The Classic: Biomaterial-Centered Infection

Anthony Gristina, MD Anthony Gristina (see photo) was born in New York City in 1931. He grew up in the Bronx and attended the prestigious Bronx High School of Science. He attended New York University for his undergraduate studies, followed by medical school in Albany and an Internship at Bellevue Hospital in New York. He served in the United States Air Force from 1957 to 1959 and was stationed at the Strategic Air Command base in Souderstrom Fiord in Greenland. After his honorable discharge from the Air Force he began an orthopaedic residency at the Hospital For Special Surgery in New York. He finished his orthopaedic training in 1964. He entered practice on the staff of St. Luke’s Hospital in New York and remained there until 1971. In that year the Dean of the Bowman Grey Medical School of Wake Forrest University in Winston-Salem, North Carolina invited him to serve as Chairman of the Department of Orthopaedics. He remained in that post for nearly 20 years, moving to Reston, Virginia in 1990 as head of the Musculoskeletal Science Research Institute. He remained there until his death in 1998.Figure.: Anthony Gristina, MD is shown.Dr. Gristina developed an interest in musculoskeletal infection early in his career. He wondered why certain kinds of orthopaedic implants became infected whereas others did not and he related his observations on biologic adherence, eg moss and slimes on rocks in streams, to the phenomenon of bacteria to metals and plastics in humans. He defined the critical role of the glycocalyx in certain organisms that sequested them from macrophages and antibiotics and he investigated the role of the implant surface in this process. He was the recipient of a number of National Institutes of Health grants in support of his research, but he died before he completed it. The article published here summarizes the work he was doing when he was developing these concepts. Henry H. Sherk, MD THE TWO MAIN BARRIERS TO THE EXTENDED USE OF IMPLANTED biomaterials and complex artificial organ devices are the possibility of biomaterial-centered infection and the lack of successful tissue integration of biomaterial surfaces. These seemingly disparate phenomena are actually similar expressions of cell-to-substratum surface interactions. “Foreign body” (biomaterial)-centered infections are causally related to the highly adaptive ability of bacteria to colonize the surfaces of “inert” biomaterials or of adjacent, damaged tissue cells (1-9). Successful tissue integration of biomaterials depends on the ability of tissue cells to arrive at an intimate, possibly chemically bonded relation between their membrane molecular entities and the biomaterial surface (6, 10, 11). Interactions between bacteria or tissue cells and a substratum surface depend largely on the surface and near-surface atomic structure and composition of implanted biomaterials (6, 10, 12). This article reviews recent studies in the composite science of cells and surfaces and outlines the significance of and relation between microbial colonization of biomaterials and tissue cell integration of those surfaces in the “race for the surface.” It is suggested that the fate of an available surface may be conceptualized as a race for the surface, which is a contest between tissue cell integration and bacterial adhesion to that same surface. Host defense systems that are perturbed by biomaterials are a vital factor. If the race is won by tissue, then the surface is occupied and defended and is thus less available for bacterial colonization. Numerous biomaterial components are permanently or temporarily implanted in humans, including the artificial heart, joint replacements, contact lenses, heart valves, vascular prostheses, dental implants, fabrics and sutures, and intravascular catheters. Ultimately, almost every human in technologically advanced societies will host a biomaterial. Resistant, recurrent, often catastrophic, and always costly infection is a frequent complication of the use of these materials. Infection of a vascular or total joint prosthesis will almost always result in reoperation, osteomyelitis, amputation, or death. Combined rates of death or amputation from infected cardiac, abdominal, and extremity vascular prostheses may exceed 30% (13-15). Transcutaneous or transmucosal devices such as intravenous catheters, peritoneal dialysis catheters, and urologic devices rarely escape infection if left indwelling for any length of time (13, 14). Pathogenic Sequence in Substratum-Induced Infection When nonliving substrata (the artificial heart, biomaterial implants, and some tissue transplants) are introduced into mammalian hosts, they may become favored sites for adhesive bacterial colonization, especially in the immunocompromised host. Adhesion-mediated infections develop that are notoriously resistant to antibiotics and host defenses and that tend to persist until the biomaterial or foreign body is removed (4, 5, 8, 15). The pathogenesis of adherent infections is related, in part, to preferential colonization of inert substrata whose surfaces are not integrated with healthy tissues composed of living cells and intact extracellular polymers (5, 7, 16-19). Progression to clinical infection in biomaterial-related disease in normal or immunosuppressed patients involves the maturation of an inoculum of known pathogens (for example, Staphylococcus aureus or Pseudomonas aeruginosa) or the transformation of nonpathogens (Staphylococcus epidermidis) to a septic focus of adhesive, “slime-producing,” virulent organisms. This transformation occurs in the presence of, and is potentiated by, the surface of the biomaterial (6, 15). A major organ device such as the total artificial heart (TAH), which interacts with hemodynamic and solid tissue systems and traverses body cavities to the external environment, is particularly susceptible to infection. Recent experience indicates that biomaterial-centered infection of the TAH restricts its use to that of a bridging device to heart transplants for periods of less than 100 days. The massive surface area and systemic placement of the TAH create a locus for colonization and a source of seeding, causing abscess of distant organs and death by massive sepsis (20). Patients with a TAH are also particularly at risk because of their depressed host defense status. Even in healthy patients, host defense mechanisms may be perturbed by the presence of biomaterials. Microbial Adhesion and Tissue Integration Microbial adhesion, aggregation, and disaggregation (dispersion) involve interactions between cells and substrata surfaces in an ambient fluid milieu. The surface may be inorganic or organic, inert or reactive, devitalized or living; the organisms may be of the same or different species; the cell types may be prokaryocytes or eukaryo-cytes; and the environment may be any that supports life (3, 21-23). Bacteria in natural habitats, certain diseases, infections related to biomaterials or damaged tissue, and ostemyelitis have a common survival mode based on the adhesive colonization of substrata (3, 21-23). In biomaterial infections or osteomyelitis, compromised tissue, bone, or prosthetic devices provide those substrata. Interaction of physical and biological factors then allows bacterial attachment and adhesion. Proteinaceous adhesins (fimbriae in Gramnegative bacteria), polysaccharide polymers, and surface and milieu substances interact and intermix to form an aggregate of bacteria, elemental substances, glycoproteins, and polysaccharides in a biofilm (3, 21-23). Additional symbiotic species may join in consortia and present as a polymicrobial infection. Characteristically, these infections do not respond to treatment until the substratum is removed. Thus, bacterial adhesion and its denominators direct the pathogenesis of damaged tissue and biomaterial infections (3, 6, 21, 23). Tissue integration is a desired phenomenon for the biocompatibility of certain implants and biomaterials. Tissue integration requires a form of eukaryocytic adhesion or compatibility with possible chemical integration to an implant surface (10, 11). In effect, this is the goal of the science of biomaterials for solid tissue system implants. For hemodynamic systems, a biocompatible, nonadhesive, luminal surface is desirable to prevent thrombus formation or infection. Many of the fundamental principles of interfacial science apply to microbial adhesion, tissue integration, and biocompatibility and are general to and independent of the substratum materials involved (2, 10, 21, 23). Bacteria in Biomaterial Sepsis The ability to adhere to surfaces is a general property of almost all bacteria and depends on an intricate and sometimes exquisitely specific series of events. These events are based on determinants and characteristics of the bacteria, the substratum surface to be colonized, and the ambient fluid milieu. Studies have most frequently resulted in isolation of Staphylococcus epidermidis and Staphylococcus aureus from infected biomaterial surfaces (3, 6, 15). Additional organisms isolated include Escherichia coli, peptococci, Pseudomonas aeruginosa, Proteus mirabilis, and beta hemolytic Streptococcus (3, 6). The variety of organisms recovered is expanding as awareness increases and methodology improves. Staphylococcus epidermidis, usually thought of as a nonpathogenic, commensal, human skin saprophyte, has emerged as a serious pathogen in biomaterial-related infections and is a leading cause of infections of vascular prostheses, neurosurgical shunts, and orthopedic implants (13-15, 24). Staphylococcus epidermidis is frequently involved when the biomaterial surface is a polymer or when a polymer is a component of a complex device, such as in extended-wear contact lenses, vascular prostheses, the TAH, and total joints (6). Staphylococcus aureus is often the major pathogen in biometal, bone and joint, and soft tissue infections; however, it is less frequently associated with polymersited infections than Staphylococcus epidermidis (6). Staphylococcus aureus is the most common pathogen isolated in osteomyelitis when damaged or dead bone acts as a substratum (5, 6, 25). Our studies in vitro verify preferential adhesion to the surfaces of polymers for Staphylococcus epidermidis and to metals for Staphylococcus aureus (6). Similar findings have been presented by other investigators (2, 26). Staphylococcus epidermidis is also a factor in polymicrobial infections associated with other substrata, such as metals, compromised bone, and tissue. However, in those cases it is less frequently seen and tends to augment or be augmented by other organisms (6, 27). Pseudomonas aeruginosa is the most frequently identified cause of bacterial associated with the use of extended-wear contact It may to be the as the use of polymers in sites example, extended-wear contact and the TAH Studies of osteomyelitis have polymicrobial infection in than of the cases (5, 25). The most common pathogens isolated Staphylococcus aureus and Staphylococcus epidermidis and and Proteus to be an of are present often than is and be as a for The extracellular polysaccharide of bacteria is a composed of a of and molecular polymers associated in interactions. In are composed of such as and and and and may be an factor in the and of biomaterial-centered This complex is to as an for to with to to and to in of surface adhesion, aggregation, and polymicrobial (2, 5, the and in the of Staphylococcus epidermidis have been and have been to be major components of the by Staphylococcus epidermidis These Staphylococcus epidermidis from clinical to biomaterial Recent studies of a Staphylococcus epidermidis the presence of These and other of the between and composition and or of bacteria may with and of the environment from fluid or and other almost a biomaterial or tissue substratum and provide sites for bacterial or tissue adhesion (2, The specific role of of the of this will for or of tissue The of and is by biomaterial surface studies with specific of on a biomaterial surface have of to and implants than also form on the surface of in bone and Staphylococcus aureus has sites for and this a role for in adhesion and possibly infection in may not cause (3, attachment depends on the general physical characteristics of the the fluid and the adhesion, which occurs chemical that in depend on specific as as on polymer The of complex natural into such as or is but may not be of or specific events. Bacteria may arrive the surface of a foreign or tissue substrata by direct from cells or by of as in the or by (for example, heart valves, joint replacements, or of their atomic surfaces tend to present or available sites for interactions For a to almost and the For polymers and metals, sites are by surface and and by and from the host The atomic and or in a human host have not been defined for a but these factors be to be specific for the host environment, and the or tissue cell adhesion or integration (2, 10, in to of is that surfaces may also as for molecular and that at (6, 10, The cell surface is as is that of most substratum however, of materials at the with and tissue by and infection of the biomaterial also and The common of the and substratum tend to but at the a or the surface (2, occurs until the is entered than to occurs not (2, Studies that are at as as and at to are to 100 as as of for bacteria and most surfaces (2, interactions tend to and bacteria at the When a or tissue cell is or or is to the surface, it is that chemical interactions and with extracellular to or with specific adhesins and substratum may interact if they are present in the biological as in cell pathogenesis or that implants may also or with inorganic substratum may also to surfaces or to surface and may in aggregation, adhesion and formation If such as and are bacterial or to and cells on the of the expanding may or and is in the pathogenesis of the septic that biomaterial infection. In natural it is a survival and but it has been as a factor in human infection the general of septic a and molecular disaggregation a of and such as hemodynamic or or total joint in extracellular polysaccharide polymer and composition may an role in or disaggregation and cell or of by or cell and in some cases to are usually with a or that may be to the characteristics of natural phenomena such as or cell of colonization that are the and of and bacteria and the formation by Pseudomonas species The aggregate or Staphylococcus epidermidis on the surface of an extended-wear contact also a form not For some as a or or cells tend to or to form from the that to be in available the in a in of these may be in clinical infection. from a of cells as In a environment when a surface area or when factors of bacteria or aggregate from are available for This may the or phenomena of or bacterial The Many implants are composed of or metals or foreign and devitalized tissue and bone in a biological environment are and susceptible substrata because they are and do not infection. In of they are and may adhesion or interact with host defenses (4, 7, 8, of and surfaces and to surface which are to be adhesive for tissue cells The of at the surface and thus the number of depends on surface A surface and is and of chemical an role in to surfaces as the to is from of the molecular other and interact frequently than in at specific sites may also the for specific chemical that the may at a especially those of and and are resistant to by of their elemental and surface that form or are by an their These surface form the with of the and possibly with the surfaces of bacterial have surface that of and cells (10, will interact as for prokaryocytes and and to and tissue cell than polymers or However, which form an surface in substrata. medical polymers are are in and whereas polymers are for which tend to the in surface The that result are not as complex as those of surfaces such as metals or but are of biologic rates of may on a surface because molecular contact is in a or membrane system than in a molecular medical polymers in general are thought to be resistant to by bacteria, for example, molecular that are to by Pseudomonas aeruginosa and has a structure that surface area for and molecular Staphylococcus epidermidis has a of adhesion to polymers than Staphylococcus aureus Tissue adhesion to polymers such as is and is often by an especially of are adhesive for bacterial pathogens It may be that and tend to be specific to polymer and its process. This of bacterial and are as are metals, and are as dental and orthopedic implants. are of in an are and are to chemically with biological tissue, integration, but at the same time to be that to be with foreign and by tissues The of these materials is with adhesion to and but the clinical significance and characteristics of infections of these surfaces before any be Studies of the colonization of metals, polymers, and by Staphylococcus epidermidis that substrata metals and are less than polymers tissue as substrata. soft tissue is by of tissue and is in microbial and and a surface for colonization by bacteria that the and damaged tissues are to colonization. a particularly of dead tissue, bone, and that have a of infection of to cells are by a When this polysaccharide is by or sites and may be may then be available for bacterial adhesion, leading to the of vascular infection as as the presence of a may in the colonization and infection of vascular by and other may also be a factor in by or by septic in cell vascular polymer surfaces may bacterial adhesion or events also in infection. bacteria, Staphylococcus Streptococcus Streptococcus and Streptococcus which are common of bacterial to or to natural heart or of by and may be an in the colonization of heart of may bacterial to damaged tissues (3, This is also possible in is a composite structure composed of and a similar to or to bone a substratum for bacterial colonization have and the of its and as bacterial (5, 6, of Biomaterial surfaces present that or sites and elemental that are related to the or (10, such as surface and surface be by the and of the However, because of the complex and interactions between biomaterials and their environment, surface are not from composition of surfaces may be different for surface atomic to a of to than for composition because of of specific at the surface These surfaces are by 100 to on and biologic may be and perturbed by and The and of the biomaterial or surface will the and of from the host The surface and of or polymers are also to based on molecular composition or structure and Even polymers such as their surface because of mechanisms molecular and of polymers in and with by in It has been suggested that of biologic at the surface in an environment polymer surface and is by the structure and surface of the polymer in Adhesion or Integration to on surfaces. bacteria or tissue cells or or contact a substratum surface, their and are to molecular at the substratum surface and to on the substratum surface. tissue cells or bacteria then or less and with of integration, to the substratum by of this complex is a of and to these interactions. chemical the formation of at and the presence of from the or as may the of bacterial that result in polysaccharide and and biofilm formation on specific substrata they are by bacteria not (6). These same phenomena interact in tissue compatibility or tissue the physical and chemical of biomaterial especially of metals or substances, may be the for and in some bacteria and possibly in (6, For metals, and or at the surface and involved in may serve as for in and and Tissue cell or may at the between the bone tissue and a surface It is the chemical of the surface with which tissue cell (for example, and The composition of the has not been However, it is that molecular interactions are at that chemical The may involve the same as those involved with and bacterial adhesion. These interactions and are specific and (6, For a form of direct contact is seen at the as molecular between cells and substrata, and or of or integration is a of the Studies that to of the surface that chemical to bone tissue may be tissue the and by bacterial or chemical for provide an for the of and from or or they may be The is an that at a surface and a complex of and bacterial biofilm This may be to biomaterial surfaces when adhesive, possibly colonization a which are and from which factors are It is possible that and compromised tissue may be the and are available to the bacterial or tissue cell The may from with host and that those by bacteria of than of by may in by of and of in a or environment may also to of and an to bacteria has been to for Staphylococcus Staphylococcus epidermidis, and Pseudomonas aeruginosa and to and for Escherichia In may as and are available in or especially Even with such as some of at may when is or or chemical with biologic not by of and other substances may also be present as a result of polymer or (6). such as and may to of complex in and adhesion and to external (2, It is also that polymers may be or may provide of and polymers, such as and that may be by and Integration The of implants in to general that a for orthopedic and dental implants and for vascular of the prosthesis or artificial organ be by host cells to provide or integration (for example, a total joint requires in bone and be adhesive for or intravascular by of a of and for tissue or For orthopedic implants, a is to the between and bone, to and as a This be adhesive to and however, is not adhesive for tissue or bone it may an host and provide an substratum for bacterial colonization. prostheses have similar general they may be composed of polymers, the hemodynamic for whereas the are for tissue and however, it is that occurs than chemical often a The TAH as it is a composite of including metals and polymers, and involves compatibility the materials and between materials and is by the for adhesive system tissue and environment or hemodynamic system there is usually a that traverses organ body and skin to the external ambient and microbial The a not for the source but for as The surfaces of the artificial heart colonization sites for bacteria, with biomaterial a The hemodynamic interactions the device create fluid and tissue that are to and the events of microbial adhesion. The integration of and natural a of and sites for bacterial adhesion (20). The of hemodynamic to septic or that may have on luminal biomaterial or damaged tissue and host defense mechanisms not In bacteria may host tissue cells in the race for the surface and thus cause infection of tissue bacterial adhesion has it is that tissue cells will be to these to and the surface. are in susceptible to infection because they are usually not integrated if not or surfaces are by and have in been by an number of in Even in a colonization will be by a bacteria that have attachment and use of the determinants of adhesion. These provide a for or for colonization, as their surfaces and polysaccharides are adhesive for other a biomaterial or surface that is adhesive for tissue cells and that eukaryocytic colonization or integration may be the for bacterial colonization. The implant environment be in a resistant to bacterial colonization and for tissue cells by surface and or by with the before the surface is and when colonization by bacteria antibiotics may be known biomaterial pathogens that with bacterial polymer and adhesive that or that are from the substratum be or are an that may provide an A is of the atomic and of substrata surfaces and their interactions with or bacteria, and tissue cells before biomaterials for specific be Bacteria are and highly adaptive organisms. are but they substrata for which bacteria, but not tissue have colonization and survival Biomaterial surfaces be to compatibility and tissue integration and to microbial colonization in the race for the surface.