Cardiovasc Patbol Vol. 2, No. 3 (Suppl.

)
33s
July-September 1993:333-415

CHAPTER 4
Mechanisms of Inflammation
and Infection With Implanted Devices
James M. Anderson, MD, PhD

Institute of Pathology, Case Western Reserve University, Cleveland, Ohio

Inflammation,wound healing, and foreign body responses are generally considered as parts of the
tissue or cellular host responsesto injury. Table 1 lists the sequence of these events following injury.
From the biomaterials perspective, placement of a biomaterlal in the in vivo environment involves
injection, insertion, or surgical implantation, all of which injure the tissues or organs involved (1,2).
The implantation procedure initiates a response to injury, and mechanisms are activated to produce
healing (3,4). The degree to which the homeostatic mechanisms are perturbed and the extent of
pathophysiologic responses and their resolution are measures of the host reactions to the biomaterial,
and they may ultimately determine its biocompatibility and its success or failure as a device or
prosthesis. Although it is convenient to consider blood-material interactions separately from
tissue-material interactions, it should be kept in mind that the mechanisms involved in both sets of
interactions involve both blood and tissue. Furthermore, host reactions are tissue dependent, organ
dependent, and species dependent. Obviously, the extent of injury varies depending on the
implantation procedure.
This chapter is intended as an overview of the inflammatory and infectious responses to implanted
devices. Specific details regarding components of the inflammatory and wound healing processes are
found in other chapters in this volume.

Temporal Sequence of Inflammation and
Wound Healing
Inflammation is generally defined as the reaction of
vascularized living tissue to local injury. Inflammation
serves to contain, neutralize, dilute, or wall off the injurious
agent or process. In addition, it sets into motion a series of
events that may heal and reconstitute the implant site
through replacement of the injured tissue by regeneration
of native parenchymal cells, formation of fibroblastic scar
tissue, or a combination of these two processes (3,4).
The sequence of events following implantation of a
biomaterial is illustrated in Figure 1. The size, shape, and
chemical and physical properties of the biomaterial and the
physical dimensions and properties of the cardiovascular
prosthesis or device may be responsible for variations in
Address for reprints: James M. Anderson, MD, PhD, Institute of
Pathology, Case Western Reserve University, Cleveland, Ohio 44106-4907.
the intensity and time duration of the inflammatory and
wound healing processes. Thus, intensity and/or time
duration of inflammatory reaction may characterize the
biocompatibility of a biomaterial, prosthesis, or device
(5,Q
In general, the biocompatibility of a material with tissue
has been described in terms of the acute and chronic
inflammatory responses and of the fibrous capsule forma-
tion that is seen over various time periods following
implantation. Histologic evaluation of tissue adjacent to
implanted materials as a function of implant time has been
the most commonly used method of evaluating the
biocompatibility (2). Classically, the biocompatibility of an
implanted material has been described in terms of the
morphological appearance of the inflammatory reaction to
the material; however, the inflammatory response is a
series of complex reactions involving various types of cells
the densities, activities, and functions of which are
controlled by various endogenous and autocoid mediators.
The simplistic view of the acute inflammatory response

0 1993 by Elsevier Science F’ubli$hingCO., Inc. 10548807/93/%6.00

 34s ANDERSON
Ih’FLAMMATION/INFECTlON IN IMPLANTED DEVICES
+-ACUTE - CHRONIC - GRANULATION TISSUE -
(_-------------
) - - - - - - - - - -
Time
(Minutes, Hours, Days, Weeks)
progressing to the chronic inflammatory response may be
misleading with respect to biocompatibility studies and the
inflammatory response to implants. Studies using the cage
implant system show that monocytes and macrophages are
present in highest concentrations when neutrophils are also
at their highest concentrations, i.e., the acute inflammatory
response (7,8). Neutrophils have short lifetimes-hours to
days-and disappear from the exudate more rapidly than
do macrophages, which have lifetimes of days to weeks to
months, Eventually macrophages become the predominant
cell type in the exudate, resulting in a chronic inflammatory
response. Monocytes rapidly differentiate into macro-
phages, the cells principally responsible for normal wound
healing in the foreign body reaction. Classically, the
development of granulation tissue has been considered to
be a part of chronic inflammation, but because of unique
tissue-material interactions, it is preferable to differentiate
the foreign body reaction-with its varying degree of
granulation tissue development, including macrophages,
fibroblasts, and capillary formation-from chronic inflam-
mation.
Quantitative in vivo evaluation of components of the
inflammatory response and the biocompatibility of biomedi-
cal polymers has been carried out using subcutaneous
wound cages (9-l 1). Quantitative assays of the components
of inflammatory response have been determined for poly-
mers such as Biomer, Pellethane, and the NHLBI-DTB
reference materials, polydimethylsiloxane (PDMS) and
low-density polyethylene (PE) (12-14).
Table 1. Sequence of Local Events Following Implantation
Injury
Acute inflammation
Chronic inflammation
Granulation tissue
Foreign body reaction
Fibrosis
Cardiovaw Pathol Vol. 2. No. 3 (Suppl.)
July-September 1993:33S-41s
Macrophages
Neovascularization Figure 1. The temporal variation in
the acute inflammatory response,
Foreign Body Giant Cells chronic inflammatory response, gran-
ulation tissue development, and for-
eign body reaction to implanted
biomaterials. The intensity and time
variables are dependent upon the
extent of injury created in the im-
plantationand the size, shape,topog-
raphy, and chemical and physical
properties of the biomaterial.
Blood-Material Interactions and
Inflammation
Blood-material interactions and the inflammatory re-
sponse are intimately linked, and in fact, early responses to
injury involve mainly blood and the vasculature (1,3,4).
Regardless of the tissue or organ into which a biomaterial
is implanted, the initial inflammatory response is activated
by injury to vascularized connective tissue (Table 2).
Because blood and its components are involved in the initial
inflammatory responses, thrombus also forms.
Thrombus formation involves activation of the extrinsic
and intrinsic coagulation systems, the complement system,
the fibrinolytic system, the kinin-generating system, and
platelets. Specific blood interactions with biomaterials are
discussed in chapter 3.
Immediately following injury, changes occur in vascular
flow, caliber, and permeability. Fluid, proteins, and blood
cells escape from the vascular system into the injured tissue
in a process called exudation. Following changes in the
vascular system, which also include changes induced in
blood and its components, cellular events occur and
characterize the inflammatory response (1516). The effect
of the injury and/or biomaterial in situ on plasma or cells can
produce chemical factors that mediate many of the vascular
and cellular responses of inflammation. Although injury
initiates the inflammatory response, released chemicals
from plasma, cells, and injured tissue mediate the response.
Important classes of chemical mediators of inflammation are
presented in Table 3. Several important points must be noted
in order to understand the inflammatory response and how it
relates to biomaterials. First, although chemical mediators
are classified on a structural or functional basis, different
mediator systems interact and provide a system of checks
and balances regarding their respective activities and
functions. Second, chemical mediators are quickly inac-
tivated or destroyed, suggesting that their action is predomi-
nantly local (i.e., at the implant site). Third, generally the

Cardiovasc Path01Vol. 2, No. 3 (SuppI.)
July-September 1993:333-41s
Table 2. Cells and Componentsof VascularizedConnective
Tissue
Intravascular
(blood)cells
Erythrocytes(RBC)
Neutrophils
Monocytes
Eosinophils
Lymphocytes
Basophils
Platelets
Connective tissue cells
Mast Cells
Fibroblasts
Macrophages
Lymphocytes
Extracellular matrix components
Collagens
Elastin
Proteoglycans
Fibronectin
Laminin
lysosomal proteases and oxygen-derived free radicals
produce the most significant damage or injury. These
chemical mediators are also important in the degradation of
biomaterials.
The predominant cell type present in the inflammatory
response varies with the age of the injury. In general,
neutrophils predominate during the first several days
following injury and then are replaced by monocytes as the
predominant cell type. Three factors account for this change
in cell type: (i) Neutrophils are short-lived and disintegrate
and disappear after 24 to 48 hours; neutrophil emigration is
of short duration because chemotactic factors for neutrophil
migration are activated early in the inflammatory response.
(ii) Following emigration from the vasculature, monocytes
differentiate into macrophages, and these cells are very
long-lived (up to months). (iii) Monocyte emigration may
continue for days to weeks, depending on the injury and
implanted biomaterial, and chemotactic factors for mon-
ocytes are activated over longer periods of time.
Acute Inflammation
Acute inflammation is of relatively short duration, lasting
from minutes to days, depending on the extent of injury. The
main characteristics of acute inflammation are the exudation
of fluid and plasma proteins (edema) and the emigration of
leukocytes (predominantly neutrophils). Neutrophils and
other motile white cells emigrate or move from the blood
vessels to the perivascular tissues and the injury (implant)
site (17-19).
The accumulation of leukocytes, in particular neutrophils
and monocytes, is the most important feature of the
inflammatory reaction. Leukocytes accumulate through a
series of processes including margination, adhesion, emigra-
ANDERSON 35s
INPLAMMATION/INFECTION IN IMPLANTED DEVICES
tion, phagocytosis, and extracellular release of leukocyte
products (20). Increased leukocytic adhesion in inflamma-
tion involves specific interactions between complementary
“adhesion molecules” present on the leukocyte and
endothelial surfaces (see chapter 14) (21,22). The surface
expression of these adhesion molecules is modulated by
inflammatory agents; mechanisms of interaction include
stimulation of leukocyte adhesion molecules (C5a, LTBJ,
stimulation of endothelial adhesion molecules (IL-l), or
both effects (TNF). Integrins comprise a family of trans-
membrane glycoproteins that modulate cell-matrix and
cell-cell relationships by acting as receptors to extracellular
protein ligands and also as direct adhesion molecules (23).
An important group of integrins (adhesion molecules) on
leukocytes include the CD1 l/CD1 8 family of adhesion
molecules. These integrins have identical beta (CD18)
subunits but different alpha (CD1 la, b, c) subunits.
Inflammatory mediators, i.e., cytokines, stimulate a rapid
increase in these adhesion molecules on the leukocyte surface
as well as increased leukocyte adhesion to endothelium.
Leukocyte-endothelial cell interactions are also controlled
by endothelial-leukocyte adhesion molecules (ELAMs,
E-selectins) or intracellular adhesion molecules (ICAM-1,
ICAM-2, and VCAMs) on endothelial cells (see Table 2 in
chapter 5) (24).
White cell emigration is controlled in part by chemotaxis,
which is the unidirectional migration of cells along a
chemical gradient. A wide variety of exogenous and
endogenous substances have been identified as chemotactic
agents (15,17-28). Important to the emigration or move-
ment of leukocytes is the presence of specific receptors for
chemotactic agents on the cell membranes of leukocytes.
These and other receptors may also play a role in the
activation of leukocytes. Following localization of leuko-
cytes at the injury (implant) site, phagocytosis and the
release of enzymes occur following activation of neutrophils
and macrophages. The major role of the neutrophils in acute
inflammation is to phagocytose microorganisms and foreign
materials. Phagocytosis is seen as a three-step process in
which the injurious agent undergoes recognition and
neutrophil attachment, engulfment, and killing or degrada-
tion. With regard to biomaterials, engulfment and degrada-
tion may or may not occur, depending on the properties of
the biomaterial.
Although biomaterials are not generally phagocytosed by
neutrophils or macrophages because of the size disparity
(i.e., the surface of the biomaterial is greater than the size of
the cell), certain events in phagocytosis may occur. The
process of recognition and attachment is expedited when the
injurious agent is coated by naturally occurring serum
factors called opsonins (see chapter 18.) The two major
opsonins are IgG and the complement-activated fragment,
C3b. Both of these plasma-derived proteins are known to
adsorb to biomaterials, and neutrophils and macrophages
have corresponding cell membrane receptors for these
36s ANDERSON CardiovascPatholVol. 2, No. 3 (Suppl.)
INFLAMMATION/INFECllON IN IMPLANTED DEVICES July-September 19931338-41s

Table 3. Important Chemical Mediators of Inflammation Derived from Plasma, Cells, or Injured Tissue

Mediators Examples

Vasoactive agents Histamines, serotonin, adenosine, endothelial-derived relaxing factor (EDRF), prostacyclin, endothelin,
thromboxane az

Plasma proteases
Kinin system Bradykinin, kallikrein
Complement system C3a, C5a, C3b, C5bC9
CoagulationItibrinolytic system Fibrin degradation products, activated Hageman factor (FXIIA), tissue plasminogen activator (tPA)

Leukotrienes Leukotriene B, (LTBS, hydroxyeicosa-tetraenoic acid (HETE)

Lysosomalproteases
Oxygen-derived free radicals
Platelet activating factors
Cytokines
Collagenase,
elastase
H202, superoxide anion
Cell membrane lipids
Interleukin I (IL-l), tumor necrosis factor (TNF)

Growth factors Platelet derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor (TGF-a or
TGF-fJ), epithelial growth factor (EGF)

opsonization proteins. These receptors may also play a role
in the activation of the attached neutrophil or macrophage.
Because of the size disparity between the biomaterial
surface and the attached cell, “frustrated phagocytosis”
may occur (25,26). This process does not involve en-
gulfment of the biomaterial but does cause the extracellular
release of leukocyte products in an attempt to degrade the
biomaterial. Neutrophils adherent to complement-coated
and immunoglobulin-coated nonphagocytosable surfaces
may release enzymes by direct extrusion or exocytosis from
the cell (25,26). The amount of enzyme released during this
process depends on the size of the polymer particle, with
larger particles inducing greater amounts of enzyme release.
This suggests that the specific mode of cell activation in the
inflammatory response in tissue is dependent upon the size
of the implant and that a material in a phagocytosable form
(e.g., powder or particulate) may provoke a degree of
inflammatory response different from that of the same
material in a nonphagocytosable form (e.g., film).
Chronic Inflammation
Chronic inflammation is less uniform histologically than
is acute inflammation. In general, chronic inflammation is
characterized by the presence of macrophages, monocytes,
and lymphocytes with the proliferation of blood vessels and
connective tissue (3,4,29,30). It must be noted that many
factors modify the course and histologic appearance of
chronic inflammation.
Persistent inflammatory stimuli lead to chronic inflamma-
tion. Although the chemical and physical properties of the
biomaterial may lead to chronic inflammation, motion in the
implant site by the biomaterial may also produce chronic
inflammation. The chronic inflammatory response to bio-
materials is confined to the implant site. Inflammation with
the presence of mononuclear cells, including lymphocytes
and plasma cells, is given the designation chronic inflamma-
tion, whereas the foreign body reaction with granulation
tissue development is considered the normal wound healing
response to implanted biomaterials (i.e., the normal foreign
body reaction) (1).
Lymphocytes and plasma cells are involved principally in
immune reactions and are key mediators of antibody
production and delayed hypersensitivity responses. Their
roles in nonimmunologic injuries and inflammation are
largely unknown. Little is known regarding humoral
immune responses and cell-mediated immunity to synthetic
biomaterials. The role of macrophages must be considered
in the possible development of immune responses to
synthetic biomaterials. Macrophages process and present the
antigen to immunocompetent cells and thus are key
mediators in the development of immune reactions.
The macrophage is probably the most important cell in
chronic inflammation because of the great number of
biologically active products it produces (29). Important
classes of products produced and secreted by macrophages
include neutral proteases, chemotactic factors, arachidonic
acid metabolites, reactive oxygen metabolites, complement
components, coagulation factors, growth-promoting factors,
and cytokines.
Growth factors such as PDGF, FGF, TFG-@, TGF-
a/EGF, and IL-l or TNF are important to the growth of
fibroblasts and blood vessels and the regeneration of
epithelial cells. Growth factors, released by activated cells,
stimulate production of a wide variety of cells; initiate cell
migration, differentiation, and tissue remodeling; and may
be involved in various stages of wound healing (31-36).
Table 4 indicates the complexity of interactions that may
occur with cytokines and growth factors. It is clear that there
is a lack of information regarding interaction and synergy
among various cytokines and growth factors and their
Cadiovasc Pathol Vol. 2, No. 3 (Suppl.)
July-September 1!993:33S-413
Table 4. MonocytelMacrophage-DerivedGrowth Factors and
Cytokines and Cellular Interactions
Endothelial Cells
Chemotaxis Mitogenesis Angiogenesis
IL-1 ? yes ? ?
IL-6 ? yes ? ?
TFG-a ? yes yes
TGF-B ? yes yes
TNF-a yes yes yes
PDGF ? no ? yes
bFGF yes yes yes
abilities to exhibit chemotactic, mitogenic, and angiogenic
properties. For additional information and perspective, see
chapters 5 and 17.
Granulation Tissue
Within one day following implantation of a biomaterial
(i.e., injury), the healing response is initiated by the action of
monocytes and macrophages, followed by proliferation of
fibroblasts and vascular endothelial cells at the implant site,
leading to the formation of granulation tissue, the hallmark
of healing inflammation. Granulation tissue derives its name
from the pink, soft granular appearance on the surface of
healing wounds, and its characteristic histologic features
include the proliferation of new small blood vessels and
fibroblasts. Depending on the extent of injury, granulation
tissue may be seen as early as 3 to 5 days following
implantation of a biomaterial.
The new small blood vessels are formed by budding or
sprouting of preexisting vessels in a process known as
neovascularization or angiogenesis (37-39). This process
involves proliferation, maturation, and organization of
endothelial cells into capillary tubes. Fibroblasts also
proliferate in developing granulation tissue and are active in
synthesizing collagen and proteoglycans. In the early stages
of granulation tissue development, proteoglycans predomi-
nate; later, however, collagen-especially type III colla-
gen-predominates and forms the fibrous capsule. Some
fibroblasts in developing granulation tissue may have
features of smooth muscle cells. These cells are called
myofibroblasts and are considered to be responsible for the
wound contraction seen during the development of granula-
tion tissue.
The wound healing response is generally dependent on
the extent or degree of injury or defect created by the
implantation procedure. Wound healing by primary union
(or first intention) is the healing of clean, surgical incisions
in which the wound edges have been approximated by
surgical sutures. Healing under these conditions occurs
without significant bacterial contamination and with a
minimal loss of tissue. Wound healing by secondary union
ANDERSON 37s
INFLAMMATION/INFECl’ION IN IMPLANTED DEVICES
Fibroblast Smooth Muscle Monocyte
Chemotaxis Mitogenesis Mitogenesis Mitogenesis
yes yes yes
yes yes yes
? yes Yes ?
yes yes yes yes
? yes ? ?
yes yes ?
yes yes yes ?
(or second intention) occurs when there is a large tissue
defect that must be filled or there is extensive loss of cells
and tissue. In wound healing by second intention, regenera-
tion of parenchymal cells cannot completely reconstitute the
original architecture, and much more granulation tissue is
formed, resulting in larger areas of fibrosis or scar
formation.
Granulation tissue is distinctly different from granulo-
mas, which are small collections of modified macrophages
called epithelioid cells, usually surrounded by a rim of
lymphocytes. Foreign body-type giant cells may surround
nonphagocytosable particulate materials in granulomas.
Foreign body giant cells are formed by the fusion of
monocytes/macrophages in an attempt to phagocytose the
material.
Foreign Body Reaction
The foreign body reaction to biomaterials is composed of
foreign body giant cells and the components of granulation
tissue, which consist of macrophages, fibroblasts, and
capillaries in varying amounts, depending upon the form
and topography of the implanted material. Relatively flat
and smooth surfaces, such as those found on breast
prostheses, have a foreign body reaction that is composed of
a layer of macrophages one to two cells in thickness.
Relatively rough surfaces, such as those found on the outer
surfaces of expanded poly(tetrafluoroethylene) (ePTFE)
vascular prostheses, have a foreign body reaction composed
of macrophages and foreign body giant cells at the surface.
Fabric materials generally have a surface response com-
posed of macrophages and foreign body giant cells with
varying degrees of granulation tissue subjacent to the
surface response.
As previously discussed, the form and topography of the
surface of the biomaterial determines the composition of
the foreign body reaction. With biocompatible materials,
the composition of the foreign body reaction in the implant
site may be controlled by the surface properties of the
biomaterial, the form of the implant, and the relationship
between the surface area of the biomaterial and the volume
 38s ANDERSON
INFLAMMATION/HWECTION IN IMPLANTED DEVICES
FIBROSIS
Tissue Encapsulation
t
EXTRACELLULAR MATRIX PRODUCTION
Endothelial Cell
Fibronectin
Proliferation/Inhibition
Collagen
HemostasislThrombosis
Laminin
Growth Factor
Glycosaminoglycans
Autocrine
Growth Factors
IL-l. TGF-6
TGk-A PDGF, & BIOMEDICAL
TGF-B,
bFGF
Figure 2. Polymer/protein/macrophage interfacial interactions
leading to cellular activation, proliferation, and synthesis. Cytoki-
nes and growth factors control cellular processes important in
biocompatibility and the wound healing response.
of the implant. For example, high-surface-to-volume
implants such as fabrics or porous materials will have
higher ratios of macrophages and foreign body giant cells
in the implant site than will smooth-surface implants,
which will have fibrosis as a significant component of the
implant site.
The foreign body reaction consisting mainly of macro-
phages and/or foreign body giant cells may persist at the
tissue-implant interface for the lifetime of the implant (Fig.
2) (1,40-42). Generally, fibrosis (i.e., fibrous encapsulation)
surrounds the biomaterial or implant with its interfacial
foreign body reaction, isolating the implant and foreign
body reaction from the local tissue environment. Early in the
inflammatory and wound healing response, the macroph-
ages are activated upon adherence to the material surface.
Although it is generally considered that the chemical and
physical properties of the biomaterial are responsible for
macrophage activation, the nature of the subsequent events
regarding the activity of macrophages at the surface is not
clear. Tissue macrophages, derived from circulating blood
monocytes, may coalesce to form multinucleated foreign
body giant cells. Very large foreign body giant cells
containing large numbers of nuclei are typically present on
the surface of biomaterials. Although these foreign body
giant cells may persist for the lifetime of the implant, it is not
known if they remain activated, releasing their lysosomal
constituents, or become quiescent.
Cxdiovasc F’athol Vol. 2. No. 3 (SuppI.)
July-September 1993:338-418
ANGlOGENESIS
neovascularizatlon
f
Plasmlnogen
Proliferahonl
POLYMER
Fibrosis and Fibrous Encapsulation
The end-stage healing response to biomaterials is gener-
ally fibrosis or fibrous encapsulation. However, there may
be exceptions to this general statement (e.g., porous
materials inoculated with parenchymal cells or porous
materials implanted into bone).
Repair of implant sites involves two distinct processes:
regeneration, which is the replacement of injured tissue by
parenchymal cells of the same type, or replacement by
connective tissue that constitutes the fibrous capsule
(3,43&I). These processes are generally controlled by either
(i) the proliferative capdcity of the cells in the tissue or organ
receiving the implant and the extent of injury as it relates to
the destruction or (ii) persistence of the tissue framework of
the implant site. The regenerative capacity of cells permits
classification into three groups: labile, stable (or expanding),
and permanent (or static) cells. Labile cells continue to
proliferate throughout life, stable cells retain this capacity
but do not normally replicate, and permanent cells cannot
reproduce themselves after birth. Perfect repair with
restitution of normal structure theoretically occurs only in
tissues consisting of stable and labile cells, whereas all
injuries to tissues composed of permanent cells may give
rise to fibrosis and fibrous capsule formation with very little
restitution of the normal tissue or organ structure. Tissues
composed of permanent cells (e.g., nerve cells, skeletal
muscle cells, and cardiac muscle cells) most commonly
undergo an organization of the inflammatory exudate,
leading to fibrosis. Tissues composed of stable cells (e.g.,
parenchymal cells of the liver, kidney, and pancreas),
mesenchymal cells (e.g., fibroblasts, smooth muscle cells,
osteoblasts, and chondroblasts), and vascular endothelial
CardiovascPath01Vol. 2, No. 3 (SuppI.)
July-September1!993:33S-41s
and labile cells (e.g., epithelial cells and lymphoid and
hematopoietic cells) may also follow this pathway to
fibrosis or may undergo resolution of the inflammatory
exudate, leading to restitution of the normal tissue structure.
The condition of the underlying framework or supporting
stroma of the parenchymal cells following an injury plays an
important role in the restoration of normal tissue structure.
Retention of the framework may lead to restitution of the
normal tissue structure, whereas destruction of the frame-
work most commonly leads to fibrosis. It is important to
consider the species-dependent nature of the regenerative
capacity of cells. For example, cells from the same organ or
tissue but from different species may exhibit different
regenerative capacities and/or connective tissue repair.
Following injury, cells may undergo adaptations of
growth and differentiation. Important cellular adaptations
are atrophy (decrease in cell size or function), hypertrophy
(increase in cell size), hyperplasia (increase in cell number),
and metaplasia (change in cell type). Other adaptations
include a change in which cells stop producing one family of
proteins and start producing another (phenotypic change) or
begin a marked overproduction of protein. This may be the
case in cells producing various types of collagens and
extracellular matrix proteins in chronic inflammation and
fibrosis. Causes of atrophy may include decreased workload
(e.g., stress-shielding by implants), as well as diminished
blood supply and inadequate nutrition (e.g., fibrous capsules
surrounding implants).
Local and systemic factors may play a role in the wound
healing response to biomaterials or implants. Local factors
include the site (tissue or organ) of implantation, the
adequacy of blood supply, and the potential for infection.
Systemic factors may include nutrition, hematologic and
immunologic derangements, glucocortical steroids, and
preexisting diseases such as atherosclerosis, diabetes, and
infection.
Infection/Material/Inflammation
Interactions
The nature of the relationship among infection, thrombo-
sis, inflammation, and wound healing with cardiovascular
devices and prostheses is poorly understood (45-48).
Infection and thrombosis, the two major clinical complica-
tions of cardiovascular devices, have in common early
adhesive/adsorptive interactions that occur at the surfaces of
biomaterials and cardiovascular devices and prostheses. The
initiation of these complications have in common protein
adsorption at the material or device surface (49-53). Thus
protein adsorption, an early event in the inflammatory
reaction to cardiovascular devices, is also an early event in
the infection and colonization by bacteria and the thrombo-
sis and thromboembolism seen in cardiovascular devices
(see chapter 13). The relationship among biomaterials,
ANDERSON 39s
INFLAMMATION/INFECTION IN IMPLANTED DEVICES
microbial adhesion, and tissue integration is ultimately
determined by the relative binding characteristics. Initially
the binding may be with the tissue cell; then the surface is
occupied and defended and is thus less available for
bacterial colonization. However, prior to the cellular influx
and adhesion, binding may occur with proteins from the
blood and tissues within the implant site. These proteins
adsorbed to the surface may be pro- or anticoagulant, pro- or
antithrombotic, and pro- or antiadhesive for bacteria. Little
is known regarding the complex milieu of proteins that are
adsorbed to surfaces following blood contact in an implant
(injury) site.
Staphylococcal species are the most frequently isolated
organisms from device and prosthesis infections, and
Staphylococcus epidermidis is a leading cause of infection
of cardiovascular prostheses. These infections are persistent
and refractory to inflammation and antimicrobial therapies.
It is generally accepted that diagnosis of a cardiovascular
implant infection requires surgical removal of the device or
prosthesis. The resistance of cardiovascular prosthetic
infections to host defenses (inflammation) and antimicrobial
therapies has produced a major challenge for biomedical
materials scientists today: namely, the development of
antimicrobial surfaces or materials that are biocompatible
and thromboresistant for cardiovascular application.
It is clear that a complex interrelationship exists among
thrombosis, infection, and inflammation with cardiovascular
prostheses and devices. Unfortunately, little is known about
the interplay among specific events in these regulatory
mechanisms or regarding their respective roles in potenti-
ating or inhibiting the infectious process. Table 5 lists a
series of proposed pathogenic events in cardiovascular
device infections. These events are considered to be
important in modulation of primary or secondary thrombo-
sis, infection, and inflammation. Recent efforts have
focused on the binding of bacterial receptors to host proteins
adsorbed on surfaces. Extracellular matrix proteins (e.g.,
fibronectin, collagen, and laminin) and plasma proteins
(e.g., fibrinogen, fibrin, and vitronectin) have been shown to
interact with or promote adherence of Staphylococcus
aureus (51-54). The persistence of cardiovascular device
infection despite the use of appropriate antibiotics has been
linked to the metabolic state of adherent bacteria and
Table 5. Proposed Pathogenic Events in Cardiovascular Device
Interactions
Protein adsorption to surfaces
Bacterial adhesion to plasma and matrix proteins
Metabolic state of adherent bacteria
Adhesion of leukocytes to protein-adsorbed surfaces
Metabolism of surface-adherent leukocytes
Biotilm production by adherent bacteria
Procoagulant activity of adherent bacteria and leukocytes
Fibrin formation and inhibition of inflammatory responses and
antimicrobials
40s ANDERSON
INFLAMMATION/INFECTION IN IMPLANTED DEVKXS
“slime” or biofilm production by the adherent bacteria. It
has been shown that bacteria grown as biofilms on various
materials are resistant to the cytolytic effects of antimicro-
bial agents (55). Dormant bacteria are considered to be
resistant to antibiotics, but little is known regarding the
dormancy of adherent bacteria to surfaces. The adhesion of
leukocytes to protein-adsorbed surfaces may play a role in
cardiovascular device infections. Leukocyte adhesion to
surfaces has been shown to modulate the process of
phagocytosis. Other studies have indicated that adherent
leukocytes may be “exhausted” in their ability to be
bacteriocidal. Those leukocyte receptors that may play a role
in the downregulation in their bacteriocidal capability are
the same leukocyte receptors responsible for adhesion to
proteins. Thus the process of leukocyte adhesion to
adsorbed proteins on surfaces may downregulate their
bacteriocidal effect through receptor-mediated events. By
similar mechanisms, adherent bacteria and mononuclear
cells may produce and secrete procoagulants, which
adversely affect the blood-material interactions. Increased
coagulation and thrombosis may lead to the phenomenon of
fibrin capping, which has been implicated in inhibiting the
migration of leukocytes as well as the permeation and
diffusion of antibiotics into the infectious site.
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