Prevalence

Epidemiologic study of apical periodontitis documents that the prevalence of apical periodontitis varies among patients aged 20 to 30 (33% prevalence of apical periodontitis), 30 to 40 (40%), 40 to 50 (48%), 50 to 60 (57%), and older than 60 years of age (62%).¹⁸¹ Most studies on the prevalence of apical periodontitis are from European and Scandinavian countries.^64,106,212 According to a survey by the American Dental Association in 1990, an estimated 14 million root canal treatments were performed in the United States alone.⁸ Apical periodontitis is a very prevalent problem.⁶⁵

Innate Immune Response

Adaptive/Specific Immune Response

The specificity of adaptive immunity is regulated at genetic levels in B and T lymphocytes through a complex process leading to the generation of molecules that recognize and bind to foreign or self-antigens. These molecules are specific receptors on T cells (T-cell antigen receptors or TCRs) and on B cells (B-cell antigen receptor or BCRs; also termed immunoglobulins). TCRs on T cells interact with antigens that are presented by MHC molecules along with other accessory molecules, whereas BCRs on B cells interact with antigens directly. BCRs may be secreted in the blood circulation or in the tissues as antibodies. The variable region of both TCR and BCR proteins are rearranged at the genomic level via genetic recombination of the V(D)J segments. The estimated total diversity after this recombination for TCR is approximately 10¹⁸ and for BCR is approximately 10¹⁴ that generates the repertoire of different individual T and B cell clones.^1,105 Each T or B cell clone generated in the bone marrow carries a specific TCR and BCR. They undergo a positive and negative selection process through which most clones are deleted via apoptosis because they bind to self-antigens. This initial “negative screening” process serves to reduce the potential for autoimmune disorders. Only those that do not interact with self-antigens are released into the lymphatic system and blood circulation. The naïve T cells circulate back and forth between the lymphatic system and blood circulation until they encounter foreign antigens presented by antigen-presenting cells. About 97% of T cells undergo apoptosis, and only a small percentage of these cells are exported to the periphery as mature T cells.¹

The interaction between TCR and the antigen peptide/MHC complex and costimulators activate T cells, leading to the synthesis of T-cell growth factor, IL-2, and its receptor that causes T-cell clonal expansion/proliferation. Some of these T cells differentiate into armed, effector T cells and other become memory cells. There are a number of T-cell subpopulations, categorized by their functions: (1) T helper cells (T_H), (2) T regulatory cells (T_reg), (3) T suppressor cells (T_S), and (4) T cytotoxic (cytolytic) (T_C) cells.^1,50,261 Some of them can be distinguished by their cell surface markers, cytokine profiles, or transcriptional factors. See also Chapter 13 for additional details.

Upon antigen stimulation, naïve CD4 T cells proliferate and differentiate into T_H0, which are subsequently committed to develop into T_H1 or T_H2 cells. Monocytoid DC (DC1) induces T_H1-type responses; plasmacytoid DC (DC2) selectively induces T_H2 responses. Each subset of T_H cells has distinct functions and cytokine profiles. T_H1 cells mainly produce IL-2 and interferon (IFN)-γ, which activate macrophages and induce B cells to produce opsonizing antibody. T_H2 cells produce IL-4, -5, -10, and -13, which activate B cells to make neutralizing antibody. Overall, T_H1 and T_H2 have mutually inhibitory effects.¹ The development of CD4 T_H cells involves the encounter of antigen presented by antigen-presenting cells (APCs) in association with class II MHC. All cells express MHC class I, but only certain cells express class II MHC. These class II MHC–expressing cells comprise the body’s population of APCs and consist of (1) dendritic cells, (2) macrophages, (3) B cells, (4) vascular endothelial cells, and (5) epithelial cells. The former three are considered “professional” APCs, since they are dedicated to this function. The latter two APCs are quiescent under normal conditions but can be induced to express class II MHC when exposed to elevated concentrations of IFN-γ.^1,105

Dendritic cells and macrophages phagocytose foreign antigens, while B cells utilize the membrane-bound immunoglobulin to bind and internalize antigens. Other APCs endocytose foreign antigens into the cytoplasm for antigen processing. The processed antigens are partially degraded into small peptides. Many of them are 10 to 30 amino acids long and capable of binding onto the newly synthesized class II MHC molecules before the antigen/class II MHC complex is transported to the surface of cells and presented to TCRs of CD4⁺ T cells.

While controversial, evidence has suggested that CD8⁺ T_S and CD8⁺ CTLs represent distinct subpopulations of CD8⁺ T cells. T_S are MHC class I–restricted CD8⁺/CD28⁻ T_S cells, which act on antigen-presenting cells (APC) by a contact-dependent manner, rendering them tolerogenic to T_H cells. They inhibit the proliferation of T_H cells.^44,285 T cytotoxic cells (CD8⁺T_C), also known as cytolytic T lymphocytes (CTLs), are a subset of T cells that kill target cells expressing MHC-associated peptide antigens. The majority of T_C express CD8 and recognize antigens degraded in the cytosol and expressed on the cell surface in association with class I MHC molecules of the target cells. Functional T_C acquire specific membrane-bound cytoplasmic granules, including a membrane pore-forming protein called perforin or cytolysin and enzymes called granzymes.¹

The role of B cells in adaptive immunity is mainly the production of antibodies that constitute the host humoral immune response. The V(D)J gene recombination occurs in both heavy and light (κ and λ) chains. A recombinase system, which is an enzymatic complex consisting of several enzymes—including recombination activating gene 1 and 2 (RAG-1, RAG-2), terminal deoxynucleotidyl transferase (TdT), DNA ligase IV, Ku proteins, and XRCC4—is essential for successful recombination. This recombinase system is also used for TCR recombination. Mature IgM/IgD coexpressing B cells undergo isotype switching via a process called switch recombination after encountering antigen. The rearranged V(D)J gene segment recombines with a downstream C region gene (γ, ε, or α), and the intervening DNA sequence is deleted. This gives rise to other classes of immunoglobulins (IgG, IgE, IgA) besides IgM. In addition to isotype switching, activated B cells also undergo somatic mutation in the V region gene, leading to affinity maturation of antibodies and alternative splicing of VDJ RNA to membrane or secreted immunoglobulin mRNA. A large quantity of antibody is secreted when B cells terminally differentiate into plasma cells.^1,105 The ability of antigens to selectively stimulate the differentiation of plasma cells supports the clinical finding that plasma cells isolated from periapical lesions secrete antibodies specific for the particular bacteria found in the adjacent root canal system.

The immune response and the role of lymphocyte subpopulations in apical periodontitis lesions were investigated by employing lymphocyte-deficient rodents as study models. T-cell deficiency appears to accelerate bone loss at the early phase of apical periodontitis lesions (2 weeks) but does not affect the overall course of lesion development.^242,266 Using RAG-2 SCID mice (both T- and B-cell-deficient), it was found that approximately a third of the RAG-2 mice developed endodontic abscesses, while no immunocompetent controls had abscesses.²⁴⁴ In another study, specific RAG 2 knockout (k/o) mice were used to determine which immune element was important for the defense mechanism in endodontic infection. The results demonstrated that B cells, but not T cells, played a pivotal role in preventing dissemination of endodontic infection.⁹⁵ Therefore, both T and B cells mediate the observed immune responses in apical periodontitis lesions.¹⁵²

Neurogenic Inflammation

Certain primary afferent nerve fibers, upon stimulation by various irritants, release neuropeptides, which cause vasodilation, protein extravasation, and recruitment/regulation of immune cells such as macrophages, neutrophils, mast cells, and lymphocytes. This phenomenon is termed neurogenic inflammation. Pivotal neuropeptides in the induction of neurogenic inflammation are CGRP, for vasodilation, and SP, for the induction of protein extravasation. Neuropeptides and their receptors are widely distributed throughout the body. During inflammation, there is a sprouting of afferent fibers⁸⁹ and local increases in inflammatory mediators that trigger neuropeptide release, leading to neurogenic inflammation.^23,38 Besides the cardinal functions of the key neuropeptides that cause the first sign of inflammation—vasodilation and increased vascular permeability—the role of these neuropeptides in the process of inflammation is now known to be far more complex. In the development of chronic apical periodontitis lesions, neuropeptides are also involved in immune regulation, bone resorption, and wound healing. At sufficient concentrations, SP increases the secretion of IL-1, TNF-α, and IL-6 from macrophages and stimulates T-lymphocyte proliferation and enhances antigen-induced IFN-γ production by T cells.²²⁵ Certain neuropeptides, such as SP, upregulate immune and inflammatory responses, whereas other neuropeptides, such as vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), inhibit inflammatory responses. Synergistic interactions among neuropeptides, such as CGRP and other inflammatory mediators, eicosanoids, and bradykinin, suggests a complex interplay between these molecules in the immune response.^77,189,225

In chronic apical periodontitis lesions, specific receptors for SP and CGRP are expressed in certain immune cells, including macrophages and lymphocytes. Both CGRP and VIP may play a role in inhibiting bone resorption by suppressing osteoclastic functions. The level of VIP in apical periodontitis lesions is inversely related to lesion size. Osteoclast cell culture studies have demonstrated that the presence of greater concentrations of VIP leads to a decrease in their ability to form lacunae of osseous resorption, causing rapid cytoplasmatic contraction and reduced cell mobility. VIP exerts an effect on macrophages to block the production of TNF-α, IL-6 and IL-12, suggesting that VIP could have a role in controlling growth of apical periodontitis lesions.³⁸

The major innate and adaptive immune responses and neurogenic inflammation in the pathogenesis of apical periodontitis caused by root canal infection is illustrated in Fig. 14-1.

FIG. 14-1 Major innate and adaptive immune responses and neurogenic inflammation in the pathogenesis of apical periodontitis. APC, Antigen presenting cell; GM-CSF, granulocyte/monocyte colony-stimulating factor; MC, mast cell; Mφ, macrophage; OB, osteoblast; OC, osteoclast; PAMPs, pathogen-associated molecular patterns; PMN, polymorphonuclear leukocyte; RANKL, receptor activator of nuclear factor κB ligand; TKR, toll-like receptor.

(Courtesy Dr. Lin.)

Correlation Between Clinical and Histologic Findings

Clinical diagnosis of inflammatory periapical disease is mainly based on clinical signs and/or symptoms, duration of disease, pulp tests, percussion, palpation, and radiographic findings. In contrast, a histologic diagnosis is a morphologic and biologic description of cells and extracellular matrix of diseased tissues. The clinical diagnosis represents a provisional diagnosis based upon signs, symptoms, and testing results, whereas the histologic diagnosis is a definitive diagnosis of tissue disease.

Similar to pulpitis,²⁰⁶ apical periodontitis is not always symptomatic or painful. Although many inflammatory mediators (histamine, bradykinin, prostaglandins) and proinflammatory cytokines (IL-1, IL-6, TNF, nerve growth factor [NGF]), as well as neuropeptides (SP, CGRP), are capable of sensitizing and activating nociceptive sensory nerve fibers,^89,90 other mediators such as endogenous opioids and somatostatin released by inflammatory cells during inflammation are able to inhibit firing of sensory nerve fibers.^93,211 Activation of nociceptive sensory nerve fibers may also be related to concentrations of inflammatory mediators. The complexity of these findings supports the clinical observation that there is no good correlation between clinical symptoms and histopathologic findings of apical periodontitis.^24,143,213 For example, many teeth with apical periodontitis are free of symptoms.

Correlation Between Radiographic and Histologic Findings

Radiography is designed to detect pathologic changes at tissue not cellular levels. Even using very sensitive imaging systems such as ultrasound, cone-beam computed tomography, and other technologies, it is impossible to detect the presence of inflammatory cells or other subtle changes in the periapical tissues. Using conventional radiographic and histologic methods in the same cadavers, evidence of inflammation was often observed in the periapical tissues of endodontically treated teeth with normal radiographic features.^15,32,78 This finding is supported by the fact that lesions localized in the cancellous bone may not be visible radiographically unless they involve cortical bone.^17,19,98 In addition, radiographic findings are unable to predict asymptomatic apical periodontitis (granuloma) from asymptomatic apical periodontitis with cyst formation (radicular cyst).^125,238 Accordingly, radiographic findings and histopathologic features of apical periodontitis have a poor correlation based on available case series studies.

The absence of clinical symptoms and negative periapical radiographic findings of endodontically involved teeth does not necessarily indicate absence of apical periodontitis. By the same token, clinical success of endodontically involved teeth (i.e., absence of signs and symptoms and negative periapical radiographic findings) after nonsurgical root canal therapy does not necessarily imply complete histologic healing of periapical lesions. Thus, currently available diagnostic methods used in endodontics, such as percussion, palpation, and pulp tests (cold, heat, electric), are not sensitive enough to provide histologic diagnosis of an inflammatory periapical disease. In fact, all endodontic tests are basically used to examine the functions of nociceptive sensory nerves and not the pathologic changes of the pulp and/or periapical tissues. Until we have more advanced and sophisticated clinical diagnostic technologies, we will continue to face the problem of clinical diagnosis of inflammatory periapical disease. Nevertheless, the treatment of various types of apical periodontitis lesions is basically the same: nonsurgical root canal therapy. Interestingly, this treatment does provide a consistently good clinical outcome, as measured by either clinical signs of success or survival of the treated tooth. Future research should focus on developing testing methods that provide greater insight into the status of the periapical tissue.

Cell Biology

The immunoinflammatory response is a dynamic interaction between host defense mechanisms and microbial insults. The interlacing activation and control pathways of cellular and humoral components involved in the immunoinflammatory response are complex. The cells involved—neutrophils, monocytes/macrophages, platelets, mast cells, T lymphocytes, B lymphocytes, NK cells, dendritic cells, endothelial cells, fibroblasts, eosinophils, and basophils—each have numerous functions that are activated and modulated by a multiplicity of biochemical messengers.^1,121,148 Cell activation means that the cell acquires the ability to perform one or more new functions or to perform normal functions at a higher rate;¹ it often results in transcription of new genes and synthesis of new proteins.¹

Inflammatory Mediators

Numerous biochemical mediators are involved in the acute innate immunoinflammatory response. They are mainly derived from plasma and cells. The main biologic functions of inflammatory mediators are to cause vasodilation and increased vascular permeability and recruit inflammatory cells, mainly neutrophilic leukocytes and macrophages from blood circulation to the site of tissue injury. Some mediators can also cause tissue damage. The major mediators involved in vascular changes, cell recruitment, and tissue damage in the acute immunoinflammatory response are listed in Table 14-2.

TABLE 14-2 Major Mediators in Inflammation

CGRP, Calcitonin gene–related peptide; fMLP, formyl-methionyl-leucyl-phenylalanine; IL-1, interleukin-1; PAF, platelet activation factor; NK cell, natural killer cell; SP, substance P; TNF, tumor necrosis factor.

Data from Kumar V, Abbas AK, Fausto N, et al: Robbins and Cotran pathologic basis of disease, ed 8, Philadelphia, Saunders, 2010; Slauson DO, Cooper BJ: Mechanisms of disease, ed 3, St Louis, Mosby, 2002; Majno G, Joris I: Cell, tissues, and disease, ed 2, Oxford, Oxford University Press, 2004; Abbas AK, Lichtman, Pober JS: Cellular and molecular immunology, ed 5, Philadelphia, Saunders, 2003.

All listed inflammatory mediators have been shown to be present in apical periodontitis.^249,250 Bradykinin is the product of kinin-system activation; fibrinopeptides, the products of blood-clotting system activation; and fibrin degradation products, the products of fibrinolytic-system activation. Kinin, fibrinolytic, and clotting systems are initiated by activated Hageman factor. Prostaglandins and leukotrienes are the products of arachidonic acid metabolism. Activated phospholipase A2 splits cell membrane phospholipid molecules into arachidonic acid and platelet activating factor. Arachidonic acid molecules can be processed along two pathways: the cyclooxygenase pathway, which leads to production of prostaglandins and thromboxanes, and the lipoxygenase pathway, which produces leukotrienes.^121,148

Complement components, such as C3a, C3b, C5a, C5b, and C5-C9, are products of the complement cascade, which can be activated by two pathways. The classic pathway is initiated by activation of C1 by multimolecular aggregates of IgG or IgM antibody complexed with specific antigen. The alternate pathway is activated by microbial cell components (lipopolysaccharide, teichoic acid) and plasmin. C3a and C5a are anaphylatoxins which stimulate mast cells and basophils to release histamine. They also cause phagocytes to release lysosomal enzymes. C3b is an opsonin and can coat bacteria to enhance phagocytosis by phagocytes. In addition, C3b can also bind to antibody bound to antigen or microbes. C5a is a strong chemotaxin for neutrophils. C5b-C9 is a membrane attack complex and able to cause cell lysis if activated on the host cell and bacterial cell membrane.^121,148

Besides inflammatory mediators, the immunoinflammatory response is also dependent upon the timing and extent of various cytokine and chemokine secretions. IL-1, TNF, IL-6, IL-12, and IFN-γ are present in the acute inflammatory response.^1,84,148 IL-6 is produced by activated mononuclear phagocytes, endothelial cells, and fibroblasts in response to microbial infection and other cytokines, such as IL-1 and TNF. IL-6 stimulates the synthesis of acute-phase proteins by hepatocytes.¹ The major source of IL-12 is activated mononuclear phagocytes and dendritic cells. IL-12 provides a link between innate and adaptive immune responses.¹ IFN-r is produced by activated NK cells, T_H1 cells, and cytotoxic T cells and can activate macrophages and enhance their microbial killing ability. IL-1β and TNF are associated with apical bone resorption during chronic apical periodontitis.²²⁴

Chemokines are a large family of structurally homologous cytokines that stimulate leukocyte movement and regulate the transmigration of leukocytes from the blood vessel to tissue space.¹ They are produced by leukocytes, endothelial cells, and fibroblasts. The secretion of chemokines is induced by microbial infection, TNF, and IL-1.^1,84,214 Different types of leukocytes express different chemokine receptors.¹

Neuropeptides are released via axon reflexes of afferent sensory neurons in response to various stimuli. Neuropeptides, as mediators of the immunoinflammatory process, are described in detail in Neurogenic Inflammation in this chapter. Inflammatory mediators such as histamine, kinins, prostaglandins, and proinflammatory cytokines are capable of sensitizing and activating sensory nerves to release neuropeptides.^{26,89,90,191,202}

Histopathology

The acute immunoinflammatory response is practically immutable in all vascularized living tissues, largely due to the programmed actions of the innate immune system. Initially, blood vessels are engorged by a local infiltration of inflammatory cells, mainly activated neutrophilic leukocytes and some macrophages in the apical periodontal ligament of the infected/inflamed root canal.^3,180 In addition, sprouting of sensory nerve fibers has been shown early in the inflamed periapical tissues.^35,115 Several studies have also demonstrated the presence of inflamed vital pulp tissue with intact nerve fibers in the apical portion of the root canal in association with apical periodontitis.^{140,192,193,226,279} This explains the clinical observation that a patient may experience some pain if an instrument is introduced into the canal short of the apex in some teeth with apical periodontitis lesions.

In primary acute apical periodontitis, apical bone destruction is usually not observed radiographically because the duration of acute response is short, and activated neutrophilic leukocytes and macrophages are not able to resorb bone. Only osteoclasts are capable of resorbing bone, and they have to differentiate from the monocyte/macrophage cell lineage in the blood circulation. However, in a rat model experiment, Stashenko et al.²²⁶ showed histologically that periapical inflammatory cell infiltration increases osteoclast numbers, and that bone destruction was apparent well in advance of total pulpal necrosis.

Bacteria are usually not present in acute apical periodontitis lesions.

Clinical Features

As discussed earlier, there is no correlation between clinical and radiographic findings and histologic appearance of inflammatory periapical disease. Teeth with acute apical periodontitis are usually symptomatic and painful to bite and percussion, which results from mechanical allodynia and hyperalgesia.¹¹³ Pain is induced by sensitization and activation of nociceptive sensory nerve fibers by inflammatory mediators, proinflammatory cytokines, nerve growth factor, and pressure.¹¹³ Sprouting of sensory nerve fibers in inflamed periapical tissues could also increase receptive field size in teeth with apical periodontitis.^34,35 Radiographic examination usually does not show periapical bone destruction of involved tooth in acute apical periodontitis, although occasional slight widening of the apical periodontal ligament space and loss of the apical lamina dura of the involved tooth may be present.

Outcomes

The fundamental purpose of the acute immunoinflammatory response is to restore the structural and functional integrity of damaged tissue by eliminating irritants as soon as possible.²⁷⁰ Tissue damage can also occur in acute inflammation by release of lysosomal enzymes, toxic oxygen radicals, and nitric acid from disintegrated neutrophilic leukocytes and macrophages into tissue.¹⁴⁸ Depending on the dynamic interaction between host defenses and microbial insults, acute apical periodontitis can result in (1) restitution of normal periapical tissues if irritants are immediately eliminated by root canal therapy; (2) abscess formation if massive invasion of periapical tissues by highly pyogenic bacteria occurs; (3) organization by scarring if extensive destruction of periapical tissues results; or (4) progression to chronic apical inflammation if irritants continue to persist.

Abscess is a focal localized collection of purulent exudate in a tissue or an organ.¹²¹ It is a morphologic variation of acute and chronic inflammation.^121,148,270 The development of an abscess in apical periodontitis lesions is probably caused by invasion of a combination of specific pyogenic bacteria in the inflamed periapical tissues.^{29,179,234,262} Neutrophilic leukocytes are the predominant cells in acute apical periodontitis with abscess formation. Abscess begins as a furious battle between highly virulent pathogens and an army of neutrophilic leukocytes. The pathogens produce massive toxins to kill neutrophils. As neutrophils attack the pathogens, they secrete lysosomal enzymes that digest not only the dead cells but also some live ones. Many neutrophils die fighting against pathogens. The resulting purulent fluid is poorly oxygenated and has a low pH. The bactericidal ability of leukocytes appears to be impaired because of deprivation of oxygen and interference of respiratory burst. The purpose of respiratory burst is to generate bactericidal agents.^12,148 However, the phagocytic activity of leukocytes is not impaired in aerobic conditions.¹⁴⁸

Histologically, apical abscess formation is characterized by local collection of suppurative or purulent exudate composed of dead and live neutrophilic leukocytes, disintegrated tissue cells, degraded extracellular matrix, and lysosomal enzymes released by dead neutrophilic leukocytes. It also contains dead and live bacteria and bacterial toxins released by dead bacteria in the inflamed periapical tissues. Abscess formation also involves destruction of periodontal ligament and sometimes periapical bone—especially in chronic apical periodontitis with abscess formation—and a surrounding layer of viable neutrophilic leukocytes and a band of fibrovascular granulation tissue. Both layers are thought to serve as protective barriers to prevent the spread of infection. Epithelial cell proliferation is scanty in acute apical periodontitis with abscess formation (Fig. 14-3).^39,193,205

FIG. 14-3 Structure of a secondary periapical abscess. A, Axial section of an abscessed apical periodontitis. The microabscess (AB) contains a focus of neutrophils (NG inset in A). Note the phagocytosed bacteria in one of the neutrophils (further magnified in large inset in B). A secondary abscess forms when bacteria (BA in oval inset) from the apical root canal (RC) advance into the chronic apical periodontitis lesion (B). Note the tissue necrosis immediately in front of the apical foramen and the bacterial front in the body of the lesion (arrowhead in lower inset). BV, Blood vessels; D, dentin. (A ×130; B ×100; oval inset, ×400; inset in A, ×2680; upper inset in B, ×4900; lower inset in B, ×250.)

(From Nair PNR: Periodontol 2000 13:121, 1997.)

Clinically, teeth with acute apical abscess formation usually have symptoms such as pain to biting and percussion. The periapical area of the involved tooth may be very tender to palpation. Intraoral or extraoral swelling is often present. Because of a sudden outpouring of suppurative exudate in the periapical area, tissue pressure increases such that mechanical stimuli are capable of activating terminals of nociceptive neurons in the inflamed periapical tissues. The severe pain of an acute apical abscess can be due to activation of nociceptors by inflammatory mediators and sensitization to mechanical stimuli due to increased interstitial pressures.²⁰⁷ If the periapical purulent exudate can be evacuated through the root canal (or through incision and drainage when indicated) during root canal therapy, the patient usually experiences an immediate relief of acute pain. Radiographically, the involved teeth may show slight widening of the apical periodontal ligament space to loss of apical lamina dura. In chronic apical abscess, the involved teeth may be symptomatic or asymptomatic. If an intraoral or extraoral draining sinus tract is present, swelling is usually absent. Radiographic bone destruction is obvious in teeth with chronic apical abscess formation.

In most cases, if the source of infection in the root canal is eliminated by root canal therapy, the abscess will heal by reabsorption of the pus in teeth with an acute apical abscess. Phagocytes will kill all bacteria in the abscess. The continued influx of leukocytes stops because the chemotactic stimuli have been removed, and the existing neutrophilic leukocytes die of apoptosis. Finally, macrophages move in to clean up necrotic neutrophilic leukocytes and disintegrated tissue cells. In chronic apical abscess formations, wound healing will take place mainly by means of regeneration and to some degree by tissue repair. However, if bacterial virulence and numbers of pathogens overwhelm the host’s defenses, the abscess may break through the cortical bone, periosteum, and oral mucosa or facial skin to develop an intraoral or extraoral draining sinus tract. Sometimes, the uncontrolled abscess may spread along the fascial planes of the head and neck to develop serious cellulitis (see also Chapter 15).^126,205

Cell Biology

Osteoclasts

Periapical bone destruction is a hallmark of asymptomatic apical periodontitis. During the chronic stage of apical periodontitis, both osteoclast and osteoblast activity are decreased,²⁶⁸ so the periapical osteolytic lesion remains stationary. Based on magnified radiographic and automated image analysis, periapical bone destruction was observed at 7 days after the pulps of experimental teeth were exposed to oral microorganisms in animal studies. A period of rapid bone destruction took place between 10 and 20 days, with slower bone resorption thereafter.²⁶⁸ The stationary phase of bone resorbing activity was correlated to asymptomatic apical periodontitis.²⁶⁸ Increased expression of bone resorptive cytokines such as IL-1, IL-6, and TNF was related to the period of active bone resorption.²⁶⁹ T_H cells appear to outnumber T_S cells during the active stage of periapical bone destruction in induced rat periapical lesions, but T_S cells dominate T_H cells during the stationary stage of bone destruction.²²⁷

Bone resorption is caused by osteoclasts. The formation of osteoclasts involves differentiation of the osteoclast precursor from the monocyte-macrophage cell lineage in bone marrow. Several cytokines and growth factors, such as granulocyte/macrophage colony-stimulating factor (GM-CSF), RANKL (receptor activator of nuclear factor κB ligand), osteoprotegerin (OPG), IL-1, IL-6, TNF, as well as prostaglandins, bradykinin, kallidin, and thrombin, have been shown to mediate osteoclast differentiation.^{59,131,159,186,243} Parathyroid hormone is capable of stimulating osteoblasts to synthesize GM-CSF and RANKL. Bone stromal cells and T cells also produce RANKL. Osteoclast progenitor cells express receptor activator of nuclear factor κB (RANK). OPG, a decoy receptor for RANKL secreted by osteoblasts, negatively regulates the differentiation of osteoclasts by absorbing RANKL and reducing its ability to activate the RANK pathway.¹¹⁴

RANKL activates the RANK pathway on osteoclast progenitor cells, resulting in differentiation of these cells along the osteoclast lineage. Proinflammatory cytokines, IL-1, TNF, and IL-6 also mediate the differentiation of osteoclast progenitor cells to osteoclasts. The differentiation of the mononuclear osteoclast progenitor cells terminates with fusion to latent multinucleated osteoclasts, which are finally activated to become bone-resorbing osteoclasts. The mature osteoclasts then attach to mineralized bone surface after osteoblasts have primed the unmineralized bone surface and released chemotactic factor to attract osteoclasts.¹⁶⁹ Osteoclasts attach to bone by the vitronectin receptor (integrin superfamily), expressed preferentially in the sealing zone. Vitronectin has binding sites for the arginine-glycine-aspartic amino acid (RDG) sequences present in many extracellular matrix proteins, including osteopontin, bone sialoprotein, and fibronectin, on the surface of the exposed mineralized bone.⁷⁵ When bound to bone extracellular matrix, osteoclasts develop a ruffled border. Inside the ruffled border, osteoclasts use ATP to drive H⁺ pumps, leading to the acidification of the extracellular compartment. They subsequently secrete proteolytic lysosomal enzymes and carbonic anhydrase to degrade both the mineralized and unmineralized components of bone.^13,14,25,243 (See Fig. 14-5 for the mechanism of bone resorption by osteoclasts in apical periodontitis.)

The resorption of root cementum and/or dentin in apical periodontitis lesions is less well understood than resorption of bone. Bone is constantly remolding (resorption and deposition) through physiologic and functional processes and thus is much easier to study. In contrast, cementum and dentin are more stable. The cells responsible for dental hard-tissue resorption are called odontoclasts.¹⁹⁷ It has been shown in ultrastructure and gene expression studies that odontoclasts and osteoclasts are similar.^198,199 Therefore, it is believed that the cellular mechanisms of bone, cementum, and dentin resorption are similar.¹⁹⁸ Nevertheless, little is known about how the precursors of the odontoclasts appear and what causes odontoclast differentiation and activation to resorb dentin and cementum. Bone resorption by osteoclasts in apical periodontitis is illustrated in Fig. 14-4.

FIG. 14-4 Bone resorption by osteoclasts in apical periodontitis. DC, Dendritic cell; HSC, hematopoietic stem cell; Mφ, macrophage; MSC, mesenchymal stromal cell; Nφ, neutrophil; OB, osteoblast; OC, osteoclast; OCP, osteoclast precursor; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor κB; RANKL, receptor activator of nuclear factor κB ligand.

(Courtesy Dr. Huang.)

Epithelial Cell Rests of Malassez

Proliferation of epithelial cell rests of Malassez (ERM) is evident in approximately 52% of inflammatory periapical lesions collected from extracted teeth.¹⁶⁴ It is a form of pathologic (inflammatory) hyperplasia. This type of hyperplasia is caused by stimulation of growth factors and cytokines produced during the immunoinflammatory response. Hyperplasia is a self-limiting process and is reversible when the causative stimulus is eliminated.^121,148,220 During periapical inflammation, innate and adaptive immune cells and stromal cells (e.g., activated macrophages, neutrophilic leukocytes, NK cells, T cells, fibroblasts) in the periapical tissues produce many inflammatory mediators (e.g., prostaglandin, histamine), proinflammatory cytokines (e.g., IL-1, IL-6, TNF), and growth factors (e.g., PDGF, epidermal growth factor [EGF], keratinocyte growth factor [KGF], FGF). These inflammatory mediators,³¹ proinflammatory cytokines,^80,155,201 and growth factors* are capable of stimulating epithelial cell rests to proliferate (Fig. 14-5). The extent of cellular proliferation appears to be related to the degree of inflammatory cell infiltration.^192,193

FIG. 14-5 Schematic illustration of the major mechanisms that activate proliferation of epithelial cell rests in apical periodontitis.

(From Lin LM, Huang GT-J, Rosenberg P: Proliferation of epithelial cell rests, formation of apical cysts, and regression of apical cysts after periapical wound healing. J Endod 33:908, 2007.)

Inflammatory Mediators

Many inflammatory mediators present in symptomatic apical periodontitis are also expressed in asymptomatic apical periodontitis. In addition, several different cytokines and growth factors are secreted by cells such as activated macrophages, lymphocytes, dendritic cells, and fibroblasts, in the chronic/adaptive immunoinflammatory response described earlier.

Histopathology

Macrophages and lymphocytes are predominant cells in asymptomatic apical periodontitis lesions (Fig. 14-6). Occasionally, foamy macrophages and giant cells are seen, especially associated with cholesterol crystal deposits, which are products of disintegrated cell membranes. Cholesterol crystals are present in approximately 18% to 44% of all apical periodontitis lesions.^30,210,257 Bone resorption is a hallmark of asymptomatic apical periodontitis. Multinucleated osteoclasts may sometimes be seen in resorptive Howship’s lacunae. Proliferation of epithelial cell rests is often present in asymptomatic apical periodontitis lesions. ERM proliferate in three dimensions and form irregular strands or islands of epithelium, which are often infiltrated by varying degrees of inflammatory cells (see Fig. 14-6, B). A key feature of asymptomatic apical periodontitis is a proliferation of fibrovascular granulation tissue that is an attempt to prevent further spread of infection/inflammation and to repair wounded periapical tissues.

FIG. 14-6 Chronic asymptomatic apical periodontitis without (A) and with (B) epithelium (EP). The root canal contains bacteria (BA) in A and B. The lesion in A has no acute inflammatory cells, even at the mouth of the root canal with visible bacteria at the apical foramen (BA). Note the collagen-rich maturing granulation tissue (GR) infiltrated with plasma cells and lymphocytes (inset in A and B). BV, Blood vessels; D, dentin. (A ×80; B ×60; inset in A, ×250; inset in B, ×400.)

(From Nair PNR: Periodontol 2000 13:121, 1997.)

Little information is available concerning cemental changes in apical periodontitis. Using a scanning electron microscope, Simon et al.²¹⁶ observed that projections, depressions, and fibers of cementum were haphazardly arranged in root canal infection under scanning electron microscopy. There was an increase of mineralized projections, cementum lacunae, and surface resorptions and a decrease in fibers. All these changes may provide a more favorable condition for attachment of bacterial biofilm on the apical external root surface in extraradicular infection.

It is a general belief that asymptomatic apical periodontitis lesions are usually devoid of innervation, so local anesthesia may not be necessary if teeth with asymptomatic apical periodontitis require root canal therapy. However, light and transmission electron microscopic studies have demonstrated that teeth with chronic apical periodontitis were well innervated (Fig. 14-7).^141,150 This explains why instruments accidentally introduced into inflamed periapical tissues without local anesthesia can cause the patient pain.

FIG. 14-7 Presence of intact myelinated and nonmyelinated nerve fibers in chronic apical periodontitis lesion. ly, Lymphocyte; M, myelinated nerve fiber; N, nucleus of Schwann cell; nl, neutrophilic leukocyte; NM, nonmyelinated nerve fiber; p, plasma cell (EM, ×1600).

(From Lin L, Langeland K: Innervation of inflammatory periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 51:535, 1981.)

External root resorption that involves cementum or both cementum and dentin usually occurs in asymptomatic apical periodontitis lesions.^127,263 Fortunately, cementum and dentin appear to be less readily resorbed than bone by inflammatory processes.⁸⁵ However, the radiographic presence of root “blunting” should be interpreted by the astute clinician as evidence for resorption of dentin and cementum, and the working length of the instrumentation and obturation phases of nonsurgical endodontic treatment should be adjusted by a corresponding amount.

Using light and transmission electron microscopy and microbiologic culturing, bacteria have been shown to be present in many asymptomatic apical periodontitis lesions.^{2,101,162,255,271} Inadvertent contamination is a major concern when culturing bacteria from these lesions. Under meticulous transmission electron microscopic examination, Nair¹⁶² was unable to observe bacteria in most asymptomatic apical periodontitis lesions. If bacteria are present in the inflamed periapical tissues, they are usually found inside the phagocytes (Fig. 14-8).¹⁴⁰ Importantly, the mere presence of bacteria in the inflamed periapical tissues (colonization) does not necessarily imply periapical infection. Bacteria have to be able to establish an infectious process, such as survival and tissue destruction, in the inflamed periapical tissues to be considered etiologic factors for the resulting infection. Most apical periodontitis lesions are not infected; nonsurgical root canal therapy of teeth with apical periodontitis can achieve a high success rate, provided root canal infection is controlled.

FIG. 14-8 Bacteria phagocytosed by phagocytes in chronic apical periodontitis lesion. A, Bacteria (arrows) in phagosome of a neutrophil. ls, Lysosome; N, part of nucleus; pv, phagocytic vacuole (EM, ×6300). B, Part of the cell structure of a macrophage. Note longitudinally and cross-cut bacteria cells with unit membrane (arrows) in phagocytic vacuoles (EM, ×10,000).

(From Lin L, Langeland K: Light and electron microscopic study of teeth with carious pulp exposures. Oral Surg Oral Med Oral Pathol 51:292, 1981.)

Clinical Features

Involved teeth are usually asymptomatic and show an ill-defined or well-defined periapical radiolucent lesion. The chronic apical abscess and associated sinus tract are usually asymptomatic. Occasionally, the sinus tract from an apical abscess may drain along the root surface and opens into the gingival sulcus. This leads to the development of a deep, narrow pseudopocket that often mimics a periodontal pocket or a vertical root fracture (see Chapter 18 for details).

Outcomes

Asymptomatic apical periodontitis may result in (1) regeneration or repair of the periapical tissues after root canal therapy; (2) severe periapical tissue destruction; (3) acute exacerbation; (4) development of an abscess with an intraoral or extraoral draining sinus tract; or (5) development of a serious cellulitis.

Cell Biology

In addition to the presence of all chronic inflammatory cells, the epithelial cells are the most prominent cell type found in asymptomatic apical periodontitis with cyst formation. ERM can be considered unipotent or restricted-potential stem cells. They can be stimulated to divide symmetrically and asymmetrically into basal cells and suprabasal squamous cells of lining epithelium of radicular cysts.¹³⁹ Many theories about apical cyst formation have been proposed. The nutritional deficiency theory assumes that when islands of epithelium keep growing, the central cells of the epithelial island will move farther away from their source of nutritional supply and undergo necrosis and liquefaction degeneration. The products accumulated attract neutrophils and granulocytes into the necrotic area. Microcavities then coalesce to form a cyst cavity lined by stratified squamous epithelium.²⁴⁵ The abscess theory postulates that when an abscess is formed in connective tissue, epithelial cells proliferate and line the abscess cavity because of their inherent tendency to cover exposed connective-tissue surface.^168,178 The theory of merging of epithelial strands proposes that proliferating epithelial strands merge in all directions to form a three-dimensional spherelike structure composed of fibrovascular connective tissue, with varying degrees of inflammatory cells trapped, that gradually degenerates due to lack of blood supply. This leads to formation of a cyst cavity.¹³⁹ Regardless of how a radicular cyst (pocket or true) is formed, it is likely caused by inflammatory proliferation (hyperplasia) of epithelial cell rests in these lesions.

It has been speculated that radicular cyst expansion is caused by increased osmotic pressure in the cyst cavity,²⁴⁸ but this hypothesis overlooks the cellular aspects of cyst growth and the biochemistry of bone destruction.^66,155 Radicular cyst expansion is likely caused by degradation of fibrous connective tissue capsule by matrix metalloproteinases, which are produced by activated neutrophils, fibroblasts, and macrophages²⁴⁶ and bone resorption. The ERM have also been shown to be capable of secreting a bone resorbing factor.²² Most inflammatory mediators and proinflammatory cytokines that stimulate proliferation of epithelial cell rests also mediate bone resorption in apical periodontitis lesions.

Inflammatory Mediators

Mediators are basically similar to those present in chronic apical periodontitis.

Histopathology

Two types of cysts have been described in chronic apical periodontitis lesions. The pocket cyst’s lumen opens into the root canal of the involved tooth (Fig. 14-9).^164,215 The true cyst is completely enclosed by a lining epithelium, and its lumen has no communication with the root canal of the involved tooth (Fig. 14-10).^164,215 Apical cysts are lined by hyperplastic, nonkeratinized stratified squamous epithelium of variable thickness, which is separated from the fibrovascular connective tissue capsule by a basement membrane. Both the lining epithelium and the connective tissue capsule are usually infiltrated with inflammatory cells, indicating that inflammatory cells are attracted to these tissues by chemotactic irritants, either in the root canal system and/or in the periapical tissues. In nonproliferating epithelium, there is less inflammatory cell infiltration.^39,205 Occasionally, mucous cell metaplasia or ciliated respiratory-type cells are present in cystic epithelial lining.¹⁷⁴ The epithelial cells of lining epithelium do not show any characteristic features of neoplastic changes, such as pleomorphism, lack of polarity, nuclear enlargement, large nucleoli, abnormal nuclear/cytoplasmic ratio, hyperchromatism, or abnormal mitosis. Unlike odontogenic keratocysts and calcifying odontogenic cysts, the basal cells of radicular cystic lining epithelium are incapable of proliferation by themselves without stimulation of growth factors or cytokines released by innate and adaptive immune cells during periapical inflammation. The lumen of cysts may contain inflammatory exudates, cholesterol crystals, clear fluid, or bacterial colonies (Fig. 14-11; Fig. 14-12).^164,193

FIG. 14-9 A, A well-developed pocket cyst in apical periodontitis lesion. B, Note the saclike epithelial lumen. C-D, Sequential axial serial section passing through the apical foramen in the root canal plane (RC) shows the continuity of the lumen with the root canal. D, Dentin (A, C, ×16; B, D, ×40).

(From Nair PNR: Endod Topics 6:96, 2003.)

FIG. 14-10 A, Two distinct cysts lined by epithelium in apical periodontitis lesion. There is no evidence of communication with the foramen in serial sections (H & E, ×25). B, Cyst cavity on the left side in A. Accumulation of foamy macrophages (H & E, ×50; inset ×1000). C, Lower part of cavity in B. Dense infiltration of neutrophilic leukocytes (H & E, ×1000). D, Cyst cavity on the right side in A. Necrotic tissue debris in the lumen; infiltration of inflammatory cells in the epithelium (H & E, ×50). E, Cystic wall in D. Cyst’s lining epithelium is infiltrated with acute and chronic inflammatory cells. Lu, Lumen (H & E, ×1000). F, Foamy macrophages, neutrophilic leukocytes, and necrotic tissue inside the cyst (inset), but no bacteria (Brown & Brenn, ×25, inset ×1000). G, Area indicated by an open arrow in F. Bacterial colonies in the apical foramen (Brown & Brenn, ×1000).

(From Ricucci D, Pascon EA, Pitt Ford TR, Langeland K: Epithelium and bacteria in periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101:241, 2006.)

FIG. 14-11 A, A radicular cyst in which the lumen is completely filled with cholesterol crystals (H & E, ×25). B, High magnification of cholesterol crystals in A (H & E, ×100). C, High magnification of rectangular area in B. Multinucleated giant cells associated with cholesterol crystals (H & E, ×400).

(Courtesy Dr. Ricucci, Rome, Italy.)

FIG. 14-12 A, An apical true cyst in apical periodontitis lesion. Bacterial colonies are seen in the foraminal areas (Brown & Brenn, ×25). B, Bacterial colonies in the cyst lumen, surrounded by inflammatory cells (Brown & Brenn, ×400).

(From Ricucci D, Bergenholtz G: Histologic features of apical periodontitis in human biopsies. Endod Topics 8:68, 2004, Fig. 6.)

Clinical Features

The involved tooth is usually asymptomatic. Periapical osteolytic lesions of endodontically involved teeth may sometimes show a well-demarcated radiolucency surrounded by a rim of radiopaque border.

Outcomes

There is no direct evidence demonstrating whether asymptomatic apical periodontitis with cyst formation (pocket and true) can or cannot regress after nonsurgical root canal therapy. Unfortunately, apical cysts cannot be diagnosed clinically and can only be diagnosed after surgical biopsy or extraction of teeth with apical periodontitis. Clinical outcome studies have shown that after proper nonsurgical root canal therapy, teeth with apical periodontitis heal in 78% of cases, regardless of whether preobturation bacterial cultures are negative or positive.²¹⁹ Therefore, it is speculated that some cysts, especially pocket cysts, may heal after nonsurgical root canal therapy.¹⁶³ Apical true cysts are less likely to heal after nonsurgical root canal therapy because of their self-sustaining nature; surgical intervention is necessary.¹⁶³ Nonetheless, similar to the periapical pocket cyst, a periapical true cyst is also formed within an apical periodontitis lesion and is not a neoplastic lesion. Any disease caused by inflammation/infection should be able to heal if the causative irritant/irritants are removed, unless the irritant/irritants are neoplasm-inducing agents or a carcinogen.

Cell Biology

As described previously, during the chronic stage of apical periodontitis, both osteoclast and osteoblast activity is decreased.²⁶⁸ However, in asymptomatic apical periodontitis with reactive bone formation, osteoblasts appear to be stimulated to produce more bone. It is not clear what factor/factors stimulate osteoblasts to produce more bone mass. It could be due to increased expression of growth factors/cytokines, such as TGF-β, BMP, PDGF, and transcription factor Cbfa1 (core-binding factor family).¹¹⁴

Histopathology

There is an excessive apposition of bone mass without bone resorption in the apical area. As the bone marrow spaces become smaller and obliterated, the bone resembles compact bone which is infiltrated by a small number of lymphocytes. The compact bone has few lacunae, and many of them are empty of osteocytes. It has many prominent resting and reversal lines, similar to an idiopathic osteosclerosis or a Pagetoid appearance.^39,174,188

Clinical Features

The lesion is usually observed in young patients, and the mandibular first molar is most commonly involved. The teeth often have gross carious lesions and can be vital or nonvital. They are usually asymptomatic. Radiographically, the lesion may have a well-defined or ill-defined radiopaque mass associated with the apex of an endodontically involved tooth. The lamina dura around the root apex is usually intact.

Outcomes

Most apical periodontitis lesions with reactive bone formation demonstrate healing after nonsurgical root canal therapy. The excessive compact bone in most cases will be remodeled to normal appearance.⁶³

Periapical Wound Healing After Nonsurgical Root Canal Therapy

Understanding of wound healing is as important as knowing the pathogenesis of disease, because satisfactory wound healing is the ultimate goal of treatment. If we are able to understand the mechanisms of periapical wound healing, we can design treatment approaches that maximize favorable conditions for wound healing to occur, such as effective disinfection of the root canal system in nonsurgical root canal therapy, control of periapical inflammation by medication, or incorporation of growth factors in bone grafts in surgical endodontic therapy (see also Chapters 9 and 21).

Interestingly, healing begins as soon as inflammation starts. When irritants (microbial and nonmicrobial) in the canal systems or in the periapical tissues are eliminated by nonsurgical or surgical endodontic therapy, inflammatory mediators are no longer produced in the periapical tissues because of reduction of immunoinflammatory cells. Inflammatory mediators already present are inactivated by the body’s control mechanisms to prevent an inflammatory reaction from going unchecked. This process precedes wound healing. Although a great deal of information is known about what turns on the inflammation, relatively little is known about what turns off the inflammatory system after elimination of irritants. Examples of host antiinflammatory control mechanisms are (1) enzyme destruction of inflammatory activators; (2) natural inhibitors of inflammatory mediators (e.g., opioids, somatostatin, glucocorticoids, etc.); (3) relative balance between intracellular levels of cyclic AMP and cyclic GMP; (4) the antiphlogistic role of histamine; (5) inhibitors of the complement system²⁵⁸; and (6) antiinflammatory cytokines, such as IL-4, IL-10, IL-13 and TGF-β.^86,172 In addition, the major cellular inducer of inflammation, neutrophilic leukocytes, undergo apoptosis,⁸² and the major cellular player of wound healing, macrophages, secrete antiinflammatory molecules.¹⁷²

The process of wound healing is tightly regulated by cell-to-cell and cell-to–extracellular matrix interactions, as well as the temporal and spatial expression of a variety of cytokines, growth factors, and neuropeptides and apoptosis (Table 14-3).^{26,79,82,228,273} All these cellular and humoral factors operate together in either an antagonistic or synergistic manner and are precisely orchestrated during wound healing. This results in a highly organized response permitting regeneration of the original tissue architecture. Wound healing appears to be a programmed event. Much information concerning the pathogenesis of apical periodontitis has been gained from animal studies.^69,108,251 Although studies of wound healing of teeth with apical periodontitis after nonsurgical root canal therapy and endodontic surgery are available in a few animal experiments and a human study,^11,129,130 no studies of wound healing of apical periodontitis lesions with cyst formation after nonsurgical root canal therapy exist in the literature.

TABLE 14-3 Important Growth Factors/Cytokines in Wound Healing

CGRP, Calcitonin gene–related peptide; CSF, colony-stimulating factor; EGF, epidermal growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

Modified from Majno G, Joris I: Cell, tissues, and disease, ed 2, Oxford, Oxford University Press, 2004; Slauson DO, Cooper BJ: Mechanisms of disease, ed 3, St Louis, Mosby, 2002; Werner S, Grose R: Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835, 2003.

Wound healing of apical periodontitis lesions after proper nonsurgical root canal therapy follows the general principle of wound healing of connective tissues elsewhere in the body, with the formation of fibrovascular granulation tissue, removal of necrotic tissue and dead bacteria by activated macrophages, and finally repair and/or regeneration of the wounded tissue. Healing of apical periodontitis lesions is largely accomplished by regeneration and to some degree by fibrosis. Local tissue resident cells involved in periapical wound healing are osteoblasts and bone marrow stromal cells in alveolar bone and multipotent stem cells in periodontal ligament.²⁰⁹ During periapical wound healing, many unwanted hyperplastic cells (e.g., endothelial cells, fibroblasts, epithelial cells) are deleted by apoptosis,^53,79,82 and the extracellular matrix is remodeled by metalloproteinases. Pathologic processes such as extensive fibrosis do not occur, and the damaged periapical tissues can be ideally restored to their original structure by the process of regeneration.

The temporal and spatial relationship between alveolar bone, cementum, and periodontal ligament during periapical wound healing after nonsurgical root canal therapy cannot be clearly delineated. Nevertheless, wound healing appears to recapitulate the initial histogenesis of damaged tissues or organs in many instances. The process of periapical wound healing after nonsurgical root canal therapy may be similar to wound healing following guided tissue regeneration in periodontal therapy: regeneration of new periodontal ligament, new cementum, and new alveolar bone.^61,256 Both nonsurgical root canal therapy and guided tissue regeneration therapy are able to remove irritants and provide a favorable environment conducive to regeneration of periodontal tissues damaged by apical periodontitis and marginal periodontitis, respectively.

During periapical wound healing, the cells of viable periodontal ligament from adjacent root surfaces proliferate to cover the root surfaces in which the periodontal ligament was damaged by apical periodontitis and removed by macrophages. Proteins derived from Hertwig’s epithelial root sheath (i.e., enamel matrix proteins) are required for cementoblast differentiation from ectomesenchymal stem cells in the dental follicle during tooth development.¹⁷¹ The cells of Hertwig’s epithelial root sheath are absent in mature teeth.^147,223

Nevertheless, the extracellular matrix and growth factors of cementum (i.e., IGF-1, FGFs, EGF, BMP, TGF-β, PDGF) sequestered after cemental resorption in mature teeth are capable of inducing proliferation, migration, attachment, and differentiation of multipotent stem cells in the periodontal ligament into cementoblast-like cells and produce cementoid tissue on the root surface denuded of periodontal ligament.^81,209 This is similar to reparative dentin formation by pulp stem cells in direct pulp capping procedures where growth factors such as TGF-β are released from dentin matrix binding sites.^170,195,260 Root resorption that involves cementum or both cementum and dentin can only be repaired by cementoid tissue, because multipotent stem cells of the periodontal ligament are incapable of differentiating into odontoblasts that produce dentin.²⁰⁹

Bone has a remarkable capacity for regeneration in response to injury. During periapical wound healing, the osteoblasts or mesenchymal cells lining the surfaces of endosteum—stimulated by TGF-β, BMPs, IGFs, PDGF, VEGF, and cytokines released by stromal cells, osteoblasts, platelets, and bone matrix after bone resorption—can undergo proliferation and differentiation into osteoblasts and produce bone matrix.^6,145 When one of the cortical bone plates (buccal or lingual/palatal) is destroyed, mesenchymal cells in the inner layer of periosteum beneath the oral mucosa—stimulated by TGF-β, BMPs, IGFs, PDGF, and VEGF—are also capable of proliferation and differentiation into osteoblasts and can produce bone matrix.^114,145 If both buccal and lingual/palatal cortical bone plates are destroyed by large apical periodontitis lesions, it is possible that the lesion may be repaired with fibrous scar tissue because of extensive destruction of the periosteum beneath the oral mucosa.¹¹ Accordingly, a guided tissue regeneration procedure using membrane barriers and bone grafts is recommended to prevent ingrowth of fibroblasts from periosteum or submucosa into the bony defect and to enhance periapical wound healing if periapical surgery is necessary.^48,49 The cellular and molecular mechanisms of excess scar tissue formation in periapical wound healing is not completely understood. Growth factors/cytokines may play an important role in regulating fibroblast gene expression and excess scar tissue formation.²⁵⁹

The newly regenerated periodontal ligament will finally undergo remodeling into mature periodontal ligament, with one group of collagen fibers (Sharpey’s fibers) inserted into the newly formed cementum and another group of collagen fibers inserted into the newly formed alveolar bone. Thereby, regeneration of damaged periapical tissues, cementum, periodontal ligament, and alveolar bone is completed.

Periapical Wound Healing After Surgical Endodontic Therapy

The mechanism of periapical wound healing after nonsurgical and surgical endodontic therapy is quite similar, but the kinetics of healing of the periapical wound after endodontic surgery is much faster than nonsurgical endodontic therapy.¹²² In surgical endodontic therapy, a surgeon performs removal of irritants, such as necrotic cells, tissue debris, and bacteria in the periapical lesions, which is called surgical débridement. In contrast, in nonsurgical endodontic therapy, activated macrophages perform bacterial killing and cleanup of periapical lesions, which is called biologic débridement.¹³⁸ Surgical débridement is very effective and of course quite rapid, whereas biologic débridement takes time. However, endodontic surgery is more invasive. In addition, proper case selection is more important in endodontic surgery than in nonsurgical endodontic therapy. The distinctive difference between nonsurgical and surgical endodontic therapy is that the goal of nonsurgical endodontic therapy is to remove primary microbial etiology from the root canal system, and the goal of surgical endodontic therapy is often to seal microbial etiology within the root canal system by root-end filling in most cases (see also Chapter 21).

Can Radicular Cysts in Apical Periodontitis Lesions Regress After Nonsurgical Endodontic Therapy?

Based on histology and cell biology, no studies have ever shown that apical true cysts are different from apical pocket cysts. It was suggested that pocket cysts in apical periodontitis lesions might regress after nonsurgical root canal therapy by the mechanism of apoptosis or programmed cell death, based on molecular cell biology.¹³⁹ In contrast, apical true cysts may be less likely to heal after nonsurgical root canal therapy because of their self-sustaining nature.¹⁶³ Histologically, inflammatory cell infiltration is always present in the lining epithelium and/or fibrous connective tissue capsule of apical true cysts.^164,192,193 This indicates there is continued presentation of irritants (such as bacteria)—present in the root canal system, the periapical tissues, or the lumen of cysts—to attract inflammatory cells to the cystic lining epithelium and/or fibrous connective tissue capsule.^164,192,193 It is not known if epithelial cells of apical true cysts alone are capable of acting as autocrine cells and secreting growth factors to sustain their own survival. It is important to realize that the apical true cyst is completely different from the odontogenic keratocyst, which is self-sustaining because it is a neoplastic lesion. Biologically, it is very unlikely that the hyperplastic epithelial cells of inflammatory apical true cysts would suddenly transform into cells that behave like self-sustaining neoplasms. Any disease caused by infection should be able to regress after removal of its causative irritant(s), unless the irritants themselves are neoplasm-inducing agents or carcinogens, such as some viruses and human malignant tumors.^148,265 From pathogenesis, histology, and molecular cell biology, apical true cysts are similar to pocket cysts. Accordingly, apical true cysts, similar to pocket cysts, may be able to regress after nonsurgical root canal therapy by the mechanism of apoptosis if root canal infection is effectively under control.¹³⁹ This prediction is consistent with the high level of healing observed after nonsurgical root canal treatment.

In apical periodontitis lesions with cyst formation, the cysts have to regress before the periapical tissues can be restored to their original architecture. It is not known what matrix serves as a scaffold for endothelial cells, fibroblasts, and osteoblasts to migrate into the lumen of regressing cysts after nonsurgical root canal therapy. Complete regression of radicular cysts after nonsurgical root canal therapy could be due to any of several possible scenarios. Regression of radicular cysts and regeneration of bone may occur concurrently; or during regression of radicular cysts, part of the cystic lining epithelium could disintegrate due to apoptosis of local epithelial cells. Together with degradation of the basal lamina by matrix metalloproteinases, this could allow a fibrous connective tissue capsule to grow into the lumen of radicular cysts. Eventually, the cystic lining epithelium will completely regress or become remnants of epithelial cell rests remaining in the periodontal ligament.

Taken together, our knowledge of cyst mechanisms and healing offer tantalizing clinical implications and clearly support the conclusion that more studies are required to understand the complex mechanisms of regression of inflammatory apical cysts, both pocket and true.