Review ArticleGuided Tissue Regeneration in Periapical SurgeryLouis Lin, BDS, DMD, PhD,* Melody Y.-H. Chen, DDS, MS,† Dome...
Review Article  Periodontal Tissue Destruction in Periodontal       Disease and in Apical Periodontitis      The etiology ...
Review ArticleFigure 2. (A) Preoperativer radiograph of tooth #19. A large osteolytic lesion associated with the distal ro...
Review Article                                                                                    human inflammatory periap...
Review Articlethe mesial and distal line angles was removed corono-apically from the       and cementum. Histologically, v...
Review Articlefibroblast growth factor (FGF) (91, 92). During wound healing, fibrin                                     Conc...
Review Articlecomponent of the periapical tissues (10). The clinician is advised not to                   22. Yoshikawa G,...
Review Article 55. Pecora G, Kim S, Celletti R, Davarpanah M. The guided tissue regeneration prin-         83. Stassen LFA...
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  1. 1. Review ArticleGuided Tissue Regeneration in Periapical SurgeryLouis Lin, BDS, DMD, PhD,* Melody Y.-H. Chen, DDS, MS,† Domenico Ricucci, DDS, MD,‡and Paul A. Rosenberg, DDS*AbstractTissue regeneration by using membrane barriers andbone grafting materials in periapical surgery is anexample of tissue engineering technology. Membrane S ystematic review of the literature concerning guided tissue regeneration in periap- ical surgery is not possible because of wide variations in research methodology. Tissue engineering involves the use of biologic and engineering sciences to develop bio-barriers and/or bone grafts are often used to enhance logic substitutes that restore, maintain, or enhance tissue function (1). In general, thereperiapical new bone formation. However, the periapical are 3 main approaches to tissue engineering: (1) to use isolated cells or cell substitutestissues also consist of the periodontal ligament (PDL) as cellular replacement parts, (2) to use acellular biomaterials (scaffolds) capable ofand cementum. For regeneration of the periapical tissues inducing tissue regeneration, and (3) to use a combination of cells and biomaterials (1,after periapical surgery, one of the important require- 2). These approaches are suitable for single tissue regeneration such as new bonements is recruitment and differentiation of progenitor/ formation. For example, in terms of multiple tissue regeneration, new periodontalstem cells into committed pre-osteoblasts, pre-PDL cells, or periapical tissue formation, the involvement of tissue engineering technologyand pre-cementoblasts. Homing of progenitor/stem cells might be even more complex (2). The process of introducing biomaterials into theinto the wounded periapical tissues is regulated by host to enhance or modify natural wound healing can be considered as tissuefactors such as stromal cell–derived factor 1, growth engineering (1, 2). Tissue regeneration by using membrane barriers and/orfactors/cytokines, and by microenvironmental cues bone grafting materials in periapical surgery is an example of tissue engineeringsuch as adhesion molecules and extracellular matrix technology.and associated noncollagenous molecules. Tissue regen- Guided tissue regeneration is a technique(s) for enhancing and directing celleration after injury appears to recapitulate the pathway growth to repopulate specific parts of the periodontium that have been damaged byof normal embryonic tissue development. Multiple tissue periodontal diseases, tooth diseases, or trauma (3). Guided tissue regeneration byregeneration involves a complex interaction between using membrane barriers and bone grafting materials has been extensively investigateddifferent cells, extracellular matrix, growth/differentia- in periodontal regenerative therapy to induce new attachment of periodontiumtion factors, and microenvironmental cues. Little is damaged by periodontal disease (4–8). Guided tissue regeneration, especially byknown concerning the biologic mechanisms that regu- using bone grafting materials, has also been widely used in implant dentistry tolate temporal and spatial relationship between alveolar enhance new bone formation for placement of implants (9). Histologic assessmentsbone, PDL, and cementum regeneration during periapi- of guided tissue regenerative therapy in periodontal disease often show down-growthcal wound healing. Simply applying a membrane barrier of junctional epithelial cells between the membrane barrier and root surface (10).and/or bone graft during periapical surgery might not Bone grafting materials have little osteoinductive capacity and generally become en-result in complete regeneration of the periapical tissues. cased in a dense fibrous connective tissue (10). In addition, junctional epithelium stillIt has not been clearly demonstrated that these biomate- appears to form between the bone grafts and root surface (10–12). Bone graftingrials are capable of recruiting progenitor/stem cells and materials are not capable of inducing new connective tissue attachment afterinducing these undifferentiated mesenchymal cells to guided tissue regenerative therapy in periodontal disease (13). The variability indifferentiate into PDL cells and cementoblasts after safety, clinical effectiveness, and stability over time of bone grafting materials usedperiapical surgery. (J Endod 2010;36:618–625) for guided tissue regeneration in periodontal therapy has been questioned (10, 14, 15). A systematic review of the literature concerning bone replacement grafts inKey Words the treatment of periodontal osseous defects concludes that alloplastic graftsBone grafting materials, guided tissue regeneration, support periodontal repair rather than regeneration (16). Guided tissue regenerationmembrane barriers, periapical surgery by using membrane barriers and/or bone grafting materials has also been used in periapical surgery to enhance new bone formation (17–22). Those studies were mainly focused on new bone formation and did not address formation of periodontal ligament (PDL) and cementum, which are also components of the From the *Department of Endodontics, New York Univer- periapical tissues.sity College of Dentistry, New York, New York; †Departmentof Endodontics, Chi Mei Medical Center, Yong Kang, Tainan, Application of guided tissue regeneration concepts to periapical surgery isTaiwan; and ‡Private practice, Rome, Italy. primarily based on extensive studies of periodontal regenerative therapy. However, Address requests for reprints to Dr Louis Lin, Department of there are significant differences in the application of guided tissue regeneration in peri-Endodontics, New York University College of Dentistry, 345 E odontal regenerative therapy and in periapical surgery, and these will be discussed in24th St, New York, NY 10010. E-mail address: lml7@nyu.edu.0099-2399/$0 - see front matter this review. The purpose of this review is to provide a better understanding of basic Copyright ª 2010 American Association of Endodontists. molecular and cellular biologic concepts when using membrane barriers and/ordoi:10.1016/j.joen.2009.12.012 bone grafts in periapical surgery, with specific reference to guided tissue regeneration in periodontal regenerative therapy (8). To avoid repeating the excellent review by Bashutski and Wang (8), the types of membrane barriers and bone grafting materials will not be included in this review.618 Lin et al. JOE — Volume 36, Number 4, April 2010
  2. 2. Review Article Periodontal Tissue Destruction in Periodontal Disease and in Apical Periodontitis The etiology and pathogenesis of periodontal disease (marginal pe-riodontitis) and apical periodontitis are similar. Both diseases arecaused by bacterial biofilm infection and manifest periodontal tissuedestruction; gingival tissue, PDL, cementum, and alveolar bone areaffected in periodontal disease and the last 3 tissues as well as dentinin apical periodontitis (Fig. 1). Periodontal disease is an open wound,which is constantly challenged by direct oral infection even after therapy.Apical periodontitis is a closed wound. Destruction of periodontal tissuesin periodontal disease and in apical periodontitis is caused indirectly byactivation of the host’s innate and adaptive immune cells (23, 24).Microorganisms and their toxins in periodontal pockets are in directcontact with the sulcular epithelium of periodontium in periodontaldisease. In contrast, in the presence of apical periodontitis,microorganisms and their toxins are in the root canal system ratherthan in the periapical tissues. In certain types of periodontal defects, Figure 1. Histology of apical periodontitis of an extracted human tooth.the attachment apparatus destroyed by established periodontal disease Proliferation of epithelial strands occurs in the chronically inflamed periapicalcannot be predictably regenerated after removal of bacterial plaque tissues around the apical foramen, which is surrounded by a band of denseand calculus from the affected root surface by open flap debridement fibrous connective tissue. Note destruction of the apical alveolar bone andor even with guided tissue regenerative therapy (25). In contrast, apical periodontal ligament as well as apical root resorption involvingdamaged periapical tissues in established apical periodontitis lesions cementum and dentin (arrows) (Hematoxylin-eosin; original magnification,can be predictably regenerated after elimination of intraradicular Â16).bacteria by proper nonsurgical endodontic therapy without the needof periapical surgery and guided tissue regenerative procedures (26) the restoration of the destroyed tissue by new tissue different from the(Fig. 2). In addition, unlike guided periodontal regenerative therapy, original tissue. It does not reconstitute the architecture and functionsperiapical surgery is indicated only because nonsurgical root canal of the original tissue as, for instance, healing of a myocardial infarcttherapy is not feasible for established apical periodontitis lesions, espe- by fibrosis (29, 30). In periapical surgery, the resected root endcially in retreatment cases. The molecular and cellular biology associated cannot be regenerated.with complete regeneration of periapical tissues, cementum, PDL, and Regeneration of periapical tissues after periapical surgery requiresalveolar bone after nonsurgical and/or surgical endodontic therapies (1) recruitment of progenitor/stem cells to differentiate into committedof apical periodontitis lesions is not fully understood. osteoblasts, PDL cells, and cementoblasts (Fig. 3); (2) growth/differen- tiation factors as necessary signals for attachment, migration, prolifer- Biology of Periapical Wound Healing After ation, and differentiation of progenitor/stem cells; and (3) local Periapical Surgery microenvironmental cues such as adhesion molecules, and ECM and It is important to understand the natural wound healing potential associated noncollagenous protein molecules (10, 37). Lack of anyof periapical lesions after elimination of the etiology, before considering one of these elements would result in repair rather than regenerationthe application of biomaterials such as membrane barriers and/or bone (37). In addition, all these components must coordinate precisely ingrafts during periapical surgery. As described previously, the wound their temporal and spatial relationship to reconstitute the architecturehealing potential of apical periodontitis is different from that of marginal and functions of the damaged periapical tissues. Homing of progenitor/periodontitis after treatment. The principle of periapical wound healing stem cells to wounded periapical tissues is regulated by factors such asafter periapical surgery is similar to that of connective tissue wound stromal cell–derived factor–1, growth factors/cytokines, and by micro-healing elsewhere in the body. It is a host’s ‘‘programmed event,’’ which environmental cues (27). Although wound healing appears to recapit-begins with (1) hemostasis or coagulation phase, (2) inflammation ulate the pathway of normal embryonic tissue development, the tissuephase, (3) proliferative phase, (4) regeneration and/or repair phase, regenerated might be similar to but will not exactly replicate theand last (5) remodeling or maturation phase (27–30). damaged original tissue in architecture and functions (38). For Regardless of the size of a wound, granulation tissue in the prolif- example, mineralized tissue referred to as reparative dentin can beerative phase, a necessary element of wound healing, fills the wound and formed in uncontaminated, exposed vital pulps after capping withhelps complete the wound healing process (30). Wound healing usually appropriate biomaterials; however, the regenerated reparative dentininvolves recruitment and differentiation of progenitor/stem cells into is different from primary dentin (39–42). This is becausetissue committed cells (27, 31–35). Wound healing can result in odontoblasts are highly differentiated postmitotic cells and cannoteither regeneration or repair, depending on the nature of wound, regenerate after lethal injury. Reparative dentin is formed byavailability of progenitor/stem cells, growth/differentiation factors, and odontoblast-like cells, which are differentiated from pulp progenitor/microenvironmental cues such as adhesion molecules, extracellular stem cells. Similarly, root resorption including cementum and dentinmatrix (ECM), and associated noncollagenous protein molecules (27, in chronic apical periodontitis lesions can only be repaired by cellular35, 36). Regeneration represents the replacement of damaged tissue cementum and not by both dentin and cementum after root canalby the cells of the same tissue. Importantly, it reconstitutes, although therapy (43) (Fig. 2D). An analogy might be that Picasso’s paintingsnot completely, both the architecture and functions of the original cannot be precisely reproduced, even though numerous copies cantissue, such as healing of an uninfected simple surgical incision of the be created. It has been proposed that the local environment ofskin approximated by surgical sutures, because tissue destruction and cementum matrix and associated molecules could influence recruit-granulation tissue formation are minimum (29, 30). Repair represents ment and functions of cementum-forming progenitor/stem cells inJOE — Volume 36, Number 4, April 2010 Guided Tissue Regeneration in Periapical Surgery 619
  3. 3. Review ArticleFigure 2. (A) Preoperativer radiograph of tooth #19. A large osteolytic lesion associated with the distal root and a small lesion associated with the mesial root areshown. Histologically, resorption of the root apex is usually present in chronic apical periodontitis such as in (A). (B) Follow-up radiograph of tooth in (A) taken 3years and 7 months after nonsurgical root canal therapy shows healing of periapical lesions. (C) Follow-up radiograph of tooth in (A) taken 6 years postoperativelywhen the patient presented for emerging symptoms. The mesial root had a vertical root fracture, and the tooth was extracted for histologic examination. (D)Histology of the distal root in (C). The resorbed root apex involving cementum and dentin was repaired by deposition of cellular cementum on the externalroot surface (solid arrows) and inside the root canal (open arrow). Incremental lines indicate alternating periods of activity and quiescence of cementum depo-sition (hematoxylin-eosin; original magnification, Â50).the PDL during cementum wound healing and regeneration (36). osteoblasts is related to their life span exactly. In small periapicalHowever, the molecular and cellular biology of cementum formation lesions, resident osteoblasts, PDL cells, and cementoblasts might beon an exposed root dentin surface after inflammatory resorption and capable of restoring damaged periapical tissues. However, in largeperiapical surgery is not clear. periapical lesions, periapical wound healing requires recruitment Although resident cells, cementoblasts, PDL cells, and osteoblasts and differentiation of progenitor cells/stem cells into osteoblasts,in the periapical tissues are differentiated cells, they still retain the cementoblasts, and PDL cells. It has been well-demonstrated thatpotential to undergo cell division and proliferation on stimulation by PDL harbors adult stem cells in the paravascular spaces, and theseappropriate signals during physiologic turnover and periapical wound stem cells are capable of differentiating into PDL-like, cementoblast-healing. However, these cells are not progenitor/stem cells and are not like, and osteoblast-like cells (37, 44, 45). In addition, bonecapable of self-renewal and differentiation. Therefore, the regenerative marrow mesenchymal stem cells (46) and periosteal osteoprogenitorpotential of these committed cells is limited. In addition, it is not known cells (47, 48) are capable of differentiating into osteoblasts. Cellwhether the regenerative potential of PDL cells, cementoblasts, and differentiation involves a change from one pattern of gene expression620 Lin et al. JOE — Volume 36, Number 4, April 2010
  4. 4. Review Article human inflammatory periapical lesions after endodontic surgery (60, 61). In animal studies at 3- to 5-month observation periods, if membrane barriers were not used to cover the bony defects both PDL stem cells PDL stem cells buccally and palatally/lingually, when through-and-through osseous defects were created in jawbones, the defects were filled with fibrous connective tissue (51, 52). This is most likely due to the lack of PDL cell available osteogenic progenitor/stem cells rather than to fast Cementoblast movement of fibroblasts. Cell migration does not simply depend on cell mobility. Cells migrate directionally in response to a variety of Bone marrow Osteoblast Periosteal cues, including gradients of chemokines, growth factors, and ECMmesenchymal stem cells osteoprogenitor cells molecules. These factors engage cell surface receptors and direct cell migration (27, 62). During wound healing, activated fibroblasts Endosteal initially lay down excess new collagen of subtypes I and III. These osteoprogenitor cells collagen fibers, especially type III, become remolded or degraded by matrix metalloproteinase and collagenase released by activatedFigure 3. Schematic illustration of recruitment and differentiation of progen- macrophages and fibroblasts and are ultimately replaced by type Iitor/stem cells into osteoblasts, PDL cells, and cementoblasts during periapical collagen at a later stage of wound healing. Fibroblasts differentiatewound healing. into myofibroblasts at the remodeling phase (27, 28). Sometimes the uncontrolled matrix accumulation of collagen types I and III byto another. It does not involve a change in the DNA sequence itself myofibroblasts, often involving aberrant cytokine pathways, might(49). Cell differentiation is regulated by extrinsic local microenviron- occur and leads to excess scarring and fibrotic sequelae (27).mental cues and intrinsic master regulatory genes (49). Cell differen- Nevertheless, the cellular and molecular biology of fibrosis or scartiation is usually a part of the regenerative process (49). tissue formation is not fully understood. It has been suggested that Regardless of the size of periapical lesions, persistence of root immune regulation, up-regulation of collagen production by myofibro-canal infection is the primary cause of inflamed periapical tissues not blasts, down-regulation of matrix metalloproteinases, and up-regulationto heal after endodontic therapy (50). There are no published studies of transforming growth factor (TGF)–b, as well as dysregulation ofdemonstrating that membrane barriers and/or bone grafts contributed apoptosis of myofibroblasts might play an important role in fibrosisto the cause of periapical surgery failure. Complete periapical wound or scar tissue formation (27, 63, 64).healing after periapical surgery should include regeneration of alveolar It seems that if both buccal and palatal/lingual cortical plates arebone, PDL, and cementum. lost as a result of apical periodontitis lesions or periapical surgery, periapical wounds will most probably heal by scar tissue formation (51, 52, 60). Studies have shown no difference in bone tissue Membrane Barriers in Periapical Surgery healing if only the buccal cortical plate was destroyed, whether or The application of a membrane barrier in periodontal regenera- not a membrane barrier was used in periapical surgery (65, 66). Ontive therapy is to prevent apical migration of gingival epithelial and the basis of limited controlled clinical trials, there is no conclusiveconnective tissue cells onto the denuded root surface and to facilitate evidence to demonstrate that the application of membrane barriersthe repopulation of the damaged root surface with PDL progenitor/ in large or through-and through bony lesions/defects has a betterstem cells to differentiate into PDL cells and cementoblasts (5–7, long-term outcome than a control in periapical surgery. By definition10). Without a membrane barrier, open flap debridement does not (3), application of membrane barriers in periapical surgery does notprevent apical migration of junctional epithelium along denuded root appear to meet the concept of guided tissue regeneration. In contrast,surfaces (7). Some clinicians place a membrane barrier over a bony in periodontal regenerative therapy membrane barriers serve todefect beneath a full-thickness mucoperiosteal flap during periapical guide progenitor/stem cells to repopulate their specific parts of thesurgery. Most often the cases involve treatment of large periapical periodontium.lesions or through-and through bony defects, theoretically to prevent Clinically, the best application of membrane barriers in periapicalproliferation of fibroblasts from the periosteum into the bony defect. surgery appears to be in combined endodontic-periodontal orThis could result in scar tissue formation (19, 51–56). However, periodontal-endodontic lesions (67) or large periapical lesionsPDL also contains numerous fibroblasts (42, 57) and bone marrow communicating with the alveolar crest (68, 69). In this kind ofmesenchymal stem cells, which are capable of differentiating into apicomarginal bony defect, the PDL and cementum are destroyed.fibroblasts as well (58, 59). In addition, during the proliferative Accordingly, application of a membrane barrier is indicated duringphase of wound healing, there is proliferation of not only new periapical surgery to prevent apical migration of junctional epitheliumvasculature but also fibroblasts at the wound site (29, 30). A along the denuded root surface into the periapical wound and tomembrane barrier might actually prevent osteoprogenitor cells in the induce selective repopulation of cells of the connective tissueperiosteum from proliferating into the bony defect to help new bone attachment (67–69). In combined endodontic-periodontal orformation. The epithelial cells from gingivomucosal epithelium are periodontal-endodontic lesions, the use of a membrane to manage thenot able to proliferate into the apical bony defect after periapical lesions is directed at the periodontal tissue rather than periapical tissuesurgery if there is no periodontal involvement. A membrane barrier regeneration. Oh et al (70) have presented an excellent review of thewill not selectively allow specific cell types, such as PDL progenitor/ application of guided tissue regeneration in combined endodontic-stem cells, bone marrow mesenchymal stem cells, or endosteal periodontal lesions with apicomarginal bony defects. It should be notedosteoprogenitor cells, to repopulate a root surface damaged by apical that a true new connective tissue attachment can only be demonstratedperiodontitis or by surgical root resections during periapical surgery. by means of histologic rather than clinical examination (14). Scar tissue formation is a pathologic process occurring during In an animal study, Nyman and Karring (71) surgically elevatedtissue repair and is sometimes observed in through-and-through buccal mucoperiosteal flaps. A strip of buccal alveolar bone betweenJOE — Volume 36, Number 4, April 2010 Guided Tissue Regeneration in Periapical Surgery 621
  5. 5. Review Articlethe mesial and distal line angles was removed corono-apically from the and cementum. Histologically, very few studies of bone grafts inroots to a notch prepared in the root surface as a landmark. This was periapical surgery have investigated whether grafting materials aredone without significantly injuring the PDL and cementum. The flaps capable of inducing PDL and cementum regeneration (17, 18, 22,were then repositioned and sutured. Fibrous connective tissue reattach- 78, 79). Therefore, the nature of regenerated periapical tissues afterment and varying degrees of alveolar bone regeneration were histolog- the use of bone grafts in periapical surgery remains unknown,ically observed on the root surfaces 8 months postoperatively. despite radiographs showing some evidence of PDL space (56). The Lindhe et al (72) experimentally extracted the teeth in an animal possibility of ankylosis after bone grafts in periapical surgery shouldstudy. Immediately after tooth extraction, the buccal root surfaces of the be investigated in long-term studies because grafting materials mightteeth were planed with curettes to a level corresponding to half the root encourage osteoprogenitor cells and prevent PDL progenitor/stem cellslength. Before reimplantation of the teeth, the buccal alveolar bone from repopulating damaged root surfaces caused by apical periodonti-between mesial and distal line angles was removed to a level corre- tis or the resected root surfaces after periapical surgery. In 2 studies,sponding to half the depth of the sockets. Histologically, a fibrous calcium sulfate was placed in the osteotomy sites during periradicularconnective tissue reattachment failed to form on that part of the reim- surgery, and it did not appear to affect cementum deposition onto theplanted teeth, which had been deprived of their PDL 6 months postop- resected root surfaces (20, 22).eratively. In addition, dentogingival epithelium had migrated apically Bone grafting materials, except autogenous bone grafts, arealong the denuded root surface. foreign to the host’s tissue and can interfere with the normal wound In another animal study, Gottlow et al (73) surgically raised buccal healing process, resulting in delayed healing or a foreign body reactionmucoperiosteal flaps. The buccal alveolar bone between the mesial and (29, 30). Some studies with bone grafts in periapical surgerydistal line angles of each root was removed to a level corresponding to demonstrated favorable hard tissue healing compared with a controlapproximately 50%–75% of the length of the root. The coronal portion (17, 18, 22, 78, 79, 81, 82), whereas other studies showed noof the root surfaces was left open to bacterial plaque accumulation for 6 difference (20, 21, 80, 83). All reported outcome studies ofmonths. Subsequently, the coronal root surfaces were thoroughly periapical wound healing by using bone grafts in periapical surgeryscaled and planed, and the cementum was removed. Immediately are short term, lasting no more than 12 months. Bone is a dynamicbefore suturing of the coronally positioned flap, a membrane was tissue and, throughout life, constantly undergoes remodelingplaced over the denuded root surfaces to prevent granulation tissue (resorption and deposition). During the healing of bone, osteoblastsfrom the soft tissue flaps from reaching contact with the denuded initially produce immature trabecular woven bone, and thenroot surfaces during wound healing. New cementum with inserting osteoclasts slowly remove this provisional woven bone. Later,collagen fibers was histologically observed on the previously exposed osteoblasts replace it with lamellar bone (84, 85). Remodeling or theroot surfaces 30 days postoperatively. However, the newly formed maturation phase of wound healing can take months to years to becementum is primarily cellular and not acellular cementum. complete (29, 30). The long-term biologic nature of new bone formed Therefore, the nature of a dehiscence (naturally occurring or after using bone grafts after periapical surgery is unknown. It might bepathologic) is an important factor in determining whether application similar to reparative dentin after capping of exposed vital pulps withof a membrane barrier is necessary. If dehiscence is naturally occur- appropriate biomaterials. Reparative dentin is different from primaryring, a fibrous connective attachment is present between the root dentin in structure and/or function. Nevertheless, it is a biologicsurfaces and the mucosa. A membrane barrier is not required during product of dentin-pulpal complex after pulpal wound healing.periapical surgery because fibrous connective tissue reattachment Most bone grafts, especially calcium sulfate used in periapicalwill occur onto the root surface after reposition and suturing of a surgery, are neither osteogenic nor osteoinductive (86). Therefore,surgical flap (71). However, if the cause of dehiscence is pathologic calcium sulfate is not capable of recruiting mesenchymal stem cellsas a result of marginal periodontitis, a membrane barrier is suggested in the bone marrow or endosteum and osteoprogenitor cells in the peri-to prevent apical migration of junctional epithelium along the root osteum to differentiate into committed pre-osteoblasts. Calcium sulfatesurfaces during periapical surgery (70). is osteoconductive (8, 87, 88), which refers to the ability of some foreign materials to serve as a scaffold on which cells can attach, migrate, and grow and divide (86). Even though bone grafts are osteo- Bone Grafts in Periapical Surgery conductive, they are not ideal materials for promoting periodontal A systematic review of the literature concerning regeneration of tissue regeneration such as PDL and cementum in periodontal regener-periodontal tissues in periodontal regenerative therapy indicates that ative therapy because they are not able to stimulate the formation ofcombination of barrier membranes and grafting materials might a new connective tissue attachment (8, 13, 14). Many studies haveproduce histologic evidence of periodontal regeneration, which is clearly demonstrated that calcium sulfate can serve as scaffold forpredominantly bone repair (74). Bone grafting materials include auto- new bone formation in periapical surgery (17, 18, 78–80). However,grafts, allografts, xenografts, and alloplasts. They have been used in a question remains: can bone grafts induce regeneration of apicalperiodontal regenerative therapy as space maintainers for selective PDL and cementum damaged by large apical periodontitis lesionscell repopulation onto the denuded root surfaces or to act as osteoin- after periapical surgery? In one human histologic study, as many asductive or osteoconductive biomaterials for regeneration of bone loss 81% of the teeth with apical periodontitis revealed apicalas a result of periodontal disease (8, 75, 76). Bone grafts have also inflammatory root resorption including cementum and/or dentin (89).been successfully used to regenerate new bone formation in implant Biologically, a blood clot is a better space filler or ECM than alldentistry (9). The same bone grafting materials, especially alloplasts bone grafting materials. A blood clot is the host’s own biologic productsuch as calcium sulfate, have been widely used in periapical surgery and is essential to tissue wound healing. Without a blood clot, tissueto enhance new bone formation as well (17, 18, 20, 77–80). wound healing would be impaired (29, 30), as in a dry socket afterCalcium sulfate must dissolve in tissue fluid or integrate into bone tooth extraction. A blood clot is composed of insoluble fibrin (90)before or during new bone formation. Similar to periodontal and many growth factors/cytokines such as platelet-derived growthregenerative therapy, evaluation of wound healing after periapical factor (PDGF), TGF-b, vascular endothelial growth factor (VEGF),surgery by using bone grafts should also include regeneration of PDL endothelial growth factor, insulin-like growth factor (IGF), and basic622 Lin et al. JOE — Volume 36, Number 4, April 2010
  6. 6. Review Articlefibroblast growth factor (FGF) (91, 92). During wound healing, fibrin Conclusionfilaments cross-linked to fibronectin provide a provisional matrix for Except in apicomarginal bony defects caused by combinedattachment and migration of immune cells, fibroblasts, endothelial periodontal-endodontic or endodontic-periodontal lesions (67, 70)cells, and tissue cells (27, 30). The degraded products of fibrin, by or in large periapical lesions communicating with the alveolar crestplasmin, are chemotactic to the host’s immune cells (30). In addition, (68, 69), the use of membrane barriers in periapical surgery has notFGF, TGF-b, VEGF, and endothelial growth factor in blood clot promote been shown to have a clear benefit in regenerating periapical tissues.angiogenesis to enhance tissue wound healing (93). Bone grafts alone The ability of bone grafts to induce new bone formation has beenwithout a blood clot or angiogenic factors are unlikely to be capable of well-documented (17, 18, 20–22, 78–83). However, new PDL andpromoting periapical wound healing (25). cementum regeneration in periapical surgery has not been shown to benefit from the use of bone grafts. Similar to the outcome assessment of nonsurgical (100) and Growth/Differentiation Factors in Periapical surgical endodontic therapy (61) as well as periodontal regenerative Surgery therapy, long-term outcome studies are required to provide a better Growth factors/cytokines play a crucial role in tissue wound heal- understanding of the use of membrane barriers and/or bone grafts ining because they regulate immune function and proliferation and differ- periapical surgery. Further assessment is also needed concerning histo-entiation of cells participating in wound healing (27, 93, 94). Growth logic evaluation of periapical wound healing: complete regeneration offactors are multifunctional and often have more than 1 target cell alveolar bone, PDL, and cementum. It must be reemphasized that regen-(27, 93). Many of the host’s natural growth factors have been eration of periapical tissues after severe injury or periapical surgerysynthesized in vitro and used alone or incorporated into bone grafts requires recruitment and differentiation of progenitor/stem cells intoin periapical surgery to enhance new bone formation. In a clinical periapical tissue committed cells, growth/differentiation factors, andstudy, combination of platelet-rich plasma and tricalcium phosphate microenvironmental cues. All these factors have to work together atplaced in a bony defect after periapical surgery was shown to enhance the right time, space, and concentration to reconstitute the architecturebone regeneration (82). However, when exogenous recombinant and functions of the damaged periapical tissues. Little is known of thehuman bone morphogenetic protein-1 (rhOP-1) (95), rhBMP-2 biologic mechanisms that regulate temporal and spatial relationship of(96), IGF combined with PDGF, or FGF alone (97) was delivered to alveolar bone, PDL, and cementum regeneration during periapicalthe bony defect during periapical surgery, the growth/differentiation wound healing. Simply applying a membrane barrier and/or bone graft-factors did not demonstrate any obvious benefit to the process of ing material during periapical surgery might not result in complete peri-bone healing. The concentration and stability of exogenous growth apical tissue regeneration, because these biomaterials are not capablefactor/factors and their presence in relation to the temporal and spatial of recruiting progenitor/stem cells and signaling these undifferentiatedexpression of other growth/differentiation factors as well as their exact mesenchymal cells to differentiate into pre-osteoblasts, pre-PDL cells,target cells are important in tissue wound healing (27, 93, 94). and pre-cementoblasts. In particular, very little is known about cemen- It is challenging to study the biologic functions of growth factors togenesis after cementum injury or resorption and the mechanismsduring wound healing because many growth factors are involved at necessary for attachment between dentin and newly formed cementumthe same or different stages of the wound healing process (93, 94). (10, 101). There are several types of cementum (57), which are formedThe biologic functions of most growth factors are redundant, and by cementoblasts of different origins (101, 102). In addition, it is notthey crosstalk to each other. In addition, most growth factors affect known whether new cementum formed on the root surfaces denudedmore than a single cellular activity, and most cellular activities are of PDL and cementum is by interdigitation of collagen fibrils froma response to the summation of several growth factors (93, 94). The new cementum and dentin matrix embedded in hydroxyapatitebiologic functions of growth factors might be synergistic or crystals or by interlocking of hydroxyapatite crystals from dentin andantagonistic (93, 94). More investigations are needed in this area cementum after periapical surgery (13). The exact origin ofbecause growth factors are the host’s own biologic products and cementoblast-like cells in periapical wound healing is not clear becauseimportant in tissue wound healing. Hertwig’s epithelial root sheath (HERS) cells play pivotal roles in cementum formation through their interplay with PDL stem cells (101–104). In mature teeth, HERS cells become disintegrated and Factors Influencing Periapical Wound Healing remain as epithelial cell rests of Malassez in the PDL (103). Histologi- Numerous factors such as infection, foreign bodies, systemic cally, cellular cementum can be very similar to bone (102). There aredisease, and an impaired host’s immune system can influence wound no appropriate cell markers for cementoblasts (101). Andreasenhealing (29, 30). Infection and foreign bodies are the most (105) has described different types of cementum repair and ankylosisimportant factors that can affect periapical wound healing. Implanted after apicoectomy in humans.biomaterials such as bone grafts, despite being inert and nontoxic, Without using membrane barriers and/or bone grafts in periapicaloften trigger adverse foreign body reactions such as inflammation, surgery for large apical peridontitis lesions, complete periapical tissuefibrosis, infection, and thrombosis (98, 99). The foreign body regeneration has been observed histologically in many animal andreaction composed of activated macrophages and foreign body giant human studies (60, 106–111). This is different from severecells is the end-stage response of inflammation and wound healing after periodontal tissue destruction caused by marginal periodontitis afterimplantation of biomaterials (98). Foreign bodies favor infection due to open flap debridement without using membrane barriers and/orbiofilm formation (30). In addition, any foreign materials such as bone bone grafts, because gingival tissues, especially epithelial cells, willgrafts have to dissolve in tissue fluid or be phagocytosed by activated immediately occupy denuded root surfaces before progenitor/stemmacrophages before wound healing can be completed. If that does cells from the PDL.not occur, bone grafts will be surrounded by fibrous connective tissue To fully understand the rational basis of regenerative procedures,or embedded in newly formed bone, as in some instances of periodontal we need to have more information concerning the variety of molecularregenerative therapy (10). and cellular biologic processes associated with the formation of eachJOE — Volume 36, Number 4, April 2010 Guided Tissue Regeneration in Periapical Surgery 623
  7. 7. Review Articlecomponent of the periapical tissues (10). The clinician is advised not to 22. Yoshikawa G, Murashima Y, Wadachi R, Sawada N, Suda H. Guided bone regen-think that because there is a hole (surgical wound), it must be filled with eration (GBR) using membrane and calcium sulfate after apicectomy: a compara- tive histomorphometrical study. Int Endod J 2002;35:255–63.something such as a bone graft (10). We must be concerned not only 23. Page RC. The role of inflammatory mediators in the pathogenesis of periodontalabout regeneration of alveolar bone but also the PDL and cementum disease. J Periodontol Res 1991;26:230–42.after periapical surgery. Although periapical tissue repair such as 24. Stashenko P, Teles R. Periapical inflammatory responses and their modulation.fibrosis or ankylosis is not considered a failure, periapical tissue regen- Crit Rev Oral Biol Med 1998;9:498–521.eration is the ideal outcome of periapical surgery. As stated previously, 25. 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