Q U I N T E S S E N C E I N T E R N AT I O N A L
PERIODONTOLOGY
Aleksandar Ivanovic
Which biomaterials may promote periodontal regeneration in intrabony periodontal defects? A systematic review of preclinical studies Aleksandar Ivanovic, Dr Med Dent 1/George Nikou, Dr Med Dent, MSc 2/Richard J. Miron, MSc, PhD1,3/ Dimitris Nikolidakis, Dr Med Dent, MSc, PhD 4/Anton Sculean, Prof, DMD, Dr Med Dent, MS, PhD, Dr hc 5 Objective: To systematically analyze the regenerative effect of the available biomaterials either alone or in various combinations for the treatment of periodontal intrabony defects as evaluated in preclinical histologic studies. Data Sources: A protocol covered all aspects of the systematic review methodology. A literature search was performed in Medline, including hand searching. Combinations of searching terms and several criteria were applied for study identification, selection, and inclusion. The preliminary outcome variable was periodontal regeneration after reconstructive surgery obtained with the various regenerative materials, as demonstrated through histologic/histomorphometric analysis. New periodontal ligament, new cementum, and new bone formation as a linear measurement in mm or as a percentage of the instrumented root length were recorded. Data were extracted based on the general characteristics, study characteristics, methodologic characteristics, and conclusions. Study selection was limited to
preclinical studies involving histologic analysis, evaluating the use of potential regenerative materials (ie, barrier membranes, grafting materials, or growth factors/proteins) for the treatment of periodontal intrabony defects. Any type of biomaterial alone or in various combinations was considered. All studies reporting histologic outcome measures with a healing period of at least 6 weeks were included. A meta-analysis was not possible due to the heterogeneity of the data. Conclusion: Flap surgery in conjunction with most of the evaluated biomaterials used either alone or in various combinations has been shown to promote periodontal regeneration to a greater extent than control therapy (flap surgery without biomaterials). Among the used biomaterials, autografts revealed the most favorable outcomes, whereas the use of most biologic factors showed inferior results compared to flap surgery. (Quintessence Int 2014;45:385–395; doi: 10.3290/j.qi.a31538)
Key words: animal studies, histology, intrabony periodontal defects, preclinical studies, systematic review
1
Postgraduate Student, University of Bern, School of Dental Medicine, Department of Periodontology, Bern, Switzerland.
2
Clinician, Private periodontal practice, Tripolis, Greece.
3
Research Fellow, University Laval, Quebec City, Canada.
4
Clinician, Private periodontal practice, Heraklion, Greece.
5
Professor and Chair, University of Bern, School of Dental Medicine, Department of Periodontology, Bern, Switzerland.
Correspondence: Prof Anton Sculean, Department of Periodontology, University of Berne, Freiburgstrasse 7, Berne 3010, Switzerland. Email: [email protected]
VOLUME 45 • NUMBER 5 • MAY 2014
Intrabony periodontal defects are a frequent sequela of periodontitis and if left untreated may significantly affect the long-term prognosis of the affected teeth.1 In recent decades, various treatment modalities encompassing conventional or regenerative approaches have been proposed for their treatment.2-5 Biologically, healing following conventional periodontal therapy is mainly characterized by a long junctional epithelium and no or very limited regeneration of root cementum,
385
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
LJE
C PL
N
B
N
Fig 1 Photomicrograph illustrating a reparative type of healing following treatment of an intrabony defect with flap surgery alone. (hematoxylin-eosin stain; original magnification ×50). LJE: long junctional epithelium, N: notch.
Fig 2 Photomicrograph illustrating periodontal regeneration. The healing occurred through formation of cementum (C), periodontal ligament (PL), and bone (B) coronal to the notch (N), which indicates the most apical part of the defect (oxone-aldehyde-fuschin-Halmi stain; original magnification ×50).
periodontal ligament (PL), and alveolar bone (Fig 1).6 Despite the fact that conventional periodontal surgery may indeed lead to a decrease of probing depth and reduction or elimination of bony defects, the healing is often associated with the presence of residual pockets (eg, in cases treated by means of access flap alone) or with substantial loss of the tooth’s supporting tissues (eg, in cases treated by means of resective surgery).2,7 Moreover, data from long-term clinical studies have provided evidence which indicates that residual pockets ≥ 6 mm represent a risk factor for further periodontal destruction and may result in tooth loss.8,9 In order to avoid the shortcomings associated with conventional periodontal surgery, various regenerative techniques have been introduced. Such techniques aim to reduce probing depths and reconstruct the tooth’s supporting tissues (ie, PL, root cementum, and alveolar bone) (Fig 2) by simultaneously limiting soft tissue recession.3-5 Regenerative periodontal surgery includes
the use of various types of grafting materials, root surface conditioning, guided tissue regeneration (GTR), growth and differentiation factors and various combinations thereof, in conjunction with surgical approaches designed to allow maximum preservation of soft and hard tissues.3-5 Data from clinical studies indicate that the use of some regenerative techniques may indeed result in superior clinical outcomes in terms of probing depth reduction and clinical attachment gain compared with open flap debridement, and can significantly improve the long-term prognosis of the treated teeth.4,5 From a biologic point of view, the use of any type of regenerative technique or materials needs to be supported by histologic evidence from preclinical (ie, animal) experiments.6 However, at present no study has systematically evaluated the biologic potential of the used regenerative materials to enhance periodontal regeneration as assessed histologically in preclinical
386
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
studies. Therefore, the purpose of this paper is to review with a systematic approach all preclinical (ie, animal) studies presenting histologic support for periodontal regeneration in intrabony defects using several biomaterials.
DATA SOURCES A protocol was developed before commencing the review and covered all aspects of the systematic review methodology.10 These aspects were: definition of a focused question, search strategy, criteria for study inclusion, determination of outcome measures, screening method, data extraction and analysis, and data synthesis with drawing of conclusions. The focused question was defined as follows: “What is the regenerative effect by using several biomaterials on the treatment of periodontal angular defects evaluated in animal histologic studies?” Literature search, for articles published up to and including December 2012, was performed using MEDLINE database. Combinations of searching terms were used to identify the proper studies. The reference lists of review articles were scanned. In addition, the reference lists of articles selected for inclusion in the present review were screened. Finally, hand searching including the Journal of Dental Research, Journal of Clinical Periodontology, Journal of Periodontology, Journal of Periodontal Research, and The International Journal of Periodontics and Restorative Dentistry was performed.
RESOURCES SELECTION Study selection was limited to animal histologic studies evaluating the use of potential regenerative materials (ie, barrier membranes, grafting materials or growth factors/proteins) for the treatment of periodontal intrabony defects. Any type of biomaterial and various combinations thereof were considered. A time limitation of 6 weeks regarding postoperative evaluation period was applied. All the studies with histologic outcome parameters evaluating periodontal healing were included. Only studies published in English language were collected.
VOLUME 45 • NUMBER 5 • MAY 2014
The primary outcome variable was the formation of new periodontal tissues after the application of the regenerative materials based on histologic/histomorphometric evaluation. New PL, new cementum, and new bone formation as a linear measurement (in mm) or as a percentage of the instrumented root length (%) were registered. Postsurgical changes in the periodontal defect size based on histomorphometric measurements were also considered. When specific data were reported, defect resolution and defect fill were calculated. The healing type of defect resolution in terms of complete regeneration, long junctional epithelium, connective tissue attachment, connective tissue adhesion, or osseous repair was reported. The titles and abstracts of the studies collected were independently screened by two reviewers (GN and DN). Title and abstract screening was based on the following question: “Was the study conducted on animals having periodontal intrabony lesions prepared in order to estimate regenerative potential of biomaterials for defect resolution with treatment outcomes evaluated histologically and post-surgery evaluation period of at least 6 weeks?” The full text of an article was obtained whether the response was “yes” or “uncertain” to the screening question. Disagreement regarding inclusion was resolved by discussion. The level of agreement between reviewers was determined by kappa (κ) scores. Authors of the trials were contacted to provide missing data where possible. Data were extracted based on the general characteristics (authors and year of publication), study characteristics (number of animals and defects; tooth type; defect characteristics; intervention strategies; evaluation period; outcome measures), methodologic characteristics (study design and methodologic quality), and conclusions. There was substantial heterogeneity in the data collected regarding study design, animal type, defect type, used materials, evaluation methods, outcome measures, and observation periods. Additionally, most of the studies had either a split-mouth or a mixed design without providing data about intra-individual variance. Weighted mean differences could not be cal-
387
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
Table 1
Histomorphometric data analyzed by reporting new cementum (NC) and new bone (NB) formation, but also collagen fibers (CF) and junctional epithelium (JE) on tooth surface as linear measurements (in mm) presented as percentage of defect depth resolution
Biomaterial
Teeth (N)
DD (mm)
OW (n)
CF (%)
NC (%)
NB (%)
JE (%)
REG (%) 75
Autografts
93
3.5
3
75 ± 0
75 ± 0
75 ± 0
25± 0
Allografts
88
4.3 ± 0.3
2–3
36 ± 26
62 ± 16
58 ± 12
26 ± 15
58
Xenografts
62
4.8 ± 0.3
1–3
5±0
47 ± 16
27 ± 6
32 ± 16
27
Monotherapy
Combined therapy
Control therapy
Alloplastic
182
4.8 ± 0.9
1–3
32 ± 29
61 ± 17
56 ± 17
31 ± 14
56
GTR
201
4.9 ± 0.9
1–3
43 ± 29
66 ± 25
58 ± 25
25 ± 17
58
Factors
112
5.1 ± 1.2
1–3
23 ± 5
33 ± 30
12 ± 57
12 ± 7
12
Factors + graft
234
5.0 ± 0.6
1–3
13 ± 10
64 ± 23
53 ± 16
24 ± 20
53
GTR + factors
20
6.3 ± 1.3
1
25 ± 7
68 ± 35
61 ± 34
4±0
61
GTR + grafts
95
5.2 ± 1.1
1–3
28 ± 20
64 ± 21
58 ± 6
15 ± 13
58
Combined grafts
52
5.2 ± 1.6
2–3
64 ±31
64 ±31
64 ±31
27 ± 9
64
339
4.9 ± 1.0
1–3
37 ± 23
41 ± 22
38 ± 20
32 ± 15
38
Without biomaterials
CF, collagen fibers ; DD, defect depth; GTR, guided tissue regeneration; JE, junctional epithelium; NB, new bone; NC, new cementum; OW, osseous walls; REG, regeneration.
culated, and consequently, it was impossible to conduct a quantitative data synthesis leading to a metaanalysis. Therefore, the mean and standard deviation (SD), the 95% confidence intervals (CI), and the statistical significance were found and extracted from the reviewed articles. These data were summarized separately based on the different type of biomaterials used in the treatment of the periodontal defects. Furthermore, the results of the studies that used similar outcome measurements were combined, and the data are presented in Table 1.
REVIEW Data extraction after literature searching The MEDLINE literature search resulted in 178 potentially relevant publications identified from electronic and hand searching. After the first selection step, based on the titles and abstracts of the collected studies, 71 articles were included for further analysis (inter-reader agreement κ = 0.97). At the last step, based on text screening, 26 articles were excluded as they did not report histomorphometric results, whereas 45 publica-
388
tions completely fulfilling the inclusion criteria were finally selected (inter-reader agreement κ = 0.98). The excluded studies were screened for important histologic data. All studies were categorized into specific biomaterial groups. The flowchart of the screening of the relevant publications is presented in Fig 3.
Data analysis of the regenerative effect of each biomaterial group Seven biomaterial groups were composed and were named as autografts,11-14 allografts,15-20 xenografts,12,21-27 alloplastic materials,16,17,23,28-45 barriers,15,44,46-61 biochemical factors,32,34,51-54,62-68 and combinations of them. Combination therapy revealed four subgroups named as biochemical factors and grafts,13,23-26,29,32,34,35,62,67-74 GTR and biochemical factors,49,52-56 GTR and grafts,15-17,21,22,44, 46,56,60,61,72,75-77 and combination of grafts.15,19,27,41,78,79 Moreover, a control group was included where no biomaterial was used for the treatment of the angular def ect.16-19,23,24,26,28-31,33-38,40,41,44,46-48,50-55,57,58,60,63,67,69,70,72,73,76,78-81 The healing type of the treated defects after the regenerative treatment approach were defined as LJE (long junctional epithelium: epithelium downgrowth cover-
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
Potentially relevant publications identified from electronic and hand searching (n = 178) Publications excluded on basis of abstract evaluation (n = 107) Inter-reader agreement κ = 0.97 Potentially relevant publications retrieved for further evaluation (n = 71) Publications excluded on basis of full text evaluation (n = 26) Inter-reader agreement κ = 0.98 Publications included in the present systematic review (n = 45)
Fig 3
Flow-chart of the screening of the relevant publications.
ing the treated tooth surface), CTA (connective tissue attachment: new cementum with inserting collagen fibers on the treated tooth surface but not in contact with opposing new bone), CTAd (connective tissue adhesion: connective tissue contact to the root without apparent cementum formation), REG (regeneration: new cementum, new inserting fibers, and new bone composing a new PL structure), and OR (osseous repair: new bone formation opposite tooth surface leading to defect filling). Histologic data were included in tables reporting for each selected study author name, publication date, number and type of animals, number of defects, number of osseous walls, defect depth, healing period, biomaterial type and analyzing healing type, and histologic results. Additionally histomorphometric data analyzed by reporting new cementum (NC) and new bone (NB) formation, and also collagen fibers (CF) and junctional epithelium (JE) on tooth surface as linear measurements (in mm) were presented as percentage of defect depth resolution.
Regenerative effect of the autogenous grafts on the intrabony periodontal defects Four studies providing data on the effect of the use of autogenous graft material in intrabony defects were identified.11-14 Two out of four studies showed periodontal regeneration,11,12 and the other two studies demonstrated OR.13,14 No evidence of inflammation was
VOLUME 45 • NUMBER 5 • MAY 2014
noticed. Three types of autogenous bone were used: cancellous bone, fresh bone marrow, and frozen bone marrow. Cancellous bone revealed a higher percentage of complete regeneration, while fresh bone marrow sites showed areas of ankylosis and resorption. Autograft bone particles were embedded in newly formed bone. Autogenous bone particles located at the apical and central aspects of the defects were generally incorporated in newly formed bone. Only one of the four studies provided histomorphometric data.11 Ninetythree teeth with three-wall osseous defects were evaluated. Depending on the type of the autograft, 66.7% to 88.2% showed complete regeneration, revealing a mean of 75% of regeneration.
Regenerative effect of the allogenic grafts on the intrabony periodontal defects Six studies providing data on the effect of the use of allogenic graft material in intrabony defects were identified.15-20 All six studies reported regeneration of the periodontal tissues, and five studies15-18,20 noticed a combination of LJE and periodontal regeneration. Graft particles were found sequestered in connective tissue in one study,15 and encapsulated in another study.20 No study revealed or reported complete defect resolution. No evidence of inflammation was outlined. Additionally, in one study,20 a notch was not placed questioning the histologic results due to the fact that the histologic
389
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
observation area of interest was not premarked. One study mentioned spare ankylosis,17 and one study reported root resorption.20 Only four studies provided histomorphometric data.15,16,18,19 The mean defect depth was 4.3 mm, and NC and NB formation were calculated as 62% and 58% accordingly. Of the defects, 58% showed signs of regeneration.
Regenerative effect of the xenogenic grafts on the intrabony periodontal defects Eight studies providing data on the effect of the use of xenograft materials in intrabony defects were identified.12,21-27 Out of the eight, five studies reported regeneration of the periodontal tissues with23,25,26 or without12,24 combination of LJE. Three studies21,22,27 reported OR. A notch was not placed in two studies.21,22 Graft particles were embedded in connective tissue in two studies,24,26 in two studies12,27 they were embedded in newly formed bone, and all studies observed bone formation around the graft material. No evidence of inflammation was observed and no resorption or ankylosis was reported. Four studies provided histomorphometric data.23-26 The mean defect depth was 4.8 mm; NC and NB formation in linear measurements were 47% and 27% accordingly. Finally, 27% was the overall percentage of regeneration.
Regenerative effect of the alloplastic grafts on the intrabony periodontal defects Twenty-one studies providing data on the effect of the use of alloplastic materials in intrabony defects were identified.16,17,23,28-45 In four studies28,37,40,43 no notch was prepared, and in three studies28,37,42 cementum removal prior to graft placement was prepared. Out of 22 studies, 13 studies16,17,28,30,33-35,38-43 reported regeneration in various degrees, and six studies23,29,32,36,44,45 reported limited regeneration of the periodontal tissues mainly apically, whereas no study observed healing only by epithelium downgrowth. Graft particles were present in 10 studies, 23,29,32,34,37,38,40-42,45 in seven studies23,29,32,38,40-42 they were surrounded by fibrous tissue, and in five34,38,40,42,45 by bone. In two studies40,42 graft particles were initially surrounded by connective tissue and then
390
by osteoid and finally by new bone. No evidence of inflammation was outlined. In five studies root resorption was evident.16,17,35,37,42 Eleven studies provided histomorphometric data including 172 16,23,28-30,32-35,37,42 defects. The mean defect depth was 4.8 mm, and NC and NB formation in linear measurements were 61% and 56% accordingly. Of the defects, 56% showed signs of regeneration.
Regenerative effect of the barriers on the intrabony periodontal defects Eighteen studies exhibiting data on the effect of the use of barrier materials in intrabony defects were identified.15,44,46-61 Out of 18, nine studies15,47,49,51,52,54,58,59,61 reported regeneration of the periodontal tissues, eight studies48,50,53,55-58,60 noticed a combination of LJE and periodontal regeneration, and two studies44,46 mentioned OR. Sixteen studies15,44,46,47,50-61 used bio-resorbable membranes while three studies48,49,59 used nonbioresorbable barriers. PLGA [poly(lactic-co-glycolic acid)] barrier traces were observed after 3 months of healing in one study,46 together with minimal inflammatory cell infiltrate and limited root resorption and after 8 weeks in another study.55 In one study47 complete defect resolution occurred, whereas in another study46 defect exposure led to minimal regeneration. Additionally, in two studies47,59 notches were not placed. Thirteen studies provided histomorphometric data including 205 defects.15,46-50,53,55-60 The mean defect depth was 4.9 mm, whereas NC and NB formation in linear measurements were 66% and 58% respectively. Of the defects, 58% showed partial or complete regeneration.
Regenerative effect of the biologic factors on the intrabony periodontal defects Thirteen studies showing data on the effect of the use of biologic or chemical factors in intrabony defects were revealed.32,34,51-54,62-68 Out of them, seven studies52-54,62,63,66,67 reported regeneration of the periodontal tissues, three studies34,65,68 noticed a combination of LJE plus periodontal regeneration apically, one study32 revealed CTA and periodontal regeneration apically, one study64 showed LJE, and one65 LJE and CTA. No
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
evidence of inflammation was outlined. In two studies65,68 notches were not used. Seven studies provided histomorphometric data including 29 defects.32,34,53, 62-64,67 The mean defect depth was 5.4 mm, whereas NC and NB formation in linear measurements were 43% and 22% respectively. Of the defects, 22% showed partial regeneration.
Regenerative effect of combination of growth or biochemical factors and grafts on the intrabony periodontal defects Eighteen studies providing data on the effect of the use of combining growth or biochemical factors and grafts in intrabony defects in animals were identified.13,23-26,29,32,34,35,62,67-74 Out of them, seven studies reported regeneration of the periodontal tissues.23,24,29,62,70,73,74 Ten studies noticed a combination of LJE and CTA plus periodontal regeneration.25,26,32,34,35,67-69,71,74 Finally, two studies showed LJE,71,72 and one study reported OR.13 Graft particles were present in eight studies in a variety of healing periods (8 weeks to 5 months), and were surrounded by bone or fibrous tissue.23,24,26,29,35,62,67,74 Root resorption was evident although limited in three studies,35,69,72 and one study reported a defect with ankylosis.74 NB was found to be woven in three studies,23,25,35 and lamellar in two studies.29,74 No evidence of inflammation was observed. Additionally, in all studies except three,13,68,73 notches were used. Sixteen studies provided histomorphometric data including 234 defects.23-26,29,32,34,35,62, 67,69,70-74 The mean defect depth was 5 mm; NC and NB formation in percentages were 64% and 53% respectively. Of the defects, 53% showed signs of regeneration.
Regenerative effect of combination of growth or biochemical factors and barrier membrane on the intrabony periodontal defects Six studies providing data on the effect of the use of combining growth or biochemical factors and barrier membrane in intrabony defects in animals were identified.49,52-55,56 Out of these, five studies reported regen-
VOLUME 45 • NUMBER 5 • MAY 2014
eration49,52-54,66 and one study reported regeneration and LJE, which, however, was less than the migration of the epithelium in the GTR and the surgical control.55 One study revealed barrier remnants after 8 weeks.55 Root resorption was found to be only limited in one study.55 Three studies provided histomorphometric data.49,53,55 Twenty defects with 6.3 mm defect depth revealed 68% of NC and 61% of NB. Of the defects, 61% showed signs of regeneration.
Regenerative effect of combination of grafts and barrier membrane on the intrabony periodontal defects Fourteen studies providing data on the effect of the use of a combination of grafts and a barrier membrane in intrabony defects in animals were identified.15-17,21,22,44,46, 56,60,61,72,75-77 From these, six studies reported regeneration,15,56,61,72,76,77 three studies showed regeneration in combination with LJE,16,17,60 and the rest OR.21,22,44,46,75 The healing time varied from 1 week to 24 months. Depending on the healing time and the type of the graft used, graft particles were visible histologically.22,46,60,76 In two studies root resorption was found,72,77 and in one study ankylosis was observed.17 Three studies did not use notches.21,22,75 Eight studies provided histomorphometric data of 74 defects with a mean defect depth of 5.2 mm at one to three osseous walls.15,16,46,56,60,72,76,77 Moreover, 28% showed new CTA, 64% NC, 58% NB regeneration, and 15% JE. Overall, 58% showed signs of regeneration.
Regenerative effect of combination of grafts on the intrabony periodontal defects Six studies providing data on the effect of the use of a combination of grafts in intrabony defects in animals were identified.15,19,27,41,78,79 From these, four studies reported regeneration19,27,41,79 and two studies reported regeneration in combination with a LJE.15,78 Allogenic, xenogenic, and alloplastic grafts were used in combination with a healing period varying from 4 weeks to 6 months. In two studies with a healing period from 6 weeks to 6 months, graft particles were still visible.15,27 Three studies provided histomorphometric data of 52
391
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
defects with a mean defect depth of 5.55 mm at two or three osseous walls, 64% showed new attachment, and 27% a JE.15,19,78 Overall, approximately 64% showed signs of regeneration.
Control group Forty-three studies providing data on the effect of not using grafts in intrabony defects in animals or control group were identified.16-19,23,24,26,28-31,33-38,40,41,44,46-48,50-55,57, 58,60,63,67,69,70,72,73,76,78-81 Twenty-one studies showed regeneration in various degrees,16,17,28-30,33,34,48,50,51,55,57,58,60,67,69,70, 73,76,80,81 but in most of them regeneration was limited. Only three out of 21 studies showed adequate regeneration,33,51,73 the remaining 18 were accompanied with LJE. In 35 studies intrabony defects were healed with a varying degree of LJE.16-19,23,24,26,28-30,34,36-38,41,43,47,48,50,52-55,57, 58,60,67,69,70,72,76,78-81 In six studies root resorption in various degrees was evident,37,55,69,70,72,81 and in one study ankylosis was obvious.73 In one study orthodontic movement of teeth was used for intrabony defect treatment.80 Thirty studies provided histomorphometric data.16,19,23,24,26,28-30,33-35,37,46-48,50,53,55,57,58,60,67,69,70,72,73,76,78,80,81 From 339 defects with a mean defect depth of 4.9 mm at one, two, or three osseous walls, 41% showed NC and 38% NB. Of the intrabony defects, 38% not treated with grafts showed regeneration.
DISCUSSION The data of the present systematic review indicate that treatment of experimentally created acute or chronic intrabony defects by means of flap surgery in conjunction with various regenerative materials may result in substantially higher formation of cementum, PL, and bone compared to the use of flap surgery alone. Generally, all evaluated biomaterials appeared to be biocompatible. Biomaterial-related adverse effects such as allergies or other immunologic reactions, abscess formation, or rejection of the materials were not reported. The mean values of periodontal regeneration by means of NC with inserting PL fibers and NB were calculated as linear measurements based on relevant data. The length of NC presented as percentage of defect
392
depth for comparison ranged from 33% to 75% among the groups. The length of NB ranged from 12% to 75% among the groups. Additionally, the percentage of the treated defects that demonstrated complete or partial regeneration was also estimated. Periodontal regeneration as frequency percentage ranged from 12% to 75% among the groups. Comparing the several biomaterial groups it appears that autografts revealed the most favorable outcomes whereas the use of most biologic factors showed inferior results compared to flap surgery. The finding on the positive outcomes reported following the use of autogenous bone bears clinical relevance since it provides biologic support for its clinical use. Typically, the regenerative potential of bone grafts are classified by three fundamental mechanisms, that of osteoinduction, osteconduction, and osteogenesis. Osteoinduction refers to growth factors that trigger the recruitment of immature mesenchymal progenitor cells and their differentiation to osteoblasts, osteoconduction describes a three-dimensional scaffold that guides bone deposition on the surface of the graft, and osteogenesis refers to the presence of osteoblasts or osteoblast progenitor cells from within the bone graft capable of enhancing bone formation.82,83 Since autogenous bone is the only bone graft that contains living progenitor cells capable of further supporting regeneration, it possesses clear advantages over other grafting options with only a limited supply for osteogenesis and osteoinduction. Thus, the osteogenic potential of autogenous bone grafts is superior to that of allografts, xenografts, and alloplasts due to their ability to contain living progenitor cells able to release osteoinductive growth factors and provide a natural osteoconductive surface for cell attachment and future growth.82,83 One possible explanation for the rather disappointing results obtained with most biomaterials used in the group of biologics (ie, neutral EDTA [ethylenediaminetetracetic acid], simvastatin, fibroblast growth factor [FGF]) may be related to their limited potential for promoting periodontal regeneration. On the other hand, when analyzing the studies using biologics it is extremely important to carefully consider the used car-
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
riers, which substantially influence release kinetics and biologic effects. The large variety among the used carriers and the variability in the results indicates that this critical issue has still not been completely elucidated, and further research is needed. However, at present, based on the available preclinical data, the potential clinical relevance of most tested biologics appears doubtful. There was a substantial heterogeneity in the collected data regarding animal type (ie, dog or monkey model), study design (ie, parallel, split-mouth, or mixed), used materials alone or in various combinations, defect and tooth type, outcome measures, and observation periods (from 6 weeks to 6 months). Additionally, most of the studies had either a split-mouth or a mixed design without providing data about intraindividual variance. Therefore, the combination of the data for a meta-analysis approach was impossible. Despite the fact that animal models may closely mimic the mechanical and physiologic human clinical situation, it must be pointed out that the results need to be considered with caution since each animal model has its unique advantages and disadvantages.84 However, preclinical data can provide adequate models of biologic trends before proceeding to human application. Features of periodontal diseases in humans and animals vary greatly depending upon which form of the disease is present and the stage of the development.85 Although periodontal defects can be experimentally or surgically induced in most mammalian species, it is important to choose a laboratory animal model that has similar characteristics of human anatomy and periodontal disease. Monkey and dog models seem to respond comparably to humans regarding the treatment of periodontal defects.85,86 Taken together, the present systematic review has shown that preclinical models provide important information on the biologic potential and safety of novel regenerative therapies.
VOLUME 45 • NUMBER 5 • MAY 2014
REFERENCES 1. Papapanou PN, Tonetti MS. Diagnosis and epidemiology of periodontal osseous lesions. Periodontology 2000 2000;22:8–21. 2. Polson AM, Heijl LC. Osseous repair in infrabony periodontal defects. J Cin Periodontol 1978;5:13–23. 3. Bosshardt DD, Sculean A. Does periodontal tissue regeneration really work? Periodontology 2000 2009;51:208–219. 4. Sculean A, Alessandri R, Miron R, Salvi G, Bosshard DD. Enamel matrix proteins and periodontal wound healing and regeneration. Clin Adv Periodontics 2011;1:101–117. 5. Stoecklin-Wasmer C, Rutjes AWS, da Costa BR, Salvi GE, Jüni P, Sculean A. Absorbable collagen membranes for periodontal regeneration: A systematic review. J Dent Res 2013;92:773–781. 6. Caton JG, Greenstein GG. Factors related to periodontal regeneration. Periodontology 2000 1993;1:9–15. 7. Kaldahl WB, Kalkwarf KL, Patil KD, Molvar MP, Dyer JK. Long-term evaluation of periodontal therapy: I. Response to 4 therapeutic modalities. J Periodontol 1996;67:93–102. 8. Claffey N, Egelberg J. Clinical indicators of probing attachment loss following initial periodontal treatment in advanced periodontitis patients. J Clin Periodontol 1995;22:690–696. 9. Matuliene G, Pjetursson BE, Salvi GE, et al. Influence of residual pockets on progression of periodontitis and tooth loss: results after 11 years of maintenance. J Clin Periodontol 2008;35:685–695. 10. Needleman IG. A guide to systematic reviews. J Clin Periodontol 2002;29(Suppl 3):6–9. 11. Ellegaard B, Karring T, Davies R, Löe H. New attachment after treatment of intrabony defects in monkeys. J Periodontol 1974;45:368–377. 12. Kim CS, Choi SH, Cho KS, Chai JK, Wikesjö UM, Kim CK. Periodontal healing in one-wall intra-bony defects in dogs following implantation of autogenous bone or a coral-derived biomaterial. J Clin Periodontol 2005;32:583–589. 13. Stabholz A, Brayer L, Gedalia I, Yosipovitch Z, Soskolne WA. Effect of fluoride on autogenous iliac cancellous bone and marrow transplants in surgically created intrabony pockets in dogs. J Periodontol 1977;48:413–417. 14. Ellegaard B, Nielsen IM, Karring T. Composite jaw and iliac cancellous bone grafts in intrabony defects in monkeys. J Periodontal Res 1976;11:299–310. 15. Blumenthal NM, Alves ME, Al-Huwais S, Hofbauer AM, Koperski RD. Defectdetermined regenerative options for treating periodontal intrabony defects in baboons. J Periodontol 2003;74:10–24. 16. Kim CK, Chai JK, Cho KS, Choi SH. Effect of calcium sulphate on the healing of periodontal intrabony defects. Int Dent J 1998;48:330–337. 17. Kim CK, Kim HY, Chai JK, et al. Effect of a calcium sulfate implant with calcium sulfate barrier on periodontal healing in 3-wall intrabony defects in dogs. J Periodontol 1998;69:982–988. 18. de Waal H, Ruben MP, Castellucci G, Bloom A. Histological evaluation of lyophilized, demineralized dentin for the treatment of periodontal osseous defects in dogs. Int J Periodontics Restorative Dent 1988;8:48–63. 19. Blumenthal N, Sabe T, Barrington E. Healing responses to grafting of combined collagen-decalcified bone in periodontal defects in dogs. J Periodontol 1986;57:84–90. 20. West TL, Brustein DD. Freeze-dried bone and coralline implants compared in the dog. J Periodontol 1985;56:348–351. 21. Artzi Z, Givol N, Rohrer MD, Nemcovsky CE, Prasad HS, Tal H. Qualitative and quantitative expression of bovine bone mineral in experimental bone defects. Part 1: Description of a dog model and histological observations. J Periodontol 2003;74:1143–1152. 22. Artzi Z, Givol N, Rohrer MD, Nemcovsky CE, Prasad HS, Tal H. Qualitative and quantitative expression of bovine bone mineral in experimental bone defects. Part 2: Morphometric analysis. J Periodontol 2003;74:1153–1160.
393
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
23. Blumenthal NM, Koh-Kunst G, Alves ME, et al. Effect of surgical implantation of recombinant human bone morphogenetic protein-2 in a bioabsorbable collagen sponge or calcium phosphate putty carrier in intrabony periodontal defects in the baboon. J Periodontol 2002;73:1494–1506. 24. Fujinami K, Yamamoto S, Ota M, Shibukawa Y, Yamada S. Effectiveness of proliferating tissues in combination with bovine-derived xenografts to intrabony defects of alveolar bone in dogs. Biomed Res 2007;28:107–113. 25. Kim TG, Wikesjö UM, Cho KS, et al. Periodontal wound healing/regeneration following implantation of recombinant human growth/differentiation factor-5 (rhGDF-5) in an absorbable collagen sponge carrier into one-wall intrabony defects in dogs: a dose-range study. J Clin Periodontol 2009;36:589–597. 26. Yamamoto S, Masuda H, Shibukawa Y, Yamada S. Combination of bovinederived xenografts and enamel matrix derivative in the treatment of intrabony periodontal defects in dogs. Int J Periodontics Restorative Dent 2007;27:471–479. 27. Clergeau LP, Danan M, Clergeau-Guérithault S, Brion M. Healing response to anorganic bone implantation in periodontal intrabony defects in dogs. Part I. Bone regeneration. A microradiographic study. J Periodontol 1996;67:140–149. 28. Hayashi C, Kinoshita A, Oda S, Mizutani K, Shirakata Y, Ishikawa I. Injectable calcium phosphate bone cement provides favorable space and a scaffold for periodontal regeneration in dogs. J Periodontol 2006;77:940–946. 29. Lee JS, Wikesjö UM, Jung UW, et al. Periodontal wound healing/regeneration following implantation of recombinant human growth/differentiation factor-5 in a beta-tricalcium phosphate carrier into one-wall intrabony defects in dogs. J Clin Periodontol 2010;37:382–389. 30. Nakanishi S, Ota M, Shibukawa Y, Yamada S. C-Graft in regeneration of periodontal tissue in intrabony periodontal defect in dog. J Biomater Appl 2009;24:89–104. 31. Neamat A, Gawish A, Gamal-Eldeen AM. Beta-Tricalcium phosphate promotes cell proliferation, osteogenesis and bone regeneration in intrabony defects in dogs. Arch Oral Biol 2009;54:1083–1090. 32. Oi Y, Ota M, Yamamoto S, Shibukawa Y, Yamada S. Beta-tricalcium phosphate and basic fibroblast growth factor combination enhances periodontal regeneration in intrabony defects in dogs. Dent Mater 2009;28:162–169. 33. Schwarz F, Stratul SI, Herten M, Beck B, Becker J, Sculean A. Effect of an oily calcium hydroxide suspension (Osteoinductal) on healing of intrabony periodontal defects. A pilot study in dogs. Clin Oral Investig 2006;10:29–34. 34. Shirakata Y, Yoshimoto T, Goto H, et al. Favorable periodontal healing of 1-wall infrabony defects after application of calcium phosphate cement wall alone or in combination with enamel matrix derivative: a pilot study with canine mandibles. J Periodontol 2007;78:889–898. 35. Um YJ, Jung UW, Chae GJ, et al. The effects of hydroxyapatite/calcium phosphate glass scaffold and its surface modification with bovine serum albumin on 1-wall intrabony defects of beagle dogs: a preliminary study. Biomed Mater 2008;3:1–7. 36. Villaça JH, Novaes AB Jr, Souza SL, Taba M Jr, Molina GO, Carvalho TL. Bioactive glass efficacy in the periodontal healing of intrabony defects in monkeys. Braz Dent J 2005;16:67–74. 37. Fetner AE, Hartigan MS, Low SB. Periodontal repair using PerioGlas in nonhuman primates: clinical and histologic observations. Compendium 1994;15:932–938. 38. Barney VC, Levin MP, Adams DF. Bioceramic implants in surgical periodontal defects. A comparison study. J Periodontol 1986;57:764–770. 39. Levin MP, Getter L, Adrian J, Cutright DE. Healing of periodontal defects with ceramic implants. J Clin Periodontol 1974;1:197–205. 40. Levin MP, Getter L, Cutright DE, Bhaskar SN. Biodegradable ceramic in periodontal defects. Oral Surg Oral Med Oral Pathol 1974;38:344–351. 41. Nery EB, LeGeros RZ, Lynch KL, Lee K. Tissue response to biphasic calcium phosphate ceramic with different ratios of HA/beta TCP in periodontal osseous defects. J Periodontol 1992;63:729–735. 42. Minegishi D, Lin C, Noguchi T, Ishikawa I. Porous hydroxyapatite granule implants in periodontal osseous defects in monkeys. Int J Periodontics Restorative Dent 1988;8:50–63.
394
43. Tabata M, Shimoda T, Sugihara K, Ogomi D, Ohgushi H, Akashi M. Apatite formed on/in agarose gel as a bone-grafting material in the treatment of periodontal infrabony defect. J Biomed Mater Res A Appl Biomater 2005;75:378–386. 44. Yun JH, Hwang SJ, Kim CS, et al. The correlation between the bone probing, radiographic and histometric measurements of bone level after regenerative surgery. J Periodontal Res 2005;40:453–460. 45. Wilson J, Low SB. Bioactive ceramics for periodontal treatment: comparative studies in the Patus monkey. J Appl Biomater 1992;3:123–129. 46. Felipe ME, Andrade PF, Novaes AB Jr, et al. Potential of bioactive glass particles of different size ranges to affect bone formation in interproximal periodontal defects in dogs. J Periodontol 2009;80:808–815. 47. Hürzeler MB, Quiñones CR, Caffesse RG, Schüpbach P, Morrison EC. Guided periodontal tissue regeneration in interproximal intrabony defects following treatment with a synthetic bioabsorbable barrier. J Periodontol 1997;68: 489–497. 48. Ling LJ, Lai YL. Guided tissue regeneration in surgically created 3-walled and 2-walled periodontal osseous defects in monkeys. Zhonghua Yi Xue Za Zhi (Taipei) 1994;54:209–216. 49. Onodera H, Shibukawa Y, Sugito H, Ota M, Yamada S. Periodontal regeneration in intrabony defects after application of enamel matrix proteins with guided tissue regeneration: an experimental study in dogs. Biomed Res 2005;26:69–77. 50. Ozmeriç N, Bal B, Oygür T, Balos K. The effect of a collagen membrane in regenerative therapy of two-wall intrabony defects in dogs. Periodontal Clin Investig 2000;22:22–30. 51. Sculean A, Berakdar M, Pahl S, et al. Patterns of cytokeratin expression in monkey and human periodontium following regenerative and conventional periodontal surgery. J Periodontal Res 2001;36:260–268. 52. Sculean A, Donos N, Reich E, Karring T, Brecx M. Regeneration of oxytalan fibres in different types of periodontal defects: a histological study in monkeys. J Periodontal Res 1998;33:453–459. 53. Sculean A, Donos N, Brecx M, Reich E, Karring T. Treatment of intrabony defects with guided tissue regeneration and enamel-matrix-proteins. An experimental study in monkeys. J Clin Periodontol 2000;27:466–472. 54. Sculean A, Junker R, Donos N, Berakdar M, Brecx M, Dünker N. Immunohistochemical evaluation of matrix molecules associated with wound healing following regenerative periodontal treatment in monkeys. Clin Oral Investig 2002;6:175–182. 55. Song WS, Kim CS, Choi SH, et al. The effects of a bioabsorbable barrier membrane containing safflower seed extracts on periodontal healing of 1-wall intrabony defects in beagle dogs. J Periodontol 2005;76:22–33. 56. Yamada S, Shima N, Kitamura H, Sugito H. Effect of porous xenographic bone graft with collagen barrier membrane on periodontal regeneration. Int J Periodontics Restorative Dent 2002;22:389–397. 57. Yeo YJ, Jeon DW, Kim CS, et al. Effects of chitosan nonwoven membrane on periodontal healing of surgically created one-wall intrabony defects in beagle dogs. J Biomed Mater Res B Appl Biomater 2005,15;72:86–93. 58. Kim IY, Jung UW, Kim CS, et al. Effects of a tetracycline blended polylactic and polyglycolic acid membrane on the healing of one-wall intrabony defects in beagle dogs. Biomed Mater 2007;2:S106–S110. 59. Laurell L, Bose M, Graziani F, Tonetti M, Berglundh T. The structure of periodontal tissues formed following guided tissue regeneration therapy of intrabony defects in the monkey. J Clin Periodontol 2006;33:596–603. 60. Min DH, Kim MJ, Yun JH, et al. Effect of calcium phosphate glass scaffold with chitosan membrane on the healing of alveolar bon in 1 wall intrabony defect in the beagle dogs. Key Eng Mater 2005;284–286:851–854. 61. Moon IS, Chai JK, Cho KS, Wikesjö UM, Kim CK. Effects of polyglactin mesh combined with resorbable calcium carbonate or replamine form hydroxyapatite on periodontal repair in dogs. J Clin Periodontol 1996;23:945–951. 62. Cochran DL, Jones A, Heijl L, Mellonig JT, Schoolfield J, King GN. Periodontal regeneration with a combination of enamel matrix proteins and autogenous bone grafting. J Periodontol 2003;74:1269–1281.
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
63. Cochran DL, King GN, Schoolfield J, Velasquez-Plata D, Mellonig JT, Jones A. The effect of enamel matrix proteins on periodontal regeneration as determined by histological analyses. J Periodontol 2003;74:1043–1055. 64. Morris MS, Lee Y, Lavin MT, et al. Injectable simvastatin in periodontal defects and alveolar ridges: pilot studies. J Periodontol 2008;79:1465–1473. 65. Nemcovsky CE, Zahavi S, Moses O, et al. Effect of enamel matrix protein derivative on healing of surgical supra-infrabony periodontal defects in the rat molar: a histomorphometric study. J Periodontol 2006;77:996–1002. 66. Sculean A, Karring T, Theilade J, Lioubavina N. The regenerative potential of oxytalan fibers. An experimental study in the monkey. J Clin Periodontol 1997;24:932–936. 67. Shirakata Y, Taniyama K, Yoshimoto T, et al. Regenerative effect of basic fibroblast growth factor on periodontal healing in two-wall intrabony defects in dogs. J Clin Periodontol 2010;37:374–381. 68. Murakami S, Takayama S, Ikezawa K, et al. Regeneration of periodontal tissues by basic fibroblast growth factor. J Periodontal Res 1999;34:425–430. 69. Choi SH, Kim CK, Cho KS, et al. Effect of recombinant human bone morphogenetic protein-2/absorbable collagen sponge (rhBMP-2/ACS) on healing in 3-wall intrabony defects in dogs. J Periodontol 2002;73:63–72. 70. Kim HY, Kim CS, Jhon GJ, et al. The effect of safflower seed extract on periodontal healing of 1-wall intrabony defects in beagle dogs. J Periodontol 2002;73:1457–1466. 71. Nuñez J, Sanz-Blasco S, Vignoletti F, et al. 17beta-estradiol promotes cementoblast proliferation and cementum formation in experimental periodontitis. J Periodontol 2010;81:1064–1074. 72. Park JS, Choi SH, Moon IS, Cho KS, Chai JK, Kim CK. Eight-week histological analysis on the effect of chitosan on surgically created one-wall intrabony defects in beagle dogs. J Clin Periodontol 2003;30:443–453. 73. Ishikawa I, Kinoshita A, Oda S, Roongruangphol T. Regenerative therapy in periodontal disease: histological observations after implantation of rhBMP-2 in the surgically created periodontal defects in adult dogs. Dent Japan 1994;31:141–146. 74. Kwon HR, Wikesjö UM, Park JC, et al. Growth/differentiation factor-5 significantly enhances periodontal wound healing/regeneration compared with platelet-derived growth factor-BB in dogs. J Clin Periodontol 2010;37:739–746.
VOLUME 45 • NUMBER 5 • MAY 2014
75. Artzi Z, Weinreb M, Tal H, et al. Experimental intrabony and periodontal defects treated with natural mineral combined with a synthetic cell-binding Peptide in the canine: morphometric evaluations. J Periodontol 2006;77:1658–1664. 76. Sakata J, Abe H, Ohazama A, et al. Effects of combined treatment with porous bovine inorganic bone grafts and bilayer porcine collagen membrane on refractory one-wall intrabony defects. Int J Periodontics Restorative Dent 2006;26:161–169. 77. Stavropoulos A, Wikesjö UM. Influence of defect dimensions on periodontal wound healing/regeneration in intrabony defects following implantation of a bovine bone biomaterial and provisions for guided tissue regeneration: an experimental study in the dog. J Clin Periodontol 2010;37:534–543. 78. Blumenthal NM, Alves ME. The use of demineralized freeze-dried bone-glycoprotein matrix grafts in treating baboon periodontal infrabony defects. Int J Periodontics Restorative Dent 2000;20:61–69. 79. Nery EB, Eslami A, Van Swol RL. Biphasic calcium phosphate ceramic combined with fibrillar collagen with and without citric acid conditioning in the treatment of periodontal osseous defects. J Periodontol 1990;61:166–172. 80. Cirelli CC, Cirelli JA, da Rosa Martins JC, Lia RC, Rossa C Jr, Marcantonio E Jr. Orthodontic movement of teeth with intraosseous defects: Histologic and histometric study in dogs. Am J Orthod Dentofacial Orthop 2003;123:666–673. 81. Kim CS, Choi SH, Chai JK, et al. Periodontal repair in surgically created intrabony defects in dogs: influence of the number of bone walls on healing response. J Periodontol 2004;75:229–235. 82. Miron RJ, Gruber R, Hedbom E, et al. Impact of bone harvesting techniques on cell viability and the release of growth factors of autografts. Clin Implant Dent Relat Res 20123;15:481–489. 83. Miron RJ, Hedbom E, Saulacic N, et al. Osteogenic potential of autogenous bone grafts harvested with four different surgical techniques. J Dent Res 2011;90:1428–1433. 84. Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater 2007;13:1–10. 85. Weinberg MA, Bral M. Laboratory animal models in periodontology. J Clin Periodontol 1999;26:335–340. 86. Caton J, Mota L, Gandini L, Laskaris B. Non-human primate models for testing the efficacy and safety of periodontal regeneration procedures. J Periodontol 1994;65:1143–1150.
395
PERIODONTOLOGY
Aleksandar Ivanovic
Which biomaterials may promote periodontal regeneration in intrabony periodontal defects? A systematic review of preclinical studies Aleksandar Ivanovic, Dr Med Dent 1/George Nikou, Dr Med Dent, MSc 2/Richard J. Miron, MSc, PhD1,3/ Dimitris Nikolidakis, Dr Med Dent, MSc, PhD 4/Anton Sculean, Prof, DMD, Dr Med Dent, MS, PhD, Dr hc 5 Objective: To systematically analyze the regenerative effect of the available biomaterials either alone or in various combinations for the treatment of periodontal intrabony defects as evaluated in preclinical histologic studies. Data Sources: A protocol covered all aspects of the systematic review methodology. A literature search was performed in Medline, including hand searching. Combinations of searching terms and several criteria were applied for study identification, selection, and inclusion. The preliminary outcome variable was periodontal regeneration after reconstructive surgery obtained with the various regenerative materials, as demonstrated through histologic/histomorphometric analysis. New periodontal ligament, new cementum, and new bone formation as a linear measurement in mm or as a percentage of the instrumented root length were recorded. Data were extracted based on the general characteristics, study characteristics, methodologic characteristics, and conclusions. Study selection was limited to
preclinical studies involving histologic analysis, evaluating the use of potential regenerative materials (ie, barrier membranes, grafting materials, or growth factors/proteins) for the treatment of periodontal intrabony defects. Any type of biomaterial alone or in various combinations was considered. All studies reporting histologic outcome measures with a healing period of at least 6 weeks were included. A meta-analysis was not possible due to the heterogeneity of the data. Conclusion: Flap surgery in conjunction with most of the evaluated biomaterials used either alone or in various combinations has been shown to promote periodontal regeneration to a greater extent than control therapy (flap surgery without biomaterials). Among the used biomaterials, autografts revealed the most favorable outcomes, whereas the use of most biologic factors showed inferior results compared to flap surgery. (Quintessence Int 2014;45:385–395; doi: 10.3290/j.qi.a31538)
Key words: animal studies, histology, intrabony periodontal defects, preclinical studies, systematic review
1
Postgraduate Student, University of Bern, School of Dental Medicine, Department of Periodontology, Bern, Switzerland.
2
Clinician, Private periodontal practice, Tripolis, Greece.
3
Research Fellow, University Laval, Quebec City, Canada.
4
Clinician, Private periodontal practice, Heraklion, Greece.
5
Professor and Chair, University of Bern, School of Dental Medicine, Department of Periodontology, Bern, Switzerland.
Correspondence: Prof Anton Sculean, Department of Periodontology, University of Berne, Freiburgstrasse 7, Berne 3010, Switzerland. Email: [email protected]
VOLUME 45 • NUMBER 5 • MAY 2014
Intrabony periodontal defects are a frequent sequela of periodontitis and if left untreated may significantly affect the long-term prognosis of the affected teeth.1 In recent decades, various treatment modalities encompassing conventional or regenerative approaches have been proposed for their treatment.2-5 Biologically, healing following conventional periodontal therapy is mainly characterized by a long junctional epithelium and no or very limited regeneration of root cementum,
385
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
LJE
C PL
N
B
N
Fig 1 Photomicrograph illustrating a reparative type of healing following treatment of an intrabony defect with flap surgery alone. (hematoxylin-eosin stain; original magnification ×50). LJE: long junctional epithelium, N: notch.
Fig 2 Photomicrograph illustrating periodontal regeneration. The healing occurred through formation of cementum (C), periodontal ligament (PL), and bone (B) coronal to the notch (N), which indicates the most apical part of the defect (oxone-aldehyde-fuschin-Halmi stain; original magnification ×50).
periodontal ligament (PL), and alveolar bone (Fig 1).6 Despite the fact that conventional periodontal surgery may indeed lead to a decrease of probing depth and reduction or elimination of bony defects, the healing is often associated with the presence of residual pockets (eg, in cases treated by means of access flap alone) or with substantial loss of the tooth’s supporting tissues (eg, in cases treated by means of resective surgery).2,7 Moreover, data from long-term clinical studies have provided evidence which indicates that residual pockets ≥ 6 mm represent a risk factor for further periodontal destruction and may result in tooth loss.8,9 In order to avoid the shortcomings associated with conventional periodontal surgery, various regenerative techniques have been introduced. Such techniques aim to reduce probing depths and reconstruct the tooth’s supporting tissues (ie, PL, root cementum, and alveolar bone) (Fig 2) by simultaneously limiting soft tissue recession.3-5 Regenerative periodontal surgery includes
the use of various types of grafting materials, root surface conditioning, guided tissue regeneration (GTR), growth and differentiation factors and various combinations thereof, in conjunction with surgical approaches designed to allow maximum preservation of soft and hard tissues.3-5 Data from clinical studies indicate that the use of some regenerative techniques may indeed result in superior clinical outcomes in terms of probing depth reduction and clinical attachment gain compared with open flap debridement, and can significantly improve the long-term prognosis of the treated teeth.4,5 From a biologic point of view, the use of any type of regenerative technique or materials needs to be supported by histologic evidence from preclinical (ie, animal) experiments.6 However, at present no study has systematically evaluated the biologic potential of the used regenerative materials to enhance periodontal regeneration as assessed histologically in preclinical
386
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
studies. Therefore, the purpose of this paper is to review with a systematic approach all preclinical (ie, animal) studies presenting histologic support for periodontal regeneration in intrabony defects using several biomaterials.
DATA SOURCES A protocol was developed before commencing the review and covered all aspects of the systematic review methodology.10 These aspects were: definition of a focused question, search strategy, criteria for study inclusion, determination of outcome measures, screening method, data extraction and analysis, and data synthesis with drawing of conclusions. The focused question was defined as follows: “What is the regenerative effect by using several biomaterials on the treatment of periodontal angular defects evaluated in animal histologic studies?” Literature search, for articles published up to and including December 2012, was performed using MEDLINE database. Combinations of searching terms were used to identify the proper studies. The reference lists of review articles were scanned. In addition, the reference lists of articles selected for inclusion in the present review were screened. Finally, hand searching including the Journal of Dental Research, Journal of Clinical Periodontology, Journal of Periodontology, Journal of Periodontal Research, and The International Journal of Periodontics and Restorative Dentistry was performed.
RESOURCES SELECTION Study selection was limited to animal histologic studies evaluating the use of potential regenerative materials (ie, barrier membranes, grafting materials or growth factors/proteins) for the treatment of periodontal intrabony defects. Any type of biomaterial and various combinations thereof were considered. A time limitation of 6 weeks regarding postoperative evaluation period was applied. All the studies with histologic outcome parameters evaluating periodontal healing were included. Only studies published in English language were collected.
VOLUME 45 • NUMBER 5 • MAY 2014
The primary outcome variable was the formation of new periodontal tissues after the application of the regenerative materials based on histologic/histomorphometric evaluation. New PL, new cementum, and new bone formation as a linear measurement (in mm) or as a percentage of the instrumented root length (%) were registered. Postsurgical changes in the periodontal defect size based on histomorphometric measurements were also considered. When specific data were reported, defect resolution and defect fill were calculated. The healing type of defect resolution in terms of complete regeneration, long junctional epithelium, connective tissue attachment, connective tissue adhesion, or osseous repair was reported. The titles and abstracts of the studies collected were independently screened by two reviewers (GN and DN). Title and abstract screening was based on the following question: “Was the study conducted on animals having periodontal intrabony lesions prepared in order to estimate regenerative potential of biomaterials for defect resolution with treatment outcomes evaluated histologically and post-surgery evaluation period of at least 6 weeks?” The full text of an article was obtained whether the response was “yes” or “uncertain” to the screening question. Disagreement regarding inclusion was resolved by discussion. The level of agreement between reviewers was determined by kappa (κ) scores. Authors of the trials were contacted to provide missing data where possible. Data were extracted based on the general characteristics (authors and year of publication), study characteristics (number of animals and defects; tooth type; defect characteristics; intervention strategies; evaluation period; outcome measures), methodologic characteristics (study design and methodologic quality), and conclusions. There was substantial heterogeneity in the data collected regarding study design, animal type, defect type, used materials, evaluation methods, outcome measures, and observation periods. Additionally, most of the studies had either a split-mouth or a mixed design without providing data about intra-individual variance. Weighted mean differences could not be cal-
387
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
Table 1
Histomorphometric data analyzed by reporting new cementum (NC) and new bone (NB) formation, but also collagen fibers (CF) and junctional epithelium (JE) on tooth surface as linear measurements (in mm) presented as percentage of defect depth resolution
Biomaterial
Teeth (N)
DD (mm)
OW (n)
CF (%)
NC (%)
NB (%)
JE (%)
REG (%) 75
Autografts
93
3.5
3
75 ± 0
75 ± 0
75 ± 0
25± 0
Allografts
88
4.3 ± 0.3
2–3
36 ± 26
62 ± 16
58 ± 12
26 ± 15
58
Xenografts
62
4.8 ± 0.3
1–3
5±0
47 ± 16
27 ± 6
32 ± 16
27
Monotherapy
Combined therapy
Control therapy
Alloplastic
182
4.8 ± 0.9
1–3
32 ± 29
61 ± 17
56 ± 17
31 ± 14
56
GTR
201
4.9 ± 0.9
1–3
43 ± 29
66 ± 25
58 ± 25
25 ± 17
58
Factors
112
5.1 ± 1.2
1–3
23 ± 5
33 ± 30
12 ± 57
12 ± 7
12
Factors + graft
234
5.0 ± 0.6
1–3
13 ± 10
64 ± 23
53 ± 16
24 ± 20
53
GTR + factors
20
6.3 ± 1.3
1
25 ± 7
68 ± 35
61 ± 34
4±0
61
GTR + grafts
95
5.2 ± 1.1
1–3
28 ± 20
64 ± 21
58 ± 6
15 ± 13
58
Combined grafts
52
5.2 ± 1.6
2–3
64 ±31
64 ±31
64 ±31
27 ± 9
64
339
4.9 ± 1.0
1–3
37 ± 23
41 ± 22
38 ± 20
32 ± 15
38
Without biomaterials
CF, collagen fibers ; DD, defect depth; GTR, guided tissue regeneration; JE, junctional epithelium; NB, new bone; NC, new cementum; OW, osseous walls; REG, regeneration.
culated, and consequently, it was impossible to conduct a quantitative data synthesis leading to a metaanalysis. Therefore, the mean and standard deviation (SD), the 95% confidence intervals (CI), and the statistical significance were found and extracted from the reviewed articles. These data were summarized separately based on the different type of biomaterials used in the treatment of the periodontal defects. Furthermore, the results of the studies that used similar outcome measurements were combined, and the data are presented in Table 1.
REVIEW Data extraction after literature searching The MEDLINE literature search resulted in 178 potentially relevant publications identified from electronic and hand searching. After the first selection step, based on the titles and abstracts of the collected studies, 71 articles were included for further analysis (inter-reader agreement κ = 0.97). At the last step, based on text screening, 26 articles were excluded as they did not report histomorphometric results, whereas 45 publica-
388
tions completely fulfilling the inclusion criteria were finally selected (inter-reader agreement κ = 0.98). The excluded studies were screened for important histologic data. All studies were categorized into specific biomaterial groups. The flowchart of the screening of the relevant publications is presented in Fig 3.
Data analysis of the regenerative effect of each biomaterial group Seven biomaterial groups were composed and were named as autografts,11-14 allografts,15-20 xenografts,12,21-27 alloplastic materials,16,17,23,28-45 barriers,15,44,46-61 biochemical factors,32,34,51-54,62-68 and combinations of them. Combination therapy revealed four subgroups named as biochemical factors and grafts,13,23-26,29,32,34,35,62,67-74 GTR and biochemical factors,49,52-56 GTR and grafts,15-17,21,22,44, 46,56,60,61,72,75-77 and combination of grafts.15,19,27,41,78,79 Moreover, a control group was included where no biomaterial was used for the treatment of the angular def ect.16-19,23,24,26,28-31,33-38,40,41,44,46-48,50-55,57,58,60,63,67,69,70,72,73,76,78-81 The healing type of the treated defects after the regenerative treatment approach were defined as LJE (long junctional epithelium: epithelium downgrowth cover-
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
Potentially relevant publications identified from electronic and hand searching (n = 178) Publications excluded on basis of abstract evaluation (n = 107) Inter-reader agreement κ = 0.97 Potentially relevant publications retrieved for further evaluation (n = 71) Publications excluded on basis of full text evaluation (n = 26) Inter-reader agreement κ = 0.98 Publications included in the present systematic review (n = 45)
Fig 3
Flow-chart of the screening of the relevant publications.
ing the treated tooth surface), CTA (connective tissue attachment: new cementum with inserting collagen fibers on the treated tooth surface but not in contact with opposing new bone), CTAd (connective tissue adhesion: connective tissue contact to the root without apparent cementum formation), REG (regeneration: new cementum, new inserting fibers, and new bone composing a new PL structure), and OR (osseous repair: new bone formation opposite tooth surface leading to defect filling). Histologic data were included in tables reporting for each selected study author name, publication date, number and type of animals, number of defects, number of osseous walls, defect depth, healing period, biomaterial type and analyzing healing type, and histologic results. Additionally histomorphometric data analyzed by reporting new cementum (NC) and new bone (NB) formation, and also collagen fibers (CF) and junctional epithelium (JE) on tooth surface as linear measurements (in mm) were presented as percentage of defect depth resolution.
Regenerative effect of the autogenous grafts on the intrabony periodontal defects Four studies providing data on the effect of the use of autogenous graft material in intrabony defects were identified.11-14 Two out of four studies showed periodontal regeneration,11,12 and the other two studies demonstrated OR.13,14 No evidence of inflammation was
VOLUME 45 • NUMBER 5 • MAY 2014
noticed. Three types of autogenous bone were used: cancellous bone, fresh bone marrow, and frozen bone marrow. Cancellous bone revealed a higher percentage of complete regeneration, while fresh bone marrow sites showed areas of ankylosis and resorption. Autograft bone particles were embedded in newly formed bone. Autogenous bone particles located at the apical and central aspects of the defects were generally incorporated in newly formed bone. Only one of the four studies provided histomorphometric data.11 Ninetythree teeth with three-wall osseous defects were evaluated. Depending on the type of the autograft, 66.7% to 88.2% showed complete regeneration, revealing a mean of 75% of regeneration.
Regenerative effect of the allogenic grafts on the intrabony periodontal defects Six studies providing data on the effect of the use of allogenic graft material in intrabony defects were identified.15-20 All six studies reported regeneration of the periodontal tissues, and five studies15-18,20 noticed a combination of LJE and periodontal regeneration. Graft particles were found sequestered in connective tissue in one study,15 and encapsulated in another study.20 No study revealed or reported complete defect resolution. No evidence of inflammation was outlined. Additionally, in one study,20 a notch was not placed questioning the histologic results due to the fact that the histologic
389
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
observation area of interest was not premarked. One study mentioned spare ankylosis,17 and one study reported root resorption.20 Only four studies provided histomorphometric data.15,16,18,19 The mean defect depth was 4.3 mm, and NC and NB formation were calculated as 62% and 58% accordingly. Of the defects, 58% showed signs of regeneration.
Regenerative effect of the xenogenic grafts on the intrabony periodontal defects Eight studies providing data on the effect of the use of xenograft materials in intrabony defects were identified.12,21-27 Out of the eight, five studies reported regeneration of the periodontal tissues with23,25,26 or without12,24 combination of LJE. Three studies21,22,27 reported OR. A notch was not placed in two studies.21,22 Graft particles were embedded in connective tissue in two studies,24,26 in two studies12,27 they were embedded in newly formed bone, and all studies observed bone formation around the graft material. No evidence of inflammation was observed and no resorption or ankylosis was reported. Four studies provided histomorphometric data.23-26 The mean defect depth was 4.8 mm; NC and NB formation in linear measurements were 47% and 27% accordingly. Finally, 27% was the overall percentage of regeneration.
Regenerative effect of the alloplastic grafts on the intrabony periodontal defects Twenty-one studies providing data on the effect of the use of alloplastic materials in intrabony defects were identified.16,17,23,28-45 In four studies28,37,40,43 no notch was prepared, and in three studies28,37,42 cementum removal prior to graft placement was prepared. Out of 22 studies, 13 studies16,17,28,30,33-35,38-43 reported regeneration in various degrees, and six studies23,29,32,36,44,45 reported limited regeneration of the periodontal tissues mainly apically, whereas no study observed healing only by epithelium downgrowth. Graft particles were present in 10 studies, 23,29,32,34,37,38,40-42,45 in seven studies23,29,32,38,40-42 they were surrounded by fibrous tissue, and in five34,38,40,42,45 by bone. In two studies40,42 graft particles were initially surrounded by connective tissue and then
390
by osteoid and finally by new bone. No evidence of inflammation was outlined. In five studies root resorption was evident.16,17,35,37,42 Eleven studies provided histomorphometric data including 172 16,23,28-30,32-35,37,42 defects. The mean defect depth was 4.8 mm, and NC and NB formation in linear measurements were 61% and 56% accordingly. Of the defects, 56% showed signs of regeneration.
Regenerative effect of the barriers on the intrabony periodontal defects Eighteen studies exhibiting data on the effect of the use of barrier materials in intrabony defects were identified.15,44,46-61 Out of 18, nine studies15,47,49,51,52,54,58,59,61 reported regeneration of the periodontal tissues, eight studies48,50,53,55-58,60 noticed a combination of LJE and periodontal regeneration, and two studies44,46 mentioned OR. Sixteen studies15,44,46,47,50-61 used bio-resorbable membranes while three studies48,49,59 used nonbioresorbable barriers. PLGA [poly(lactic-co-glycolic acid)] barrier traces were observed after 3 months of healing in one study,46 together with minimal inflammatory cell infiltrate and limited root resorption and after 8 weeks in another study.55 In one study47 complete defect resolution occurred, whereas in another study46 defect exposure led to minimal regeneration. Additionally, in two studies47,59 notches were not placed. Thirteen studies provided histomorphometric data including 205 defects.15,46-50,53,55-60 The mean defect depth was 4.9 mm, whereas NC and NB formation in linear measurements were 66% and 58% respectively. Of the defects, 58% showed partial or complete regeneration.
Regenerative effect of the biologic factors on the intrabony periodontal defects Thirteen studies showing data on the effect of the use of biologic or chemical factors in intrabony defects were revealed.32,34,51-54,62-68 Out of them, seven studies52-54,62,63,66,67 reported regeneration of the periodontal tissues, three studies34,65,68 noticed a combination of LJE plus periodontal regeneration apically, one study32 revealed CTA and periodontal regeneration apically, one study64 showed LJE, and one65 LJE and CTA. No
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
evidence of inflammation was outlined. In two studies65,68 notches were not used. Seven studies provided histomorphometric data including 29 defects.32,34,53, 62-64,67 The mean defect depth was 5.4 mm, whereas NC and NB formation in linear measurements were 43% and 22% respectively. Of the defects, 22% showed partial regeneration.
Regenerative effect of combination of growth or biochemical factors and grafts on the intrabony periodontal defects Eighteen studies providing data on the effect of the use of combining growth or biochemical factors and grafts in intrabony defects in animals were identified.13,23-26,29,32,34,35,62,67-74 Out of them, seven studies reported regeneration of the periodontal tissues.23,24,29,62,70,73,74 Ten studies noticed a combination of LJE and CTA plus periodontal regeneration.25,26,32,34,35,67-69,71,74 Finally, two studies showed LJE,71,72 and one study reported OR.13 Graft particles were present in eight studies in a variety of healing periods (8 weeks to 5 months), and were surrounded by bone or fibrous tissue.23,24,26,29,35,62,67,74 Root resorption was evident although limited in three studies,35,69,72 and one study reported a defect with ankylosis.74 NB was found to be woven in three studies,23,25,35 and lamellar in two studies.29,74 No evidence of inflammation was observed. Additionally, in all studies except three,13,68,73 notches were used. Sixteen studies provided histomorphometric data including 234 defects.23-26,29,32,34,35,62, 67,69,70-74 The mean defect depth was 5 mm; NC and NB formation in percentages were 64% and 53% respectively. Of the defects, 53% showed signs of regeneration.
Regenerative effect of combination of growth or biochemical factors and barrier membrane on the intrabony periodontal defects Six studies providing data on the effect of the use of combining growth or biochemical factors and barrier membrane in intrabony defects in animals were identified.49,52-55,56 Out of these, five studies reported regen-
VOLUME 45 • NUMBER 5 • MAY 2014
eration49,52-54,66 and one study reported regeneration and LJE, which, however, was less than the migration of the epithelium in the GTR and the surgical control.55 One study revealed barrier remnants after 8 weeks.55 Root resorption was found to be only limited in one study.55 Three studies provided histomorphometric data.49,53,55 Twenty defects with 6.3 mm defect depth revealed 68% of NC and 61% of NB. Of the defects, 61% showed signs of regeneration.
Regenerative effect of combination of grafts and barrier membrane on the intrabony periodontal defects Fourteen studies providing data on the effect of the use of a combination of grafts and a barrier membrane in intrabony defects in animals were identified.15-17,21,22,44,46, 56,60,61,72,75-77 From these, six studies reported regeneration,15,56,61,72,76,77 three studies showed regeneration in combination with LJE,16,17,60 and the rest OR.21,22,44,46,75 The healing time varied from 1 week to 24 months. Depending on the healing time and the type of the graft used, graft particles were visible histologically.22,46,60,76 In two studies root resorption was found,72,77 and in one study ankylosis was observed.17 Three studies did not use notches.21,22,75 Eight studies provided histomorphometric data of 74 defects with a mean defect depth of 5.2 mm at one to three osseous walls.15,16,46,56,60,72,76,77 Moreover, 28% showed new CTA, 64% NC, 58% NB regeneration, and 15% JE. Overall, 58% showed signs of regeneration.
Regenerative effect of combination of grafts on the intrabony periodontal defects Six studies providing data on the effect of the use of a combination of grafts in intrabony defects in animals were identified.15,19,27,41,78,79 From these, four studies reported regeneration19,27,41,79 and two studies reported regeneration in combination with a LJE.15,78 Allogenic, xenogenic, and alloplastic grafts were used in combination with a healing period varying from 4 weeks to 6 months. In two studies with a healing period from 6 weeks to 6 months, graft particles were still visible.15,27 Three studies provided histomorphometric data of 52
391
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
defects with a mean defect depth of 5.55 mm at two or three osseous walls, 64% showed new attachment, and 27% a JE.15,19,78 Overall, approximately 64% showed signs of regeneration.
Control group Forty-three studies providing data on the effect of not using grafts in intrabony defects in animals or control group were identified.16-19,23,24,26,28-31,33-38,40,41,44,46-48,50-55,57, 58,60,63,67,69,70,72,73,76,78-81 Twenty-one studies showed regeneration in various degrees,16,17,28-30,33,34,48,50,51,55,57,58,60,67,69,70, 73,76,80,81 but in most of them regeneration was limited. Only three out of 21 studies showed adequate regeneration,33,51,73 the remaining 18 were accompanied with LJE. In 35 studies intrabony defects were healed with a varying degree of LJE.16-19,23,24,26,28-30,34,36-38,41,43,47,48,50,52-55,57, 58,60,67,69,70,72,76,78-81 In six studies root resorption in various degrees was evident,37,55,69,70,72,81 and in one study ankylosis was obvious.73 In one study orthodontic movement of teeth was used for intrabony defect treatment.80 Thirty studies provided histomorphometric data.16,19,23,24,26,28-30,33-35,37,46-48,50,53,55,57,58,60,67,69,70,72,73,76,78,80,81 From 339 defects with a mean defect depth of 4.9 mm at one, two, or three osseous walls, 41% showed NC and 38% NB. Of the intrabony defects, 38% not treated with grafts showed regeneration.
DISCUSSION The data of the present systematic review indicate that treatment of experimentally created acute or chronic intrabony defects by means of flap surgery in conjunction with various regenerative materials may result in substantially higher formation of cementum, PL, and bone compared to the use of flap surgery alone. Generally, all evaluated biomaterials appeared to be biocompatible. Biomaterial-related adverse effects such as allergies or other immunologic reactions, abscess formation, or rejection of the materials were not reported. The mean values of periodontal regeneration by means of NC with inserting PL fibers and NB were calculated as linear measurements based on relevant data. The length of NC presented as percentage of defect
392
depth for comparison ranged from 33% to 75% among the groups. The length of NB ranged from 12% to 75% among the groups. Additionally, the percentage of the treated defects that demonstrated complete or partial regeneration was also estimated. Periodontal regeneration as frequency percentage ranged from 12% to 75% among the groups. Comparing the several biomaterial groups it appears that autografts revealed the most favorable outcomes whereas the use of most biologic factors showed inferior results compared to flap surgery. The finding on the positive outcomes reported following the use of autogenous bone bears clinical relevance since it provides biologic support for its clinical use. Typically, the regenerative potential of bone grafts are classified by three fundamental mechanisms, that of osteoinduction, osteconduction, and osteogenesis. Osteoinduction refers to growth factors that trigger the recruitment of immature mesenchymal progenitor cells and their differentiation to osteoblasts, osteoconduction describes a three-dimensional scaffold that guides bone deposition on the surface of the graft, and osteogenesis refers to the presence of osteoblasts or osteoblast progenitor cells from within the bone graft capable of enhancing bone formation.82,83 Since autogenous bone is the only bone graft that contains living progenitor cells capable of further supporting regeneration, it possesses clear advantages over other grafting options with only a limited supply for osteogenesis and osteoinduction. Thus, the osteogenic potential of autogenous bone grafts is superior to that of allografts, xenografts, and alloplasts due to their ability to contain living progenitor cells able to release osteoinductive growth factors and provide a natural osteoconductive surface for cell attachment and future growth.82,83 One possible explanation for the rather disappointing results obtained with most biomaterials used in the group of biologics (ie, neutral EDTA [ethylenediaminetetracetic acid], simvastatin, fibroblast growth factor [FGF]) may be related to their limited potential for promoting periodontal regeneration. On the other hand, when analyzing the studies using biologics it is extremely important to carefully consider the used car-
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
riers, which substantially influence release kinetics and biologic effects. The large variety among the used carriers and the variability in the results indicates that this critical issue has still not been completely elucidated, and further research is needed. However, at present, based on the available preclinical data, the potential clinical relevance of most tested biologics appears doubtful. There was a substantial heterogeneity in the collected data regarding animal type (ie, dog or monkey model), study design (ie, parallel, split-mouth, or mixed), used materials alone or in various combinations, defect and tooth type, outcome measures, and observation periods (from 6 weeks to 6 months). Additionally, most of the studies had either a split-mouth or a mixed design without providing data about intraindividual variance. Therefore, the combination of the data for a meta-analysis approach was impossible. Despite the fact that animal models may closely mimic the mechanical and physiologic human clinical situation, it must be pointed out that the results need to be considered with caution since each animal model has its unique advantages and disadvantages.84 However, preclinical data can provide adequate models of biologic trends before proceeding to human application. Features of periodontal diseases in humans and animals vary greatly depending upon which form of the disease is present and the stage of the development.85 Although periodontal defects can be experimentally or surgically induced in most mammalian species, it is important to choose a laboratory animal model that has similar characteristics of human anatomy and periodontal disease. Monkey and dog models seem to respond comparably to humans regarding the treatment of periodontal defects.85,86 Taken together, the present systematic review has shown that preclinical models provide important information on the biologic potential and safety of novel regenerative therapies.
VOLUME 45 • NUMBER 5 • MAY 2014
REFERENCES 1. Papapanou PN, Tonetti MS. Diagnosis and epidemiology of periodontal osseous lesions. Periodontology 2000 2000;22:8–21. 2. Polson AM, Heijl LC. Osseous repair in infrabony periodontal defects. J Cin Periodontol 1978;5:13–23. 3. Bosshardt DD, Sculean A. Does periodontal tissue regeneration really work? Periodontology 2000 2009;51:208–219. 4. Sculean A, Alessandri R, Miron R, Salvi G, Bosshard DD. Enamel matrix proteins and periodontal wound healing and regeneration. Clin Adv Periodontics 2011;1:101–117. 5. Stoecklin-Wasmer C, Rutjes AWS, da Costa BR, Salvi GE, Jüni P, Sculean A. Absorbable collagen membranes for periodontal regeneration: A systematic review. J Dent Res 2013;92:773–781. 6. Caton JG, Greenstein GG. Factors related to periodontal regeneration. Periodontology 2000 1993;1:9–15. 7. Kaldahl WB, Kalkwarf KL, Patil KD, Molvar MP, Dyer JK. Long-term evaluation of periodontal therapy: I. Response to 4 therapeutic modalities. J Periodontol 1996;67:93–102. 8. Claffey N, Egelberg J. Clinical indicators of probing attachment loss following initial periodontal treatment in advanced periodontitis patients. J Clin Periodontol 1995;22:690–696. 9. Matuliene G, Pjetursson BE, Salvi GE, et al. Influence of residual pockets on progression of periodontitis and tooth loss: results after 11 years of maintenance. J Clin Periodontol 2008;35:685–695. 10. Needleman IG. A guide to systematic reviews. J Clin Periodontol 2002;29(Suppl 3):6–9. 11. Ellegaard B, Karring T, Davies R, Löe H. New attachment after treatment of intrabony defects in monkeys. J Periodontol 1974;45:368–377. 12. Kim CS, Choi SH, Cho KS, Chai JK, Wikesjö UM, Kim CK. Periodontal healing in one-wall intra-bony defects in dogs following implantation of autogenous bone or a coral-derived biomaterial. J Clin Periodontol 2005;32:583–589. 13. Stabholz A, Brayer L, Gedalia I, Yosipovitch Z, Soskolne WA. Effect of fluoride on autogenous iliac cancellous bone and marrow transplants in surgically created intrabony pockets in dogs. J Periodontol 1977;48:413–417. 14. Ellegaard B, Nielsen IM, Karring T. Composite jaw and iliac cancellous bone grafts in intrabony defects in monkeys. J Periodontal Res 1976;11:299–310. 15. Blumenthal NM, Alves ME, Al-Huwais S, Hofbauer AM, Koperski RD. Defectdetermined regenerative options for treating periodontal intrabony defects in baboons. J Periodontol 2003;74:10–24. 16. Kim CK, Chai JK, Cho KS, Choi SH. Effect of calcium sulphate on the healing of periodontal intrabony defects. Int Dent J 1998;48:330–337. 17. Kim CK, Kim HY, Chai JK, et al. Effect of a calcium sulfate implant with calcium sulfate barrier on periodontal healing in 3-wall intrabony defects in dogs. J Periodontol 1998;69:982–988. 18. de Waal H, Ruben MP, Castellucci G, Bloom A. Histological evaluation of lyophilized, demineralized dentin for the treatment of periodontal osseous defects in dogs. Int J Periodontics Restorative Dent 1988;8:48–63. 19. Blumenthal N, Sabe T, Barrington E. Healing responses to grafting of combined collagen-decalcified bone in periodontal defects in dogs. J Periodontol 1986;57:84–90. 20. West TL, Brustein DD. Freeze-dried bone and coralline implants compared in the dog. J Periodontol 1985;56:348–351. 21. Artzi Z, Givol N, Rohrer MD, Nemcovsky CE, Prasad HS, Tal H. Qualitative and quantitative expression of bovine bone mineral in experimental bone defects. Part 1: Description of a dog model and histological observations. J Periodontol 2003;74:1143–1152. 22. Artzi Z, Givol N, Rohrer MD, Nemcovsky CE, Prasad HS, Tal H. Qualitative and quantitative expression of bovine bone mineral in experimental bone defects. Part 2: Morphometric analysis. J Periodontol 2003;74:1153–1160.
393
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
23. Blumenthal NM, Koh-Kunst G, Alves ME, et al. Effect of surgical implantation of recombinant human bone morphogenetic protein-2 in a bioabsorbable collagen sponge or calcium phosphate putty carrier in intrabony periodontal defects in the baboon. J Periodontol 2002;73:1494–1506. 24. Fujinami K, Yamamoto S, Ota M, Shibukawa Y, Yamada S. Effectiveness of proliferating tissues in combination with bovine-derived xenografts to intrabony defects of alveolar bone in dogs. Biomed Res 2007;28:107–113. 25. Kim TG, Wikesjö UM, Cho KS, et al. Periodontal wound healing/regeneration following implantation of recombinant human growth/differentiation factor-5 (rhGDF-5) in an absorbable collagen sponge carrier into one-wall intrabony defects in dogs: a dose-range study. J Clin Periodontol 2009;36:589–597. 26. Yamamoto S, Masuda H, Shibukawa Y, Yamada S. Combination of bovinederived xenografts and enamel matrix derivative in the treatment of intrabony periodontal defects in dogs. Int J Periodontics Restorative Dent 2007;27:471–479. 27. Clergeau LP, Danan M, Clergeau-Guérithault S, Brion M. Healing response to anorganic bone implantation in periodontal intrabony defects in dogs. Part I. Bone regeneration. A microradiographic study. J Periodontol 1996;67:140–149. 28. Hayashi C, Kinoshita A, Oda S, Mizutani K, Shirakata Y, Ishikawa I. Injectable calcium phosphate bone cement provides favorable space and a scaffold for periodontal regeneration in dogs. J Periodontol 2006;77:940–946. 29. Lee JS, Wikesjö UM, Jung UW, et al. Periodontal wound healing/regeneration following implantation of recombinant human growth/differentiation factor-5 in a beta-tricalcium phosphate carrier into one-wall intrabony defects in dogs. J Clin Periodontol 2010;37:382–389. 30. Nakanishi S, Ota M, Shibukawa Y, Yamada S. C-Graft in regeneration of periodontal tissue in intrabony periodontal defect in dog. J Biomater Appl 2009;24:89–104. 31. Neamat A, Gawish A, Gamal-Eldeen AM. Beta-Tricalcium phosphate promotes cell proliferation, osteogenesis and bone regeneration in intrabony defects in dogs. Arch Oral Biol 2009;54:1083–1090. 32. Oi Y, Ota M, Yamamoto S, Shibukawa Y, Yamada S. Beta-tricalcium phosphate and basic fibroblast growth factor combination enhances periodontal regeneration in intrabony defects in dogs. Dent Mater 2009;28:162–169. 33. Schwarz F, Stratul SI, Herten M, Beck B, Becker J, Sculean A. Effect of an oily calcium hydroxide suspension (Osteoinductal) on healing of intrabony periodontal defects. A pilot study in dogs. Clin Oral Investig 2006;10:29–34. 34. Shirakata Y, Yoshimoto T, Goto H, et al. Favorable periodontal healing of 1-wall infrabony defects after application of calcium phosphate cement wall alone or in combination with enamel matrix derivative: a pilot study with canine mandibles. J Periodontol 2007;78:889–898. 35. Um YJ, Jung UW, Chae GJ, et al. The effects of hydroxyapatite/calcium phosphate glass scaffold and its surface modification with bovine serum albumin on 1-wall intrabony defects of beagle dogs: a preliminary study. Biomed Mater 2008;3:1–7. 36. Villaça JH, Novaes AB Jr, Souza SL, Taba M Jr, Molina GO, Carvalho TL. Bioactive glass efficacy in the periodontal healing of intrabony defects in monkeys. Braz Dent J 2005;16:67–74. 37. Fetner AE, Hartigan MS, Low SB. Periodontal repair using PerioGlas in nonhuman primates: clinical and histologic observations. Compendium 1994;15:932–938. 38. Barney VC, Levin MP, Adams DF. Bioceramic implants in surgical periodontal defects. A comparison study. J Periodontol 1986;57:764–770. 39. Levin MP, Getter L, Adrian J, Cutright DE. Healing of periodontal defects with ceramic implants. J Clin Periodontol 1974;1:197–205. 40. Levin MP, Getter L, Cutright DE, Bhaskar SN. Biodegradable ceramic in periodontal defects. Oral Surg Oral Med Oral Pathol 1974;38:344–351. 41. Nery EB, LeGeros RZ, Lynch KL, Lee K. Tissue response to biphasic calcium phosphate ceramic with different ratios of HA/beta TCP in periodontal osseous defects. J Periodontol 1992;63:729–735. 42. Minegishi D, Lin C, Noguchi T, Ishikawa I. Porous hydroxyapatite granule implants in periodontal osseous defects in monkeys. Int J Periodontics Restorative Dent 1988;8:50–63.
394
43. Tabata M, Shimoda T, Sugihara K, Ogomi D, Ohgushi H, Akashi M. Apatite formed on/in agarose gel as a bone-grafting material in the treatment of periodontal infrabony defect. J Biomed Mater Res A Appl Biomater 2005;75:378–386. 44. Yun JH, Hwang SJ, Kim CS, et al. The correlation between the bone probing, radiographic and histometric measurements of bone level after regenerative surgery. J Periodontal Res 2005;40:453–460. 45. Wilson J, Low SB. Bioactive ceramics for periodontal treatment: comparative studies in the Patus monkey. J Appl Biomater 1992;3:123–129. 46. Felipe ME, Andrade PF, Novaes AB Jr, et al. Potential of bioactive glass particles of different size ranges to affect bone formation in interproximal periodontal defects in dogs. J Periodontol 2009;80:808–815. 47. Hürzeler MB, Quiñones CR, Caffesse RG, Schüpbach P, Morrison EC. Guided periodontal tissue regeneration in interproximal intrabony defects following treatment with a synthetic bioabsorbable barrier. J Periodontol 1997;68: 489–497. 48. Ling LJ, Lai YL. Guided tissue regeneration in surgically created 3-walled and 2-walled periodontal osseous defects in monkeys. Zhonghua Yi Xue Za Zhi (Taipei) 1994;54:209–216. 49. Onodera H, Shibukawa Y, Sugito H, Ota M, Yamada S. Periodontal regeneration in intrabony defects after application of enamel matrix proteins with guided tissue regeneration: an experimental study in dogs. Biomed Res 2005;26:69–77. 50. Ozmeriç N, Bal B, Oygür T, Balos K. The effect of a collagen membrane in regenerative therapy of two-wall intrabony defects in dogs. Periodontal Clin Investig 2000;22:22–30. 51. Sculean A, Berakdar M, Pahl S, et al. Patterns of cytokeratin expression in monkey and human periodontium following regenerative and conventional periodontal surgery. J Periodontal Res 2001;36:260–268. 52. Sculean A, Donos N, Reich E, Karring T, Brecx M. Regeneration of oxytalan fibres in different types of periodontal defects: a histological study in monkeys. J Periodontal Res 1998;33:453–459. 53. Sculean A, Donos N, Brecx M, Reich E, Karring T. Treatment of intrabony defects with guided tissue regeneration and enamel-matrix-proteins. An experimental study in monkeys. J Clin Periodontol 2000;27:466–472. 54. Sculean A, Junker R, Donos N, Berakdar M, Brecx M, Dünker N. Immunohistochemical evaluation of matrix molecules associated with wound healing following regenerative periodontal treatment in monkeys. Clin Oral Investig 2002;6:175–182. 55. Song WS, Kim CS, Choi SH, et al. The effects of a bioabsorbable barrier membrane containing safflower seed extracts on periodontal healing of 1-wall intrabony defects in beagle dogs. J Periodontol 2005;76:22–33. 56. Yamada S, Shima N, Kitamura H, Sugito H. Effect of porous xenographic bone graft with collagen barrier membrane on periodontal regeneration. Int J Periodontics Restorative Dent 2002;22:389–397. 57. Yeo YJ, Jeon DW, Kim CS, et al. Effects of chitosan nonwoven membrane on periodontal healing of surgically created one-wall intrabony defects in beagle dogs. J Biomed Mater Res B Appl Biomater 2005,15;72:86–93. 58. Kim IY, Jung UW, Kim CS, et al. Effects of a tetracycline blended polylactic and polyglycolic acid membrane on the healing of one-wall intrabony defects in beagle dogs. Biomed Mater 2007;2:S106–S110. 59. Laurell L, Bose M, Graziani F, Tonetti M, Berglundh T. The structure of periodontal tissues formed following guided tissue regeneration therapy of intrabony defects in the monkey. J Clin Periodontol 2006;33:596–603. 60. Min DH, Kim MJ, Yun JH, et al. Effect of calcium phosphate glass scaffold with chitosan membrane on the healing of alveolar bon in 1 wall intrabony defect in the beagle dogs. Key Eng Mater 2005;284–286:851–854. 61. Moon IS, Chai JK, Cho KS, Wikesjö UM, Kim CK. Effects of polyglactin mesh combined with resorbable calcium carbonate or replamine form hydroxyapatite on periodontal repair in dogs. J Clin Periodontol 1996;23:945–951. 62. Cochran DL, Jones A, Heijl L, Mellonig JT, Schoolfield J, King GN. Periodontal regeneration with a combination of enamel matrix proteins and autogenous bone grafting. J Periodontol 2003;74:1269–1281.
VOLUME 45 • NUMBER 5 • MAY 2014
Q U I N T E S S E N C E I N T E R N AT I O N A L Ivanovic et al
63. Cochran DL, King GN, Schoolfield J, Velasquez-Plata D, Mellonig JT, Jones A. The effect of enamel matrix proteins on periodontal regeneration as determined by histological analyses. J Periodontol 2003;74:1043–1055. 64. Morris MS, Lee Y, Lavin MT, et al. Injectable simvastatin in periodontal defects and alveolar ridges: pilot studies. J Periodontol 2008;79:1465–1473. 65. Nemcovsky CE, Zahavi S, Moses O, et al. Effect of enamel matrix protein derivative on healing of surgical supra-infrabony periodontal defects in the rat molar: a histomorphometric study. J Periodontol 2006;77:996–1002. 66. Sculean A, Karring T, Theilade J, Lioubavina N. The regenerative potential of oxytalan fibers. An experimental study in the monkey. J Clin Periodontol 1997;24:932–936. 67. Shirakata Y, Taniyama K, Yoshimoto T, et al. Regenerative effect of basic fibroblast growth factor on periodontal healing in two-wall intrabony defects in dogs. J Clin Periodontol 2010;37:374–381. 68. Murakami S, Takayama S, Ikezawa K, et al. Regeneration of periodontal tissues by basic fibroblast growth factor. J Periodontal Res 1999;34:425–430. 69. Choi SH, Kim CK, Cho KS, et al. Effect of recombinant human bone morphogenetic protein-2/absorbable collagen sponge (rhBMP-2/ACS) on healing in 3-wall intrabony defects in dogs. J Periodontol 2002;73:63–72. 70. Kim HY, Kim CS, Jhon GJ, et al. The effect of safflower seed extract on periodontal healing of 1-wall intrabony defects in beagle dogs. J Periodontol 2002;73:1457–1466. 71. Nuñez J, Sanz-Blasco S, Vignoletti F, et al. 17beta-estradiol promotes cementoblast proliferation and cementum formation in experimental periodontitis. J Periodontol 2010;81:1064–1074. 72. Park JS, Choi SH, Moon IS, Cho KS, Chai JK, Kim CK. Eight-week histological analysis on the effect of chitosan on surgically created one-wall intrabony defects in beagle dogs. J Clin Periodontol 2003;30:443–453. 73. Ishikawa I, Kinoshita A, Oda S, Roongruangphol T. Regenerative therapy in periodontal disease: histological observations after implantation of rhBMP-2 in the surgically created periodontal defects in adult dogs. Dent Japan 1994;31:141–146. 74. Kwon HR, Wikesjö UM, Park JC, et al. Growth/differentiation factor-5 significantly enhances periodontal wound healing/regeneration compared with platelet-derived growth factor-BB in dogs. J Clin Periodontol 2010;37:739–746.
VOLUME 45 • NUMBER 5 • MAY 2014
75. Artzi Z, Weinreb M, Tal H, et al. Experimental intrabony and periodontal defects treated with natural mineral combined with a synthetic cell-binding Peptide in the canine: morphometric evaluations. J Periodontol 2006;77:1658–1664. 76. Sakata J, Abe H, Ohazama A, et al. Effects of combined treatment with porous bovine inorganic bone grafts and bilayer porcine collagen membrane on refractory one-wall intrabony defects. Int J Periodontics Restorative Dent 2006;26:161–169. 77. Stavropoulos A, Wikesjö UM. Influence of defect dimensions on periodontal wound healing/regeneration in intrabony defects following implantation of a bovine bone biomaterial and provisions for guided tissue regeneration: an experimental study in the dog. J Clin Periodontol 2010;37:534–543. 78. Blumenthal NM, Alves ME. The use of demineralized freeze-dried bone-glycoprotein matrix grafts in treating baboon periodontal infrabony defects. Int J Periodontics Restorative Dent 2000;20:61–69. 79. Nery EB, Eslami A, Van Swol RL. Biphasic calcium phosphate ceramic combined with fibrillar collagen with and without citric acid conditioning in the treatment of periodontal osseous defects. J Periodontol 1990;61:166–172. 80. Cirelli CC, Cirelli JA, da Rosa Martins JC, Lia RC, Rossa C Jr, Marcantonio E Jr. Orthodontic movement of teeth with intraosseous defects: Histologic and histometric study in dogs. Am J Orthod Dentofacial Orthop 2003;123:666–673. 81. Kim CS, Choi SH, Chai JK, et al. Periodontal repair in surgically created intrabony defects in dogs: influence of the number of bone walls on healing response. J Periodontol 2004;75:229–235. 82. Miron RJ, Gruber R, Hedbom E, et al. Impact of bone harvesting techniques on cell viability and the release of growth factors of autografts. Clin Implant Dent Relat Res 20123;15:481–489. 83. Miron RJ, Hedbom E, Saulacic N, et al. Osteogenic potential of autogenous bone grafts harvested with four different surgical techniques. J Dent Res 2011;90:1428–1433. 84. Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater 2007;13:1–10. 85. Weinberg MA, Bral M. Laboratory animal models in periodontology. J Clin Periodontol 1999;26:335–340. 86. Caton J, Mota L, Gandini L, Laskaris B. Non-human primate models for testing the efficacy and safety of periodontal regeneration procedures. J Periodontol 1994;65:1143–1150.
395
