Advanced reconstructive technologies for periodontal tissue repair


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Advanced reconstructive technologies for periodontal tissue repair

  1. 1. Periodontology 2000, Vol. 59, 2012, 185–202 Ó 2012 John Wiley & Sons A/SPrinted in Singapore. All rights reserved PERIODONTOLOGY 2000Advanced reconstructivetechnologies for periodontaltissue repairC H R I S T O P H A. R A M S E I E R , G I U L I O R A S P E R I N I , S A L V A T O R E B A T I A &W I L L I A M V. G I A N N O B I L ERegenerative periodontal therapy uses specific tech- identify clinical procedures that are predictably suc-niques designed to restore those parts of the tooth- cessful in regenerating periodontal tissues. Hence,supporting structures that have been lost as a result the extent to which various methods, in combinationof periodontitis or gingival trauma. The term Ôregen- with regenerative biomaterials, such as hard- anderationÕ is defined as the reconstruction of lost or soft-tissue grafts, or cell-occlusive barrier mem-injured tissues in such a way that both the original branes used in guided tissue-regeneration proce-structures and their function are completely restored. dures, are able to regenerate lost tooth support hasProcedures aimed at restoring lost periodontal tissues been investigated (162).favor the creation of new attachment, including the Periodontal regeneration is assessed using probingformation of a new periodontal ligament with its measures, radiographic analysis, direct measure-fibers inserting in newly formed cementum and ments of new bone and histology (133). Many casesalveolar bone. that are considered clinically successful, including Deep infrabony defects associated with periodontal those in which significant regrowth of alveolar bonepockets are the classic indication for periodontal- occurs, may histologically still show an epithelialregenerative therapy. Different degrees of furcation lining along the treated root surface, instead of newlyinvolvement in molars and upper first premolars are a formed periodontal ligament and cementum (84). Infurther indication for regenerative approaches as the general, however, the clinical outcome of periodon-furcation area remains difficult to maintain through tal-regenerative techniques is shown to depend on:instrumentation and oral hygiene. A third group of (i) patient-associated factors, such as plaque control,indications for regenerative periodontal therapy are smoking habits, residual periodontal infection, orlocalized gingival recession and root exposure be- membrane exposure in guided tissue-regenerationcause they may cause significant esthetic concern for procedures, (ii) effects of occlusal forces that deliverthe patient. The denuding of a root surface with intermittent loads in axial and transverse dimensions,resultant root sensitivity represents a further indica- as well as (iii) factors associated with the clinical skillstion for regenerative periodontal therapy in order to of the operator, such as lack of primary closure of thereduce root sensitivity and to improve esthetics. surgical wound (93). Even though modified flap de- Professional periodontal therapy and maintenance, signs and microsurgical approaches are shown tocombined with risk-factor control, are shown to positively affect the outcome of both soft- and hard-effectively reduce periodontal disease progression (7, tissue regeneration, the clinical success for peri-128). In contrast to the conventional approaches of odontal regeneration still remains limited in manyanti-inflammatory periodontal therapy, however, the cases. Moreover, the surgical protocols for regenera-regenerative procedures aimed at repairing lost tive procedures are skill-demanding and may there-periodontal tissues, including alveolar bone, peri- fore lack practicability for a number of clinicians.odontal ligament and root cementum, remain more Consequently, both clinical and preclinical researchchallenging (24). During the last few decades, peri- continues to evaluate advanced regenerativeodontal research has systematically attempted to approaches using new barrier-membrane techniques 185
  2. 2. Ramseier et al.(69), cell-growth-stimulating proteins (28, 44, 70) or sue growth factors, which recruit further inflamma-gene-delivery applications (125) in order to simplify tory cells as well as fibroblastic and endothelial cells,and enhance the rebuilding of missing periodontal thus playing an essential role in the transition of thesupport. The aim of our review was to compare these wound from the inflammatory stage to the granula-advanced regenerative concepts for periodontal tion tissue-formation stage. The influx of fibroblastshard- and soft-tissue repair with conventional and budding capillaries from the gingival connectiveregenerative techniques (Table 1). While the focus tissue and the periodontal ligament connective tissuewill be on clinical applications for the delivery of initiate the phase of granulation-tissue formation ingrowth factors, the applications for gene delivery of the periodontal wound approximately 2 days aftertissue growth factors are also reviewed. incision. At this stage, fibroblasts are responsible for the formation of a loose new matrix of collagen, fibronectin and proteoglycans (12). Eventually, cellsPeriodontal wound healing and matrix form cell-to-cell and cell-to-matrix links that generate a concerted tension, resulting in tissuePrevious research on periodontal wound healing has contraction. The phase of granulation-tissue forma-provided a basic understanding of the mechanisms tion gradually develops into the final phase of heal-favoring periodontal tissue regeneration. A number of ing, in which the reformed, more cell-rich tissue,valuable findings at both the cellular and molecular undergoes maturation and sequenced remodeling tolevels was revealed and subsequently used to engi- meet functional needs (22, 150).neer the regenerative biomaterials currently available The morphology of a periodontal wound comprisesin periodontal medicine. In order to provide an the gingival epithelium, the gingival connective tis-overview of the cellular and molecular events and sue, the periodontal ligament and the hard-tissuetheir association with periodontal tissue regenera- components, such as alveolar bone and cementum ortion, the course of periodontal wound healing is dentin on the dental root surface (Fig. 1). This par-briefly reviewed in this article. ticular composition ultimately affects the healing The biology and principles of periodontal wound events in each tissue component as well as those inhealing have previously been reviewed (123). Based the entire periodontal site. While the healing of gin-on observations following experimental incisions in gival epithelia and their underlying connectiveperiodontal soft tissues, the sequence of healing after tissues concludes in a number of weeks, the regen-blood-clot formation is commonly divided into the eration of periodontal ligament, root cementum andfollowing phases: (i) soft-tissue inflammation, (ii) alveolar bone generally takes longer, occurring withingranulation-tissue formation, and (iii) intercellular a number of weeks or months. Aiming for woundmatrix formation and remodeling (22, 150). Plasma closure, the final outcome of wound healing in theproteins, mainly fibrinogen, accumulate rapidly in epithelium is the formation of the junctional epi-the bleeding wound and provide the initial basis for thelium surrounding the dentition (16). On the otherthe adherence of a fibrin clot (167). The inflammatory hand, the healing of gingival connective tissue resultsphase of healing in the soft-tissue wound is initiated in a significant reduction of its volume, thus clinicallyby polymorphonuclear leukocytes infiltrating the fi- creating both gingival recession and a reduction ofbrin clot from the wound margins, followed shortly the periodontal pocket. Periodontal ligament isafterwards by macrophages (114). The major function shown to regenerate on newly formed cementumof the polymorphonuclear leukocytes is to debride created by cementoblasts that have originated fromthe wound by removing bacterial cells and injured periodontal ligament granulation tissue (73). Fur-tissue particles through phagocytosis. The macro- thermore, alveolar bone modeling occurs followingphages, in addition, have an important role to play in the stimulation of mesenchymal cells from thethe initiation of tissue repair. The inflammatory gingival connective tissue that are transformed intophase progresses into its later stage as the amount of osteoprogenitor cells by locally expressed bonepolymorphonuclear leukocyte infiltrate gradually morphogenetic proteins (78, 154).decreases while the macrophage influx continues. A series of classical animal studies demonstratedThese macrophages contribute to the cleansing pro- that the tissue derived from alveolar bone or gingivalcess through the phagocytosis of used polymorpho- connective tissue lacks cells with the potential tonuclear leukocytes and erythrocytes. Additionally, produce a new attachment between the periodontalmacrophages release a number of biologically active ligament and newly formed cementum (74, 112).molecules, such as inflammatory cytokines and tis- Moreover, granulation tissue derived from the gingi-186
  3. 3. Periodontal tissue-engineering technologiesTable 1. Regenerative biomaterials currently available for use in periodontologyRegenerative biomaterials Trade name(s) ReferencesBone autogenous grafts (autografts) Intra-oral autografts n⁄a Renvert et al. (134) ¨ Ellegaard & Loe (31) Extra-oral autografts n⁄a Froum et al. (39)Bone allogenic grafts (allografts) Freeze-dried bone allograft GraftonÒ (Osteotech, Eatontown, NJ, USA), Mellonig et al. (96) LifenetÒ (LifeNet Health Inc., Virginia Beach, VA, USA) Demineralized freeze-dried bone Transplant FoundationÒ (Transplant Gurinsky et al. (52) allograft Foundation Inc., Miami, FL, USA) Kimble et al. (76) Trejo et al. (156)Bone xenogenic grafts (xenografts) Bovine mineral matrix Bio-OssÒ (Geistlich Pharma AG, Wolhusen, Hartman et al. (55) Switzerland), OsteoGrafÒ (Dentsply, Tulsa, OK, Camelo et al. (13) USA), Pep-Gen P-15Ò (Dentsply GmbH, Mellonig (97) Mannheim, Germany) Nevins et al. (108) Richardson et al. (136)Bone alloplastic grafts (alloplasts) Hydroxyapatite (dense, porous, OsteogenÒ (Impladent Ltd, Meffert et al. (95) resorbable) Holliswood, NY, USA) Galgut et al. (41) Beta tricalcium phosphate SynthographÒ (Bicon, Boston, MA, USA), Palti & Hoch (117) alpha-BSMÒ (Etex Corp., Cambridge, MA, Scher et al. (143) USA) Nery et al. (107) Hard-tissue replacement polymers BioplantÒ (Kerr Corp., Orange, CA, USA) Dryankova et al. (29) Bioactive glass (SiO2, CaO, Na2O, PerioGlasÒ (Novabone, Jacksonville, FL, USA), Sculean et al. (146) P2O2) BioGranÒ (Biomet 3i, Palm Beach Gardens, FL, Reynolds et al. (135) USA) Trombelli et al. (158) Fetner et al. (35) Coral-derived calcium carbonate BiocoralÒ (Biocoral Inc., La Garenne Colombes, Polimeni et al. (122) France)Polymer and collagen sponges Collagen HelistatÒ (Dental Implant Technologies Inc., Scottsdale, AZ, USA), CollacoteÒ (Carlsbad, CA, USA), Colla-TecÒ (Colla-Tec Inc., Plainsboro, NJ, USA), GelfoamÒ (Baxter, Deerfield, IL, USA)Polylactide-copolyglycolide barrier membranes Methylcellulose n⁄a Lioubavina-Hack et al. (83) Hyaluronic acid ester n⁄a ¨ Wikesjo et al. (163) Chitosan n⁄a Yeo et al. (171)Synthetic hydrogel Polyethylene glycol n⁄a Jung et al. (69)Nonresorbable cell-occlusive barrier membranes Polytetrafluorethylene Gore-TexÒ (W. L. Gore & Associates Inc., New- Trombelli et al. (159) ark, DE, USA) Moses et al. (100) Murphy & Gunsolley (102) Needleman et al. (105) 187
  4. 4. Ramseier et al.Table 1. ContinuedRegenerative biomaterials Trade name(s) ReferencesResorbable cell-occlusive barrier membranes Polyglycolide ⁄ Polylactide (synthetic) OssixÒ (ColBar LifeScience Ltd., Rehovot, Israel) Minenna et al. (98) Stavropoulos et al. (153) Parashis et al. (118) Collagen membrane (xenogen) Bio-GideÒ (Geistlich Pharma AG, Wolhusen, Sculean et al. (144) Switzerland) Owczarek et al. (116) Camelo et al. (15)Growth factors Enamel matrix derivative EmdogainÒ (Straumann AG, Basel, Switzerland) Rasperini et al. (130) Rosing et al. (139) Sanz et al. (142) Francetti et al. (38) Tonetti et al. (155) Esposito et al. (32) Esposito et al. (33) Esposito et al. (34) Platelet-derived growth factor Gem 21SÒ (Osteohealth, Shirley, NY, USA) Nevins et al. (110) Ò Bone morphogenetic protein Infuse (Medtronic Inc., Minneapolis, MN, Fiorellini et al. (36) USA) surgical intervention, the dento–gingival epithelium migrates apically along the root surface, forming a protective barrier towards the root surface (11, 75). The findings from these animal experiments revealed that ultimately the periodontal ligament tissue con- tains cells with the potential to form a new connec- tive tissue attachment (73). Typically, the down-growth of the epithelium along the tooth-root surface reaches the level of the peri- odontal ligament before the latter has regenerated with new layers of cementum and newly inserting connective tissue fibers. Therefore, in order to enable and promote healing towards the rebuilding of cementum and periodontal ligament, the gingival epithelium must be prevented from forming a longFig. 1. Periodontal wound following flap surgery: (1) junctional epithelium along the root surface down togingival epithelium, (2) gingival connective tissue, (3) the former level of the periodontal ligament (Fig. 2).alveolar bone, (4) periodontal ligament and (5) cementum This basic acquisition of knowledge has been the keyor dentin on the dental root surface. for the engineering of standard clinical procedures for the placement of a fabricated membrane in gui-val connective tissue or alveolar bone results in root ded tissue regeneration.resorption or ankylosis when placed in contact with In summary, the principles of periodontal woundthe root surface. Therefore, it should be expected that healing presented provide a basic understanding ofthese complications would occur more frequently the events following wounding in surgical interven-following regenerative periodontal surgery, particu- tions. In order to obtain new connective tissuelarly following those procedures that include the attachment, the granulation tissue derived fromplacement of grafting materials to stimulate bone periodontal ligament cells has to be given both spaceformation. The reason for root resorption (which is and time to produce and mature new cementum andrarely observed), however, may be that following the periodontal ligament. The conventional guided tis-188
  5. 5. Periodontal tissue-engineering technologies attachment (124). Goldman & Cohen (50) originally proposed a classification for infrabony defects that referred to the number of osseous walls surrounding the defect: one-wall, two-wall or three-wall. Hard-tissue grafts In a number of clinical trials and animal experiments, the periodontal flap approach was combined with the placement of bone grafts or implant materials into the curetted bony defects with the aim of stimulating periodontal regeneration. The various graft and im- plant materials evaluated to date are: (i) autogenous graft: a graft transferred from one location to another within the same organism; (ii) allogenic graft: a graft transferred from one organism to another organism of the same species; (iii) xenogenic graft: a graft taken from an organism of a different species; and (iv) alloplastic material: synthetic or inorganic implant material used instead of the previously mentionedFig. 2. (A) Normal healing process following adaptation ofthe periodontal flap with significant reduction of the graft material.attachment apparatus. (B) In order to enable and promote The biologic rationale behind the use of bone graftshealing towards the rebuilding of cementum and peri- or alloplastic materials for regenerative approaches isodontal ligament, the gingival epithelium must be pre- the assumption that these materials may serve as avented from forming a long junctional epithelium along scaffold for bone formation (osteoconduction) andthe root surface down to the former level of the peri-odontal ligament (e.g., by placement of a bioresorbable contain the bone-forming cells (osteogenesis) ormembrane). bone-inductive substances (osteoinduction). Histological studies in both humans and animals have demonstrated that grafting procedures oftensue-regeneration techniques in periodontal practice result in healing with a long junctional epitheliumhave shown their predictable, albeit limited, potential rather than a new connective tissue attachment (17,to regenerate lost periodontal support. Consequently, 84). Therefore, multiple studies have evaluated theadvanced regenerative technologies for periodontal use of hard-tissue graft materials for periodontaltissue repair aim to increase the current gold stan- regeneration in infrabony defects when compareddards for success of periodontal regeneration. In with the periodontal flap approach alone.order to identify appropriate advanced repair tech-niques for tooth-supporting periodontal tissues, anumber of combinations of conventional regenera- Biomodification of the tooth-root surfacetive techniques have been evaluated: guided tissue A number of studies have focused on the modifica-regeneration and application of tissue growth fac- tion of the periodontitis-involved root surface in or-tor(s); guided tissue regeneration and hard-tissue der to advance the formation of a new connectivegraft and application of tissue growth factor(s); hard- tissue attachment. However, despite histologicaltissue graft and biomodification of the tooth-root evidence of regeneration following root-surfacesurface; and hard-tissue graft and application of tis- biomodification with citric acid, the outcomes ofsue growth factors. controlled clinical trials have failed to show any improvements in clinical conditions compared with nonacid-treated controls (40, 91, 99).Advanced repair of alveolar bone In recent years, biomodification of the root surfacedefects with enamel matrix proteins during periodontal sur- gery and following demineralization with EDTA hasThe morphology of the alveolar infrabony defect was been introduced to promote periodontal regenera-shown to play a significant role in the establishment of tion. Based on the understanding of the biologicala predictable outcome of regeneration of periodontal model, the application of enamel matrix proteins 189
  6. 6. Ramseier et al.(amelogenins) is seen to promote periodontal factors (44, 46, 58, 87), fibroblast growth factors (49,regeneration as it initiates events that occur during 101, 149, 77, 151) and bone morphogenetic proteinsthe growth of periodontal tissues (43, 54). The com- (42, 59, 152, 164, 165), have been used in preclinicalmercially available product EmdogainÒ, a purified and clinical trials for the treatment of large peri-acid extract of porcine origin containing enamel odontal or infrabony defects, as well as around dentalmatrix derivates, is reported to be able to enhance implants (36, 68, 110). The combined use of re-periodontal regeneration (Fig. 3). More basic re- combinant human platelet-derived growth factor-BBsearch, in addition to the clinical findings, indicates and peptide P-15 with a graft biomaterial has shownthat enamel matrix derivates have a key role in peri- beneficial effects in intraosseous defects (157). How-odontal wound healing (26, 32). Histological results ever, contrasting results were reported for growthfrom both animal and human studies have shown factors such as platelet-rich plasma and graft combi-that the application of enamel matrix derivates pro- nations, or the use of bioactive agents either alone ormotes periodontal regeneration and confidently in association with graft or guided tissue regenerationinfluences periodontal wound healing (147). Thus far, for the treatment of furcation defects (157).enamel matrix derivates, either alone or in combi-nation with grafts, have demonstrated their potentialto effectively treat intraosseous defects and the clin- Biological effects of growth factors:ical results appear to be stable long term (157). platelet-derived growth factorPeriodontal tissue growth factors Platelet-derived growth factor is a member of a multifunctional polypeptide family that binds to twoWound-healing approaches using growth factors to cell-membrane tyrosine kinase receptors (platelet-target restoration of tooth-supporting bone, peri- derived growth factor-Ra and platelet-derived growthodontal ligament and cementum have been shown to factor-Rb) and subsequently exerts its biological ef-significantly advance the field of periodontal-regen- fects on cell proliferation, migration, extracellularerative medicine. A major focus of periodontal re- matrix synthesis and anti-apoptosis (56, 71, 138, 148).search has studied the impact of tissue growth factors Platelet-derived growth factor-a and -b receptors areon periodontal tissue regeneration (Table 2) (3, 44, expressed in regenerating periodontal soft and hard104, 126). Advances in molecular cloning have made tissues (119). In addition, platelet-derived growthavailable unlimited quantities of recombinant growth factor initiates tooth-supporting periodontal liga-factors for applications in tissue engineering. Re- ment cell chemotaxis (111), mitogenesis (113), matrixcombinant growth factors known to promote skin and synthesis (53) and attachment to tooth dentinal sur-bone wound healing, such as platelet-derived growth faces (172). More importantly, in vivo application offactors (14, 46, 67, 110, 115, 140), insulin-like growth platelet-derived growth factor alone or in combina- A B C D EFig. 3. Periodontal regeneration of a three-wall infrabony frabony defect is classified and measured: the predomi-defect using Emdogain. (A) A 32-year-old male patient nant component is a 7-mm-deep three-wall defect. (D)(nonsmoker with severe periodontitis). Tooth 13 shows a One year after surgical intervention the distal site of toothprobing pocket depth of 10 mm disto-buccally and clinical 13 shows a probing pocket depth of 2 mm and clinicalattachment loss of 14 mm. (B) Pretreatment radiograph attachment loss of 7 mm. Comparison with the initialshows the infrabony defect distal to tooth 13. (C) After the measurements indicates that a probing pocket depth gainbuccal incision of the papilla, the interdental tissue is of 8 mm and a clinical attachment gain of 7 mm havepreserved attached to the palatal flap. After debridement been achieved. (E) Radiograph 1 year postsurgery showingof the granulation tissue and the root surface, the in- filling of the defect.190
  7. 7. Periodontal tissue-engineering technologiesTable 2. Effects of growth factors used for periodontal tissue engineeringGrowth factor EffectsPlatelet-derived growth factor Migration, proliferation and noncollagenous matrix synthesis of mesenchymal cellsBone morphogenetic protein Proliferation, differentiation of osteoblasts and differentiation of periodontal lig- ament cells into osteoblastsEnamel matrix derivative Proliferation, protein synthesis and mineral nodule formation in periodontal lig- ament cells, osteoblasts and cementoblastsTransforming growth factor-beta Proliferation of cementoblasts and periodontal ligament fibroblastsInsulin-like growth factor-1 Cell migration, proliferation, differentiation and matrix synthesisFibroblast growth factor-2 Proliferation and attachment of endothelial cells and periodontal ligament cellstion with insulin-like growth factor-1 results in the threonine kinases. The type I receptor protein kinasepartial repair of periodontal tissues (46, 47, 87, 88, phosphorylates intracellular signaling substrates140). Platelet-derived growth factor has been shown called Smads (the sma gene in Caenorhabditis elegansto have a significant regenerative impact on peri- and the Mad gene in Drosophila). The phosphory-odontal ligament cells, as well as on osteoblasts (90, lated bone morphogenetic protein-signaling Smads92, 113, 115). enter the nucleus and initiate the production of bone The clinical application of platelet-derived growth matrix proteins, leading to bone morphogenesis. Thefactor was shown to successfully advance alveolar most remarkable feature of bone morphogeneticbone repair and clinical attachment level gain. A first proteins is their ability to induce ectopic bone for-clinical study reported the successful repair of class II mation (160). Bone morphogenetic proteins are notfurcations using demineralized freeze-dried bone only powerful regulators of cartilage and bone for-allograft saturated with recombinant human platelet- mation during embryonic development and regen-derived growth factor-BB (109). In a second study, eration in postnatal life, but they also participate inrecombinant human platelet-derived growth factor- the development and repair of other organs such asBB mixed with a synthetic beta-tricalcium phosphate the brain, kidney and nerves (132).matrix was shown to advance the repair of deep in- Sigurdsson et al. (149) evaluated bone andfrabony pockets in a large multicenter randomized cementum formation following regenerative peri-controlled trial (110). Both studies demonstrated that odontal surgery by the use of recombinant humanthe use of recombinant human platelet-derived bone morphogenetic protein in surgically createdgrowth factor-BB was safe and effective in the treat- supra-alveolar defects in dogs (168). Histologicment of periodontal osseous defects. In a follow-up analysis showed significantly more cementum for-trial, the same sample of patients was assessed 18 or mation and regrowth of alveolar bone on bone24 months following periodontal surgery. Substantial morphogenetic protein-treated sites compared withradiographic changes in the appearance of the defect the controls.fill were observed for patients treated with re- Studies have demonstrated the expression of bonecombinant human platelet-derived growth factor-BB morphogenetic proteins during tooth development(94). and periodontal repair, including alveolar bone (1, 2). Investigations in animal models have shown the po- tential repair of alveolar bony defects using re-Biological effects of growth factors: combinant human bone morphogenetic protein-12bone morphogenetic proteins (165) or recombinant human bone morphogenetic protein-2 (86, 166). In a clinical trial by FiorelliniBone morphogenetic proteins are multifunctional et al. (36), recombinant human bone morphogeneticpolypeptides belonging to the transforming growth protein-2, delivered by a bioabsorbable collagenfactor-beta superfamily of proteins (169). The human sponge, revealed significant bone formation in agenome encodes at least 20 bone morphogenetic human buccal wall defect model following toothproteins (131). Bone morphogenetic proteins bind to extraction when compared with collagen spongetype I and type II receptors that function as serine- alone. Furthermore, bone morphogenetic protein-7, 191
  8. 8. Ramseier et al.also known as osteogenic protein-1, stimulates bone ably because of proteolytic breakdown, receptor-regeneration around teeth, endosseous dental im- mediated endocytosis and solubility of the deliveryplants and in maxillary sinus floor-augmentation vehicle (3). Because their half-lives are significantlyprocedures (49, 141, 161). reduced, the period of exposure may not be suf- ficient to act on osteoblasts, cementoblasts or periodontal ligament cells. Therefore, differentClinical application of growth factors for methods of growth-factor delivery need to beuse in periodontal regeneration considered (4).In general, the impact of topical delivery of growth Investigations for periodontal bioengineering havefactors to periodontal wounds has been promising, examined a variety of methods that combine deliveryyet insufficient to promote predictable periodontal vehicles, such as scaffolds, with growth factors totissue engineering (14, 23) (Fig. 4). Growth factor target the defect site in order to optimize bioavail-proteins, once delivered to the target site, tend to ability (85). The scaffolds are designed to optimizesuffer from instability and quick dilution, presum- the dosage of the growth factor and to control its A B C D E F G H IFig. 4. Periodontal regeneration using platelet-derived together with the graft to rebuild the lost bone. (F) Agrowth factor and bone-graft materials. (A) A 27-year-old second internal mattress suture is performed with a 7-0patient at the re-evaluation visit after the initial nonsur- Gore-TexÒ suture, to allow for optimal adaptation of thegical therapy; three sites with a probing pocket depth of flap margin without the interference of the epithelium.>6 mm were identified. One of those sites, distal to tooth The two internal mattress sutures are tied and the knots44, shows a probing pocket depth of 7 mm and no gingival are performed only after a perfect tension-free closure ofrecession. (B) The periapical radiograph shows a deep, the wound. Two additional interrupted 7-0 sutures areone-wall defect distal to tooth 44 and a lesion between placed to ensure stable contact between the connectiveteeth 45 and 46. (C) Measurement of the one-wall defect tissues of the edges of the flaps. The mesial and distalshows an infrabony component of 6 mm. (D) The grafting papillae are stabilized with additional simple interruptedmaterial (GEM 21SÒ) is mixed with particles of autoge- sutures. (G) Nine months after surgery, the probingnous bone chips collected in the surgical area with a pocket depth is 2 mm. (H) Nine months after surgery, theRhodes instrument and with the liquid component of the periapical radiograph shows good bone fill of the one-GEM 21SÒ (platelet-derived growth factor). (E) The liquid wall bony defect. (I) Nine months after surgery, the sur-platelet-derived growth factor is placed in the defect gical re-entry shows new bone formation.192
  9. 9. Periodontal tissue-engineering technologiesrelease pattern, which may be pulsatile, constant or membranes, as well as barrier materials of polylactictime-programmed (8). The kinetics of the release and acid, or copolymers of polylactic acid and poly-the duration of the exposure of the growth factor may glycolic acid, have been tested in animal and humanalso be controlled (61). studies. A new polymeric system, permitting the tissue- Following therapy, guided tissue regeneration has aspecific delivery (at a controlled dose and delivery greater effect on the probing measures of periodontalrate) of two or more growth factors, was reported in an treatment than periodontal flap surgery alone,animal study carried out by Richardson et al. (137). including increased attachment gain, reduction ofThe dual delivery of vascular endothelial growth fac- probing depth, less gingival recession and more gaintor with platelet-derived growth factor from a single, in hard-tissue probing at surgical re-entry. Referringstructural polymer scaffold results in the rapid for- to the best evidence currently available, however, it ismation of a mature vascular network (137). difficult to draw general conclusions about the clinical benefit of guided tissue regeneration. Al- though there is evidence demonstrating that guidedGuided tissue regeneration tissue regeneration has significant benefits overHistological findings from periodontal-regeneration conventional open-flap surgery, the factors affectingstudies reveal that a new connective tissue attach- outcomes are unclear from the present literaturement could be predicted if the cells from the peri- because they might be influenced by study conductodontal ligament settle on the root surface during issues, such as bias (106).healing. Hence, the clinical applications of guided In summary, guided tissue regeneration istissue regeneration in periodontics involve the currently a very well-documented regenerativeplacement of a physical barrier membrane to enable procedure used to achieve periodontal regenerationthe previous periodontitis-affected tooth root surface in infrabony defects and in class II furcations. Furtherto be repopulated with cells from the periodontal benefit may be achieved by the additional use ofligament. In the last few decades, guided tissue grafting materials (155).regeneration has been applied in many clinical trialsfor the treatment of various periodontal defects, suchas infrabony defects (25), furcation involvement (72, Gene therapeutics for periodontal89) and localized gingival recession (121). In a recent tissue repairsystematic review, the combinations of barriermembranes and grafting materials used in preclinical Although encouraging results for periodontal regen-models have been summarized. The analysis of 10 eration have been found in various clinical investi-papers revealed that the combination of barrier gations using recombinant tissue growth factors,membranes and grafting materials may result in there are limitations for topical protein delivery, suchhistological evidence of periodontal regeneration, as transient biological activity, protease inactivationpredominantly bone repair. No additional histologi- and poor bioavailability from existing delivery vehi-cal benefits of combination treatments were found in cles. Therefore, newer approaches seek to developanimal models of three-wall intrabony, class II fur- methodologies that optimize growth-factor targetingcation, or fenestration defects. In supra-alveolar and to maximize the therapeutic outcome of periodontal-two-wall intrabony defect models of periodontal regenerative procedures. Genetic approaches inregeneration, the additional use of a grafting material periodontal tissue engineering show early progress ingave superior histological results of bone repair achieving delivery of growth-factor genes, such ascompared with the use of barrier membranes alone platelet-derived growth factor or bone morphogenetic(145). protein, to periodontal lesions (Fig. 5). Gene-transfer The types of barrier membranes evaluated in clin- methods may circumvent many of the limitationsical studies vary in design, configuration and com- with protein delivery to soft-tissue wounds (10, 45). Itposition. Nonresorbable membranes of expanded has been shown that the application of growth factorspolytetrafluoroethylene have been used successfully (37, 63, 64, 78) or soluble forms of cytokine receptorsin both animal experiments and human clinical trials. (21) by gene transfer provides greater sustainabilityIn recent years, natural or synthetic bio-absorbable than the application of a single protein. Thus, genebarrier membranes have been used for guided tissue therapy may achieve greater bioavailability of growthregeneration in order to eliminate the need for fol- factors within periodontal wounds and hence providelow-up surgery for membrane removal. Collagen greater regenerative potential. 193
  10. 10. Ramseier et al. A B Fig. 5. Advanced approaches for re- generating tooth-supporting struc- tures. (A) Application of a graft material (e.g. bone ceramic) and growth factor into an infrabony de- fect covered by a bioresorbable membrane. (B) Application of gene vectors for the transduction of growth factors producing target cells. strated to promote bone allograft turnover andMethods for gene delivery in periodontal osteogenesis as a mode to enrich human bone allo-applications grafts (62). To date, combinations of vascular endo-Various gene-delivery methods are available to thelial growth factor ⁄ bone morphogenetic proteinadminister growth factors to periodontal defects, (120) and platelet-derived growth factor ⁄ vascularoffering great flexibility for tissue engineering. The endothelial growth factor (137) have had highly po-delivery method can be tailored to the specific sitive synergistic responses in bone repair.characteristics of the wound site. For example, a Promising preliminary results from preclinical stud-horizontal one- or two-walled defect may require the ies reveal that host modulation achieved through geneuse of a supportive carrier, such as a scaffold. Other delivery of soluble proteins, such as tumor necrosisdefect sites may be conducive to the use of an ade- factor receptor 1 (TNFR1:Fc), reduces tumor necrosisnovirus vector embedded in a collagen matrix. factor activity and therefore inhibits alveolar bone loss More importantly from a clinical point of view is (21). These results are comparable to the findings in thethe risk associated with the use of gene therapy in research on rheumatoid arthritis where pathogenesisperiodontal tissue engineering (51). As with maxi- includes high tumor necrosis factor activity and themizing growth-factor sustainability and accounting pathways for bone resorption are similar (127).for specific characteristics of the wound site, both theDNA vector and delivery method need to be consid- Preclinical studies evaluating growthered when assessing patient safety. In summary, factor gene therapy for periodontal tissuestudies examining the use of specific delivery meth- engineeringods and DNA vectors in periodontal tissue engi-neering aim to maximize the duration of growth In order to overcome the short half-lives of growthfactor expression, optimize the method of delivery to factor peptides in vivo, gene therapy using a vectorthe periodontal defect and minimize patient risk. encoding the growth factor is advocated to stimulate A combination of an Adeno-Associated Virus- tissue regeneration. So far, two main strategies ofdelivered angiogenic molecule, such as vascular gene vector delivery have been applied to peri-endothelial growth factor, bone morphogenetic pro- odontal tissue engineering. Gene vectors can betein signaling receptor (caALK2) and receptor acti- introduced directly to the target site (in vivo tech-vator of nuclear factor-kappa B ligand, was demon- nique) (63) or selected cells can be harvested, ex-194
  11. 11. Periodontal tissue-engineering technologiespanded, genetically transduced and then re-im- tor signaling. Gene delivery of platelet-derivedplanted (ex vivo technique) (64). In vivo gene growth factor-B generally displays higher sustainedtransfer involves the insertion of the gene of interest signal-transduction effects in human gingival fibro-directly into the body anticipating the genetic blasts compared to cells treated with recombinantmodification of the target cell. Ex vivo gene transfer human platelet-derived growth factor-BB proteinincludes the incorporation of genetic material into alone. Their data on platelet-derived growth factorcells exposed from a tissue biopsy with subsequent gene delivery may contribute to an improvedre-implantation into the recipient. Using the in vivo understanding of the pathways that are likely to playtechnique, the potential inhibition of alveolar bone a role in the control of clinical outcomes of peri-loss has been studied in an experimental periodon- odontal-regenerative therapy.titis model evaluating the inhibition of osteoclasto- In an ex vivo investigation by Anusaksathien et al.genesis by administering human osteoprotegerin, a (6), it was shown that the expression of platelet-de-competitive inhibitor of the receptor activator of rived growth factor genes was prolonged for up tonuclear factor-kappa B ligand-derived osteoclast 10 days in gingival wounds. Adenovirus encodingactivation. Significant preservation of alveolar bone platelet-derived growth factor-B (adenovirus ⁄ plate-volume was observed among osteoprotegerin:Fc- let-derived growth factor-B) transduced gingivaltreated animals compared with controls. Systemic fibroblasts and enhanced defect fill by inducingdelivery of osteoprotegerin:Fc inhibits alveolar bone human gingival fibroblast migration and proliferationresorption in experimental periodontitis, suggesting (6). On the other hand, continuous exposure ofthat inhibition of receptor activator of nuclear fac- cementoblasts to platelet-derived growth factor-Ator-kappa B ligand may represent an important had an inhibitory effect on cementum mineraliza-therapeutic strategy for the prevention of progres- tion, possibly via the upregulation of osteopontin andsive alveolar bone loss (65). the subsequent enhancement of multinucleated giant cells in cementum-engineered scaffolds. Moreover, adenovirus ⁄ platelet-derived growth factor-1308 (aPlatelet-derived growth factor gene dominant-negative mutant of platelet-derived growthdelivery factor) inhibited mineralization of tissue-engineered cementum, possibly owing to the downregulation ofPlatelet-derived growth factor-gene transfer strate- bone sialoprotein and osteocalcin and the persis-gies were originally used in tissue engineering to tence of stimulation with multinucleated giant cells.improve healing in soft-tissue wounds such as skin These findings suggest that continuous exogenouslesions (27). Both plasmid (57) and adenovirus ⁄ delivery of platelet-derived growth factor-A may de-platelet-derived growth factor (125) gene delivery lay mineral formation induced by cementoblasts,have been evaluated in preclinical and human trials. while platelet-derived growth factor is clearly re-However, the latter exhibits greater safety in clinical quired for mineral neogenesis (5).use (51). In a recent animal study reporting on safety Jin et al. (63) demonstrated that direct in vivo geneand distribution profiles, adenovirus ⁄ platelet-de- transfer of platelet-derived growth factor-B was able torived growth factor-B applied for tissue engineering stimulate tissue regeneration in large periodontal de-of tooth-supporting alveolar bone defects was well fects. Descriptive histology and histomorphometrycontained within the localized osseous defect area revealed that delivery of the human platelet-derivedwithout viremia or distant organ involvement (18). growth factor-B gene promotes the regeneration of Early studies in dental applications using re- both cementum and alveolar bone, while delivery ofcombinant adenoviral vectors encoding platelet-de- platelet-derived growth factor-1308, a dominant-neg-rived growth factor demonstrated the ability of these ative mutant of platelet-derived growth factor-A, hasvector constructs to potently transduce cells isolated minimal effects on periodontal tissue regeneration.from the periodontium (osteoblasts, cementoblasts,periodontal ligament cells and gingival fibroblasts)(48, 173). These studies revealed the extensive and Delivery of the boneprolonged transduction of periodontal-derived cells. morphogenetic protein geneBoth Chen & Giannobile (19) and Lin et al. (82) wereable to demonstrate the effects of adenoviral delivery An experimental study in rodents by Lieberman etof platelet-derived growth factor to understand, in al. (81) advanced gene therapy for bone regenera-greater detail, sustained platelet-derived growth fac- tion, with the results revealing that the transduction 195
  12. 12. Ramseier et al.of bone marrow stromal cells with recombinant differentiation of human periodontal ligament cellshuman bone morphogenetic protein 2 led to bone (170).formation within an experimental defect comparable These experiments provide promising evidenceto skeletal bone. Another group was similarly able to showing the feasibility of both in vivo and ex vivoregenerate skeletal bone by directly administering gene therapy for periodontal tissue regeneration andadenovirus5 ⁄ bone morphogenetic protein 2 into a peri-implant osseointegration.bony segmental defect in rabbits (9). Further ad-vances in the area of orthopedic gene therapy using Future perspectives: targeted geneviral delivery of bone morphogenetic protein 2 have therapy in vivoprovided further evidence for the ability of both invivo and ex vivo bone engineering (20, 79, 80, 103). Major advances have been made over the past decadeFranceschi et al. (37) investigated in vitro and in vivo in the reconstruction of complex periodontal andadenovirus gene transfer of bone morphogenetic alveolar bone wounds that have resulted from diseaseprotein 7 for bone formation. Adenovirus-trans- or injury. Developments in scaffolding matrices forduced nonosteogenic cells were also found to dif- cell, protein and gene delivery have demonstratedferentiate into bone-forming cells and to produce significant potential to provide ÔsmartÕ biomaterialsbone morphogenetic protein 7 (78) or bone mor- that can interact with the matrix, cells and bioactivephogenetic protein 2 (20) both in vitro and in vivo. factors. The targeting of signaling molecules or growthIn another study by Huang et al. (60), plasmid DNA factors (via proteins or genes) to periodontal tissueencoding bone morphogenetic protein 4 adminis- components has led to significant new knowledgetered using a scaffold-delivery system was found to generation using factors that promote cell replication,enhance bone formation when compared with blank differentiation, matrix biosynthesis and angiogenesis.scaffolds. A major challenge that has been studied less is the In an early approach to regenerate alveolar bone in modulation of the exuberant host response to micro-an animal model, it was demonstrated that the bial contamination that plagues the periodontalex vivo delivery of an adenovirus encoding murine wound microenvironment. To achieve improvementsbone morphogenetic protein 7 was found to promote in the outcome of periodontal-regenerative medicine,periodontal tissue regeneration in large mandibular scientists will need to examine the dual delivery ofperiodontal bone defects (64). Transfer of the bone host modifiers or anti-infective agents to optimize themorphogenetic protein 7 gene enhanced alveolar results of therapy. Further advancements in the fieldbone repair and also stimulated cementogenesis and will continue to rely heavily on multidisciplinary ap-periodontal ligament fiber formation. Of interest, proaches, combining engineering, dentistry, medicinealveolar bone formation was found to occur via a and infectious disease specialists in repairing thecartilage intermediate. However, when genes encod- complex periodontal wound the bone morphogenetic protein antagonistnoggin were delivered, inhibition of periodontal tis-sue formation resulted (66). In a study by Dunn et al. Acknowledgments(30), it was shown that direct in vivo gene delivery ofadenovirus ⁄ bone morphogenetic protein 7 in a col- This work was supported by NIH ⁄ NIDCR DE13397lagen gel carrier promoted successful regeneration of and NIH ⁄ NCRR UL1RR-024986. The authors thankalveolar bone defects around dental implants. Fur- Mr Chris Jung for his assistance with the figures.thermore, an in vivo synergism was found of aden-oviral-mediated coexpression of bone morphogeneticprotein 7 and insulin like growth factor 1 on human Referencesperiodontal ligament cells in up-regulating alkalinephosphatase activity and the mRNA levels of collagen 1. Aberg T, Wozney J, Thesleff I. Expression patterns of bonetype I and Runx2 (170). Implantation with scaffolds morphogenetic proteins (BMPs) in the developing mouse tooth suggest roles in morphogenesis and cell differenti-illustrated that the transduced cells exhibited osteo- ation. Dev Dyn 1997: 210: 383–396.genic differentiation and formed bone-like struc- 2. Amar S, Chung KM, Nam SH, Karatzas S, Myokai F, Vantures. It was concluded that the combined delivery of Dyke TE. Markers of bone and cementum formationbone morphogenetic protein 7 and insulin like accumulate in tissues regenerated in periodontal defectsgrowth factor 1 genes using an internal ribosome treated with expanded polytetrafluoroethylene mem- branes. J Periodontal Res 1997: 32: 148–158.entry site-based strategy synergistically enhanced the196
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