Early Transient Tissuematerial Responses Injury and Acute Responses

The process of implantation of a biomaterial, medical device, or drug delivery system results in injury to tissues or organs (1-12). It is this injury and the subsequent perturbation of homeostatic mechanisms that lead to the inflammatory responses, foreign body reaction, and wound healing. The response to injury is dependent on multiple factors, which include the extent of injury, the loss of basement membrane structures, blood-material interactions, provisional matrix formation, the extent or degree of cellular necrosis, and the extent of the inflammatory response. These events, in turn, may affect the extent or degree of granulation tissue formation, foreign body reaction, and fibrosis or fibrous capsule development. These events are summarized in Table 1: The sequence of host reactions following implantation of medical devices and the temporal sequence of events are shown in Figure 1. The host reactions are considered to be tissue dependent, organ dependent, and species dependent. In addition, it is important to recognize that these reactions occur or are initiated early, that is, within two to three weeks of the time of implantation, and may significantly modify the pharmacokinetics, pharmacodynamics, and metabolism of proteins and peptides through cellular and noncellular interactions at the tissue/implant interface.

In considering these host reactions following injury, it is important to examine whether tissue resolution or organization occurs within the injured tissue. In situations where injury has occurred and exudative inflammation is present but no cellular necrosis or loss of basement membrane structures has occurred, the process of resolution takes place. Resolution is the restitution of

TABLE 1 Sequence of Host Reactions Following Implantation of Medical Devices

Injury and acute responses Acute inflammation Chronic inflammation Granulation tissue Foreign body reaction Fibrous encapsulation

ACUTE —CHRONIC—GRANULATION TISSUE

ACUTE —CHRONIC—GRANULATION TISSUE

- Fibrosis

Macrophages Neovascularization Foreign Body Giant Cells

Mononuclear Leucocytes

Fibroblasts

FIGURE 1 The temporal variation in the acute inflammatory response, chronic inflammatory response, granulation tissue development, and foreign body reaction to implanted biomaterials. The intensity and time variables are dependent on the extent of injury created during implantation and the size, shape, topography, and chemical and physical properties of the biomaterial, medical device, or drug delivery system.

Neutrophils

- Fibrosis

Macrophages Neovascularization Foreign Body Giant Cells

Mononuclear Leucocytes

Fibroblasts

Time

(Minutes, Hours, Days, Weeks)

FIGURE 1 The temporal variation in the acute inflammatory response, chronic inflammatory response, granulation tissue development, and foreign body reaction to implanted biomaterials. The intensity and time variables are dependent on the extent of injury created during implantation and the size, shape, topography, and chemical and physical properties of the biomaterial, medical device, or drug delivery system.

the preexisting architecture of the tissue. On the other hand, with necrosis (cell death), granulation tissue grows into the inflammatory exudate and the process of organization with development of fibrous (scar) tissue occurs. With implants, the process of organization with development of fibrous tissue leads to the well-known fibrous capsule formation at the tissue/material interface. The pro-liferative capacity of cells within the tissue also plays a role in determining whether resolution or organization occurs. In general, the process of implantation in vascularized tissues leads to organization with fibrous tissue development and fibrous encapsulation.

Blood-material interactions and the inflammatory response are intimately linked, and in fact, early responses to injury involve mainly blood and the vasculature (1-5). Regardless of the tissue 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 and/or blood clot also form. Thrombus formation involves activation of the extrinsic and intrinsic coagulation systems, the complement system, the fibrinolytic system, the kinin-generating system, and platelets. Thrombus or blood clot formation on the surface of a biomaterial is related to the well-known Vroman effect of protein adsorption. From a wound-healing perspective, blood protein deposition on a biomaterial surface is described as provisional matrix formation.

Immediately following injury, that is, the initiation of surgery, 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 (11-14). The effect of the injury and/or biomaterial in situ on plasma or cells can produce chemical factors that mediate

TABLE 2 Cells and Components of Vascularized Connective 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 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. Several important points must be noted to understand the inflammatory response and how it relates to biomaterials and drug delivery systems. 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 inactivated or destroyed, suggesting that their action is predominantly local (i.e., at the implant site). Third, generally acid, lysosomal proteases, and oxygen-derived free radicals produce the most significant damage or injury. These chemical mediators may be important in the modification of released proteins and peptides and the degradation of biomaterials, for example, degradable delivery systems.

The predominant cell type present in the inflammatory response varies with the age of the injury. Neutrophils are considered professional phagocytes that can ingest or take up particulate forms of drug delivery systems in a size-dependent manner. In general, neutrophils, commonly called poly-morphonuclear leukocytes or polys, predominate during the first several days following injury and are then 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 monocytes are activated over longer periods of time.

Injury to vascularized tissue in the implantation procedure leads to immediate development of the provisional matrix at the implant site. This provisional matrix consists of fibrin, produced by activation of the coagulative and thrombosis systems, and inflammatory products released by the complement system, activated platelets, inflammatory cells, and endothelial cells (15-17). These events occur early, within minutes to hours following implantation of a medical device. Components within or released from the provisional matrix, that is, fibrin network (thrombosis or clot), initiate the resolution, reorganization, and repair processes such as inflammatory cell and fibroblast recruitment. Platelets, activated during the fibrin network formation, release platelet factor 4, platelet-derived growth factor (PDGF), and transforming growth factor b (TGF-b), which contribute to fibroblast recruitment (18,19). Monocytes and lymphocytes, upon activation, generate additional chemotactic factors including LTB4, PDGF, and TGF-b that recruit fibroblasts.

Fibrin, the major component of the provisional matrix, has been shown to play a major role in the development of neovascularization, that is, angiogenesis. Implanted porous surfaces filled with fibrin exhibit new vessel growth within four days (20). The provisional matrix is composed of adhesive molecules such as fibronectin and thrombospondin bound to fibrin as well as platelet granule components released during platelet aggregation. The provisional matrix is stabilized by the cross-linking of fibrin by factor XlIIa.

The provisional matrix may be viewed as a naturally derived, biodegradable, sustained-release system in which mitogens, chemoattractants, cyto-kines, and growth factors are released to control subsequent wound-healing processes (21-26). In spite of the rapid increase in our knowledge of the provisional matrix and its capabilities, our knowledge of the control of the formation of the provisional matrix and its effect on subsequent wound-healing events is poor. In part, this lack of knowledge is due to the fact that much of our knowledge regarding the provisional matrix has been derived from in vitro studies, and there is a paucity of in vivo studies, which provide for a more complex perspective. Little is known regarding the provisional matrix, which forms at biomaterial and medical device interfaces in vivo. Attractive hypotheses have been presented regarding the presumed ability of materials and protein-adsorbed materials to modulate cellular interactions through their interactions with adhesive molecules and cells. In considering the bioavail-ability, pharmacokinetics, and pharmacodynamics of proteins and peptides released from controlled-release systems, it must be appreciated that each of the events/reactions indicated in Table 1 may alter the efficacy and function of the protein or peptide release system.

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