacteriocidal response, does not minimize the basic need in all implants for biostructural design, electrolytic and chemical stability, and host receptivity, but rather focuses attention on the need for further study of the microbial characteristics of an implant in order to utilize creatively the information gained to achieve predictable bacterial and tissue response. Towers pointed out that the incidence of infection after operations involving buried metal was higher than the incidence of infection after operations involving no metal or operations involving pin tracks.24 Most authors agree25-30that metals should not be used in contaminated wounds and that removal of implanted metal may be required for ultimate healing if infection occurs. Acute inflammation around implants has been correlated with the incidence of i n f e ~ t i o n . However, ~ ~ ~ ~ ~ all healing takes place by a process of inflammation-the response of the body to a noxious stimulus.33 Most authors believe that the trauma of the operative procedure itself is a sufficiently inflammatory stimulus.34 It may be that the specifications for the best possible implant material have not yet been established. Perhaps the ideal implant material might combine reasonable cost, soundness and homogeneity, abrasion and wear resistance, and mechanical properties suited to use, with antibacterial activity, optimal inflammatory activity, and optimal host receptivity. It is likely that an effective antimicrobial substance could be incorporated in but structurally separable from the matrix of the implant. The qualities of biodegradability a t a controlled rate and of bacteriotoxic properties may be impossible to combine in a single substance or mixture of substances. It might be possible to compound a prosthetic device that would depend on an inert metal for structural integrity and upon a thin surface coating of a biodegradable, bacteriotoxic substance or metal for resistance to infection. Or, it might be necessary to so alter the alloy’s structure that there are provided small amounts of trace elements which would have an antimicrobial effect as they appear on the surface of the implant or as they are deposited in adjacent tissue. The authors express their appreciation to Dr. Randolph Chase, Department of Microbiology, New York University Medical Center, for his assistance in this study. This study was supported in part by a donation from the Pope Foundation, New York City.
280
GRISTINA ET AL.
References 1. P. G. Laing, in Metals and Engineering in Bone and Joint Surgery, C. 0. Bectol, A. B. Ferguson, Jr., and P. G. Laing, Eds., Williams and Wilkins, Baltimore, 1959, p. 114. 2. J. R. Cahoon and H. W. Paxton, J . Biomed. Muter. Res., 2, 1 (1968). 3. J. Cohen, J. Materials, 1, 354 (1966). 4. A. B. Ferguson, Jr., P. G. Laing, and E. S. Hodge, J . Bone Joint Surg., 42A, 77 (1960). 5. P. G. Laing, A. B. Ferguson, Jr., and E. S. Hodge, J . Biomed. Mat. Res., I, 135 (1967). 6. E. D. McBride, South. Med. J., 31, 508 (1938). 7. F. R. Morral, J . Materials, 1, 384 (1966). 8. J. T. Scales, and G. D. Winter, J . Bone Joint Surg., 41B, 810 (1959). 9. C. S. Venable, W. G. Stuck, and A. Beach, Ann. Surg., 105, 917 (1937). 10. S. Weisman, Ann. New York Acad. Sci., 146, 80 (1968). 11. A. G. Gristina, and G. D. Rovere, J . Bone Joint Surg., 45A, 1104 (1963). 12. P. Weiss, Biological Foundation of Repair a t the Cellular Level. Wound Healing: Proceedings of a Workshop. National Academy of Sciences, National Research Council, Washington, D.C., 1966, p. 116. 13. A. Albert, Selective Toxicity, Wiley, New York, 1965, p. 226. 14. P. H. Abelson, and E. Aldous, J . Bacteriol., 60, 401 (1950). 15. B. D. Davis, R. Dulbecco, H. N. Eisen, H. S. Ginsberg, and W. B. Wood, Jr., Microbiology, Harper and Row, New York, 1968, p. 345. 16. H. G. Enoch, and R. L. Lester, J . Bacteriol., 110, 1032 (1972). 17. A. Goetz, R. L. Tracy, and F. A. Harris, Jr., J . Am. Water Works $ssoc. (Abstr.), 290, 35, 579 (1947). 18. D. W. Esplin, in The Pharmacological Basis of Therapeutics, L. Goodman and A. Gilman, Eds., The Macmillan Co., New York, 1970, p. 1049. 19. R. A. MacLeod and E. E. Snell, J . Biol. Chem., 176, 39 (1948). 20. R. A. MacLeod and E. E. Snell, J . Bacteriol., 59, 783 (1950). 21. C. Ratledge and M. J. Hall, J . Bacteriol., 108, 314 (1971). 22. I. B. Romans, in Antiseptics, Disinfectants, Fungicides, and Chemical and Physical Sterilization, G . F. Reddish, Ed., Lea and Febiger, Philadelphia, 1954, p. 385. 23. C. N. A. Trotman and C. Greenwood, Biochem. J., 124, 25 (1971). 24. A. G. Towers, Lancet, 2, 379 (1965). 25. J. L. Alder, J: P. Burke, and M. Finland, Arch. Intern. Med., 127,460 (1971). 26. A. Y. Ketenjian and M. L. Shelton, J . Trauma, 12, 756 (1972). 27. J. A. Key and F. C. Reynolds, Surgery, 35, 749 (1954). 28. W. R. MacAusland, Jr. and R. G. Eaton, 1.Bone Joint Surg., 45A, 1643 (1963). 29. C. O’Riordan, J. L. Alder, H. H. Banks, and M. Finland, Am. J . Epidemiol., 95, 442 (1972). 30. C. O’Riordan, J. L. Alder, H. H. Banks, and M. Finland, Clin. Orthop. Rel. Res., 87, 188 (1972).
INERT MATERIALS
281
31. C. B. Charosky, P. G. Bullough, and P. D. Wilson, Jr., J . Bone Joint Surg., 55A, 49 (1973). 32. P. D. Wilson, Jr., Actu Orthop. Belgicu, 39, 70 (1973). 33. P. G. Laing, Orthop. Clin. North Am., 4, 249 (1973). 34. S. A. Wesolowski, A. Martinez, and J. D. McMahon, Curr. Frob. Surg., 2 (1966).
Received July 10, ,1975
VOL. 10, PP. 273-281 (1976)
An in vitro Study of Bacterial Response to Inert and Reactive Metals and to Methyl Methacrylate ANTHONY G. GRISTINA, GEORGE D. ROVERE, HIRUMO SHOJI, and JOSEPH F. NICASTRO, Section on Orthopedic Surgery, Department of Surgery, Bowman Gray School of Medicine of W a k e Forest University, Winston-Salem, North Carolina ,27104
Summary The clinical use of inert materials for internal fixation and joint replacement devices is increasing rapidly; studies on the effect of these materials on bacteria and host resistance to infection have not kept apace. Any substance placed within the body may interfere with host-parasite interaction, either by its physical presence or by physiochemical activity a t its interface with the surrounding tissue. Either mechanism, by altering the normal host defense mechanisms, may promote or retard bacterial growth. Bacterial growth may also be altered if a trace element essential to or inhibitory to the bacteria or an element that antagonizes or potentiates humoral antibacterial systems is leached from the substance. We have tested bacterial growth and inhibition in vitro in the presence of substances used as implant materials: surgical silver, iron, zinc-coated galvanized iron, aluminum alloy, stainless steel, Vitallium, and methyl methacrylate. Our results showed: 1) metals that have low grades of tissue reactivity and little bacteriotoxic effect provided a framework along which bacterial growth and propagation occurred ; 2 ) metals that have higher levels of cellular reactivity, specifically aluminum and galvanized wire, caused selective bacterial toxicity. The in vitro response of bacteria to methyl methacrylate was similar to that of Vitallium and other inert substances, i.e., growth and propagation were abundant adjacent to methyl methacrylate. These studies led us to speculate that, if similar phenomena occur in vivo, bacterial growth and dissemination might be increased when an inert implant material was used and decreased when the implant material was more reactive.
INTRODUCTION As the use of artificial joints becomes more common in orthopedic practice, it has been concluded that the ideal prosthetic material, 273 @ 1976 by John Wiley & Sons, Inc.
274
GRISTINA ET AL.
in addition to being structurally strong and composed only of elements that do not act electrolytically with one another, must be as inert as possible.1-10 Some studies t h a t we have done have made us question whether these criteria are indeed best as far as postoperative sepsis is concerned. I n , 1963, we reported an in vitro study of the effect of various substances on bacterial growth." The substances used were steel, Vitallium, stainless steel, catgut, silk, dermalon, wood, and autoclaved human bone; the bacteria tested were Xtaphylococcus aureus, Staphylococcus albus, and Escherichia coli. A suspension of bacteria was spread over one-half of a n agar plate and a strip of the substance placed so that it lay half on the inoculated and half on the bacteriafree agar. We found that the foreign substance formed a scaffold along which bacteria grew into the previously bacteria-free zone. I n no instance was growth inhibited; in all instances growth was abundant adjacent to the foreign substance. When an antibiotic disc was added to the inoculated side of the agar plate, the usual halo of antibacterial kill appeared around the disc and was not affected by the presence of the foreign substance. However, one year later, we tested a cleansed and sterilized fragment from a steel plate that had been removed from a femur after 17 years' implantation. At the time of the operation, the steel plate had been blackened and fragmented; the adjacent tissue was bluishblack and contained specks of steel. After the fragment had lain on the agar plate for 48 hr, a zone of inhibition of bacterial growth could be seen around it, similar to the zone of inhibition that develops around a n antibiotic sensitivity disc. These findings led us to wonder 1) whether the zone of inhibition was secondary to a bacteriotoxic effect of that particular metal or its corrosion products and 2) whether other metals or implant substances not previously tested might demonstrate in the same in vitro testing system a selective inhibition or enhancement of bacterial grow-th and propagation. We then carried out the following experiments.
MATERIALS AND METHODS Isolates of Staphylococcus aureus (coagulase positive and mannitol positive), Staphylococcus faecalis, Enterobacteriaceae, and Escherichia
INERT MATERIALS
275
coli were incubated overnight in trypticase soy broth at 37°C and then spread over one-half of an agar plate prepared of tryptose blood agar with 5% human blood, one isolate per plate. Two inch strips of surgical silver, iron, galvanized iron (zinc coated*), aluminum alloyt and tantalum (all .003 diameter wire), stainless steel (316 L VM, .045 diameter wire), Vitallium (.045 diameter wire),** and methyl methacrylate, all autoclaved at 121°C for 20 min at 15 lb pressure, were placed on the agar plates so that one-half lay on the bacteria-streaked zone and the other half lay on the bacteria-free zone, one strip per plate. The plates were then incubated for 48 hr at 37°C and examined a t 24 and 48 hr for bacterial growth.
RESULTS Bacterial growth into the previously bacteria-free zone occurred along the strips of stainless steel, iron, tantalum, silver, Vitallium, and methyl methacrylate, being greatest at the end of the stainless steel and Vitallium wires furthest from the inoculated zone (Fig. I), and being least along the methyl methacrylate. No bacterial migration occurred along the strips of galvanized wire and aluminum; in fact, a zone of inhibition was seen in the inoculated area adjacent to strips of these metals (Fig. 2). Results were similar for all bacteria tested.
DISCUSSION These in vitro findings led us to speculate on their in vivo significance. On the one hand, we found that smooth, inert substances such as Vitallium, methyl methacrylate, and stainless steel allowed propagakion of bacteria; on the other hand, we found that less stable substances such as galvanized wire, aluminum, and oxidized steel not only prevented bacterial propagation but actually destroyed bacteria in their immediate vicinity. Several explanations for the spread of bacteria along the inert materials tested are possible. First, propagation along smooth * Pure zinc on 98% iron, less than 1% nickel, less than 1% copper. t 92% aluminum, .3 to .9% manganese, 1.2 to 1.8% magnesium, 3.7 t o 4.997, copper. ** 19-21% chromium, 14-16% tungsten, .05-.15% carbon, 2% manganese, 1%silicone, 3% iron, 9-11% nickel, remainder cobalt.
276
GRISTINA E T AL.
Fig. 1. An example of bacterial propagation along a substance (Vitallium). The inoculated portion of the agar plate is a t the bottom of the illustration. The organism is X.aureus.
substances may be a simple piling up of bacteria as they divide at the interface between the agar and the foreign substance. Bacteria are known to divide and disperse on a plane parallel to the surface on which they are growing."J2 The presence of a second plane perpendicular to that surface (in this instance the foreign-body bridge) may allow division and propagation in that plane also, resulting in a spilling over of bacteria into the previously bacteria-free area.
INERT MATERIALS
277
Fig. 2. An example of the lack of bacterial propagation along a substance (aluminum). The inoculated portion of the agar plate is at the bottom of the illustration; note the area5 of inhibition. The organism is S. aureus. Note corrosion on the surface of the aluminum.
Second, such propagation may also have been caused by the hydrophilic properties of the foreign body which converted the agar in the immediate area into a liquid milieu through which the bacteria could spread more easily.I2 The in vivo traversing of a tissue plane by a foreign body might allow spreading of an infection or a microorganism by the same mechanism. Third, the foreign body might yield, or sequester from the surrounding medium or tissue, a growth-
278
GRISTINA ET AL.
stimulating substance. Fourth, the foreign body might detoxify a normally bacteria-inhibiting substance from the surrounding medium or tissue. There are also several explanations for the antibacterial effect of the less inert substances. 1)The foreign body might yield, or sequester from the surrounding medium or tissue, a growth-inhibiting substance. 2) The foreign body might detoxify a normally bacteriastimulating substance from the surrounding medium or tissue. Heavy metals in trace amounts are essential for all forms of life, including microorganism^.^^ Heavy metals are taken up by the living bacterial cell in the form of cations and their uptake is strictly regulated since most or all of them are toxic in excess. Just as a deficiency in a trace metal causes one sort of injury, an excess of that metal causes another sort of injury, in many cases a lethal injury rather than deficient growth. A remarkable specificity has been found. Seldom can an excess of one essential metal prevent the damage caused by a deficiency of another; in fact, such an excess often increases that damage. This response of bacteria to metals is believed to be related to enzyme ~ y s t e m s . ' ~ - ~ ~ The conclusion that any substance is essentially nonreactive (or noncorrosive) in human physiological systems need not imply that the same substance is equally so for a bacterial physiological system. Even minute amounts of steel, Vitallium, high-density polyethylene, or methyl methacrylate may positively or negatively alter the rate of growth or viability of microbes in their environment. Such an effect, if not due to chemical action on bacterial or host systems, could be caused by surface effects of the multiple particle residua of friction breakdown of implants. Heavier or lighter bacterial growth along implant substances tested may be the result of a combination of all variables. If a substance is completely inert, then only surface effects or particle size, i.e., only physical factors, are affecting bacterial growth. If a substance is even minutely unstable, as probably all substances are in the final analysis, then even the most minute amounts of elements or compounds leached from or worn from their surfaces wilkinteract with the medium or adjacent bacterial systems on a molecular or microenzymatic basis to cause a predictable response. This responsepositive or negative for bacteria in the environment-is of vital importance and must be considered and studied and, if possible, should even be used therapeutically.
I N E R T MATERIALS
279
The suggestion that the bacterial response to metals is important, especially the bacteriocidal response, does not minimize the basic need in all implants for biostructural design, electrolytic and chemical stability, and host receptivity, but rather focuses attention on the need for further study of the microbial characteristics of an implant in order to utilize creatively the information gained to achieve predictable bacterial and tissue response. Towers pointed out that the incidence of infection after operations involving buried metal was higher than the incidence of infection after operations involving no metal or operations involving pin tracks.24 Most authors agree25-30that metals should not be used in contaminated wounds and that removal of implanted metal may be required for ultimate healing if infection occurs. Acute inflammation around implants has been correlated with the incidence of i n f e ~ t i o n . However, ~ ~ ~ ~ ~ all healing takes place by a process of inflammation-the response of the body to a noxious stimulus.33 Most authors believe that the trauma of the operative procedure itself is a sufficiently inflammatory stimulus.34 It may be that the specifications for the best possible implant material have not yet been established. Perhaps the ideal implant material might combine reasonable cost, soundness and homogeneity, abrasion and wear resistance, and mechanical properties suited to use, with antibacterial activity, optimal inflammatory activity, and optimal host receptivity. It is likely that an effective antimicrobial substance could be incorporated in but structurally separable from the matrix of the implant. The qualities of biodegradability a t a controlled rate and of bacteriotoxic properties may be impossible to combine in a single substance or mixture of substances. It might be possible to compound a prosthetic device that would depend on an inert metal for structural integrity and upon a thin surface coating of a biodegradable, bacteriotoxic substance or metal for resistance to infection. Or, it might be necessary to so alter the alloy’s structure that there are provided small amounts of trace elements which would have an antimicrobial effect as they appear on the surface of the implant or as they are deposited in adjacent tissue. The authors express their appreciation to Dr. Randolph Chase, Department of Microbiology, New York University Medical Center, for his assistance in this study. This study was supported in part by a donation from the Pope Foundation, New York City.
280
GRISTINA ET AL.
References 1. P. G. Laing, in Metals and Engineering in Bone and Joint Surgery, C. 0. Bectol, A. B. Ferguson, Jr., and P. G. Laing, Eds., Williams and Wilkins, Baltimore, 1959, p. 114. 2. J. R. Cahoon and H. W. Paxton, J . Biomed. Muter. Res., 2, 1 (1968). 3. J. Cohen, J. Materials, 1, 354 (1966). 4. A. B. Ferguson, Jr., P. G. Laing, and E. S. Hodge, J . Bone Joint Surg., 42A, 77 (1960). 5. P. G. Laing, A. B. Ferguson, Jr., and E. S. Hodge, J . Biomed. Mat. Res., I, 135 (1967). 6. E. D. McBride, South. Med. J., 31, 508 (1938). 7. F. R. Morral, J . Materials, 1, 384 (1966). 8. J. T. Scales, and G. D. Winter, J . Bone Joint Surg., 41B, 810 (1959). 9. C. S. Venable, W. G. Stuck, and A. Beach, Ann. Surg., 105, 917 (1937). 10. S. Weisman, Ann. New York Acad. Sci., 146, 80 (1968). 11. A. G. Gristina, and G. D. Rovere, J . Bone Joint Surg., 45A, 1104 (1963). 12. P. Weiss, Biological Foundation of Repair a t the Cellular Level. Wound Healing: Proceedings of a Workshop. National Academy of Sciences, National Research Council, Washington, D.C., 1966, p. 116. 13. A. Albert, Selective Toxicity, Wiley, New York, 1965, p. 226. 14. P. H. Abelson, and E. Aldous, J . Bacteriol., 60, 401 (1950). 15. B. D. Davis, R. Dulbecco, H. N. Eisen, H. S. Ginsberg, and W. B. Wood, Jr., Microbiology, Harper and Row, New York, 1968, p. 345. 16. H. G. Enoch, and R. L. Lester, J . Bacteriol., 110, 1032 (1972). 17. A. Goetz, R. L. Tracy, and F. A. Harris, Jr., J . Am. Water Works $ssoc. (Abstr.), 290, 35, 579 (1947). 18. D. W. Esplin, in The Pharmacological Basis of Therapeutics, L. Goodman and A. Gilman, Eds., The Macmillan Co., New York, 1970, p. 1049. 19. R. A. MacLeod and E. E. Snell, J . Biol. Chem., 176, 39 (1948). 20. R. A. MacLeod and E. E. Snell, J . Bacteriol., 59, 783 (1950). 21. C. Ratledge and M. J. Hall, J . Bacteriol., 108, 314 (1971). 22. I. B. Romans, in Antiseptics, Disinfectants, Fungicides, and Chemical and Physical Sterilization, G . F. Reddish, Ed., Lea and Febiger, Philadelphia, 1954, p. 385. 23. C. N. A. Trotman and C. Greenwood, Biochem. J., 124, 25 (1971). 24. A. G. Towers, Lancet, 2, 379 (1965). 25. J. L. Alder, J: P. Burke, and M. Finland, Arch. Intern. Med., 127,460 (1971). 26. A. Y. Ketenjian and M. L. Shelton, J . Trauma, 12, 756 (1972). 27. J. A. Key and F. C. Reynolds, Surgery, 35, 749 (1954). 28. W. R. MacAusland, Jr. and R. G. Eaton, 1.Bone Joint Surg., 45A, 1643 (1963). 29. C. O’Riordan, J. L. Alder, H. H. Banks, and M. Finland, Am. J . Epidemiol., 95, 442 (1972). 30. C. O’Riordan, J. L. Alder, H. H. Banks, and M. Finland, Clin. Orthop. Rel. Res., 87, 188 (1972).
INERT MATERIALS
281
31. C. B. Charosky, P. G. Bullough, and P. D. Wilson, Jr., J . Bone Joint Surg., 55A, 49 (1973). 32. P. D. Wilson, Jr., Actu Orthop. Belgicu, 39, 70 (1973). 33. P. G. Laing, Orthop. Clin. North Am., 4, 249 (1973). 34. S. A. Wesolowski, A. Martinez, and J. D. McMahon, Curr. Frob. Surg., 2 (1966).
Received July 10, ,1975
