Abstract
The aim of this systematic review was to assess if the use of autologous platelet concentrates may be beneficial to the healing of extraction sockets. Medline, Embase and Cochrane Central Register of Controlled Trials were searched using a combination of specific search terms. Hand searching of the relevant journals and of the bibliographies of reviews was also performed. Prospective comparative studies evaluating the effect of a platelet concentrate on fresh extraction sockets were included. Outcome variables related to hard and soft tissue healing, aesthetics and postoperative discomfort were considered. A methodological study quality assessment was made. The initial search yielded 425 articles, eight were finally included. 207 tooth extractions (104 tests and 103 controls) in 115 patients were evaluated. The articles provided a broad range of variable outcomes to assess the regenerative potential of platelet concentrate and its possible benefits to the treatment. Favourable effects on hard and soft tissue healing and postoperative discomfort reduction were often reported. A large heterogeneity was found regarding study design, sample size, surgical techniques and methods for preparing platelet concentrates. Standardization of experimental design is needed in order to detect the true effect of platelet concentrates in regenerative procedures of extraction sockets.
Tooth extraction is performed for a wide variety of reasons, such as tooth decay that may destroy enough tooth structure to prevent restoration, or periodontal disease, which may severely affect the tooth-supporting tissues. Extraction of impacted or problematic wisdom teeth is routinely performed, as is extraction of some permanent teeth to make space for orthodontic treatment. The presence of fractured teeth or roots can be a further indication for extraction.
Following extraction of a tooth, a blood clot forms in the socket and the healing process begins. The early healing events include the formation of granulation tissue within the socket, which is progressively replaced with newly formed bone. The healing process is considered complete after 4–6 months, once bone remodelling takes place. Most often, missing teeth are replaced with an implant-supported prosthesis. In this case, the most conventional and predictable protocol dictates that implants are placed in the extraction sites after completion of the healing process, but parallel to ingrowth of bone into the socket a consistent resorption of the alveolar ridge occurs physiologically during the healing and remodelling phase of the extraction socket , reducing the available bony support for implants. This represents a concern even if implant treatment is not planned, such as in the case of wisdom teeth extraction, because the rapid post-extraction bone loss may extend to surrounding teeth, compromising their stability and causing tissue recession. The greatest amount of bone loss occurs in the horizontal dimension, mainly on the facial aspect, causing narrowing of the ridge . A consistent vertical reduction also takes place, more pronounced at the buccal side . Hence, ridge resorption may lead to a poor aesthetic appearance, which is particularly detrimental when anterior sites are involved. The preservation of hard and soft tissue following the extraction of one or more teeth is one of the most challenging objectives of dental procedures.
In order to reduce alveolar bone dimensional changes, several techniques aiming at enhancing the regeneration process in the extraction socket have been adopted , such as filling the socket with autogenous bone grafts or bone substitutes , guided bone regeneration (GBR) with resorbable or non-resorbable barriers , and the use of various bone promoting molecules such as enamel matrix derivative , recombinant growth and differentiation factors , and autologous platelet concentrates . These techniques have been used alone or in combinations, in the search for the optimal socket preservation method.
Recently, the use of platelet concentrates has been proposed as an aid for enhancing regeneration of osseous and epithelial tissues in oral surgery . Several in vitro studies, animal experiments and clinical trials suggested that platelet concentrates may effectively trigger stimulation of osseous and soft tissue regeneration, and reduce inflammation, pain and unwanted side effects . The clinical efficacy of platelet concentrates in oral surgical procedures is debated as contrasting results have been reported in different clinical applications. Such uncertainty was also evidenced by recent systematic reviews summarizing the clinical evidence on the use of platelet concentrates in dentistry . The results of all these studies can be confounding for the practitioner.
The aim of the present investigation was to review systematically the literature for studies fulfilling the criteria of evidence based medicine, in order to determine if the use of autologous platelet concentrates may improve the healing of extraction sockets.
Materials and methods
A literature search was carried out on electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), using the following search terms, alone and in combination by means of Boolean operators: ‘platelet-rich plasma’, ‘autologous platelet concentrates’, ‘platelet growth factors’ and ‘platelet-rich fibrin’. The search was limited to studies involving human subjects. No language or time restriction was applied. The last electronic search was performed on October 2010.
A further hand search was performed on the main international journals in the field of dentistry and of oral and maxillofacial surgery (British Dental Journal, British Journal of Oral and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, Clinical Oral Investigations, European Journal of Oral Sciences, Implant Dentistry, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, International Journal of Periodontics and Restorative Dentistry, Journal of Clinical Periodontology, Journal of Dental Research, Journal of Dentistry, Journal of Maxillofacial & Oral Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Periodontal Research, Journal of Periodontology, Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology).
The reference list of all identified studies and of relevant reviews was also scanned for possible additional studies. Online databases providing information about current in progress clinical trials were checked ( http://clinicaltrials.gov/ ; http://www.centerwatch.com/clinicaltrials/ ; http://www.clinicalconnection.com/ ). Manufacturing companies producing devices for concentrating platelets were contacted to identify ongoing or unpublished studies pertinent to this review.
All randomized clinical trials (RCTs) and controlled clinical trials (CCTs) assessing the efficacy of platelet concentrates for healing and regeneration of hard and soft tissues in patients undergoing dental extractions were included. All other types of study design, such as case series, case reports, technical reports, animal studies and reviews were excluded. No limitation was placed regarding the number of patients treated or the follow-up duration. Studies were included only if a test group using platelet concentrates was compared with a control group in which platelet concentrates were not used. Platelet concentrates could be used alone or in combination with other materials but they had to be the only difference between test and control.
The titles and abstracts of the retrieved articles were screened independently by two reviewers (MDF, MB) to identify all eligible studies apparently meeting the inclusion criteria. When the abstract was not available or did not provide sufficient data to allow unequivocal evaluation, the full text was obtained and checked. Publications that did not meet the selection criteria were excluded. Disagreements were resolved by discussion. The full text of all the eligible articles was obtained and the characteristics of the studies were examined by the reviewers to confirm study inclusion for data analysis or exclusion. Relevant data were extracted from the included studies and analysed.
The main outcome variable was healing process of the extraction socket. The outcome variables reported in each study for evaluating hard and soft tissue healing were examined. Patient-based variables related to aesthetics and postoperative discomfort (e.g. pain, swelling, infection, abscess), as well as any type of complication and adverse events, when reported, were also considered.
The methodological quality of the included studies was evaluated independently and in duplicate by two reviewers (MDF, MB) as part of the data extraction process. Included trials were assessed on three main quality criteria: sample size calculation; concealed allocation of treatment; completeness of information on reasons for withdrawal by trial group. Further secondary quality criteria were assessed, such as the randomization method (if applicable), the definition of exclusion/inclusion criteria, the comparability of control and treatment groups at entry, and the calibration and blinding of evaluator(s) for outcome assessment. All these criteria were judged as adequate/non adequate. The authors of the identified studies were contacted for clarification or to provide missing information whenever possible.
In order to summarize the validity of the studies, they were grouped into the following categories: low risk of bias if all main quality criteria were met (that is, they were judged adequate); moderate risk of bias if one of the main criteria was not met or if two criteria were not met but at least three of the secondary criteria were met; high risk of bias if none of the main criteria was met or if one main criteria and less than three secondary criteria were met. In case of discrepancy between the two reviewers, an agreement had to be obtained by discussion. Otherwise, a third reviewer was consulted (ST) until consensus was achieved by discussion.
Results
The electronic search provided 424 articles. One additional article was identified by hand searching. Figure 1 illustrates the selection process. After screening the titles and abstracts, 11 articles, reporting on 12 comparative studies assessing the effect of platelet concentrates on the treatment of extraction sockets were identified. After review of the full text, one article was excluded because platelet concentrate was used in both treatment groups, another article was excluded because data were reported inadequately, and a third article was excluded because the full text was unretrievable. Finally, eight articles reporting on nine comparative studies (six RCT and three CCT) fulfilled all inclusion criteria and were included in the present analysis. There was perfect agreement amongst reviewers throughout the article selection process.
Table 1 summarizes the main characteristics of the included studies. One article reported a hybrid split-mouth/parallel study design in which 20 patients, for whom a single extraction was indicated, were randomly assigned to either the test or the control group, whilst in three additional patients multiple extractions were planned in different mouth areas so that plasma rich in growth factors (PRGF) were used in one area but not in any other, therefore this article accounted for two studies. Overall, 207 teeth (104 tests and 103 controls) were extracted in 115 patients. In all studies, extraction sockets in the test group were filled with platelet concentrates, whilst sockets in the control group were left unfilled. No grafting material was used, except for the study by A nitua , in which PRGF was mixed with autologous bone to prevent tissue collapse in five patients. In the study by R utkowski et al. a resorbable porcine-derived gelatin sponge was used as a hemostatic filler in both groups. Follow-up duration varied according to the type of outcome evaluated.
| Author, publication year | Study design | No. patients | Mean age (range), y | No. teeth | Intervention | FU, weeks | ||
|---|---|---|---|---|---|---|---|---|
| Test | Ctr | Test | Ctr | |||||
| A nitua , 1999 | RCT (pa) | 20 | 41.5 (35–55) | 10 | 10 | PRGF ± ABG | None ± ABG | 10–16 |
| RCT (sm) | 3 | NR | 3 | 3 | PRGF | None | 10–16 | |
| S ammartino et al., 2005 | CCT (sm) | 18 | NR (21–26) | 18 | 18 | PRP | None | 18 |
| G ürbüzer et al., 2008 | RCT (sm) | 12 | 21.8 (NR) | 12 | 12 | PRP | None | 4 |
| V ivek and S ripathi R ao , 2009 | CCT (sm) | 10 | 27 (18–45) | 10 | 10 | PRP | None | 16 |
| A lissa et al., 2010 | RCT (pa) | 23 | 30.5 (20–52) | 15 | 14 | PRP | None | 12 |
| G ürbüzer et al., 2010 | RCT (sm) | 20 | 24.9 (NR) | 20 | 20 | PRF | None | 4 |
| M ozzati et al., 2010 | RCT (sm) | 16 | 22.5 (18–35) | 16 | 16 | PRGF | None | 1 |
| R utkowski et al., 2010 | CCT (sm) | 6 | NR (18–40) | 6 | 6 | PRP + Gelfoam ® | Gelfoam ® | 25 |
Table 2 summarizes the outcome variables, the methods and the main outcomes of the included studies. Six articles reported on the extraction of mandibular impacted third molars (152 teeth, of which 76 tests and 76 controls), whilst two articles reported on the extraction of various tooth types (55 teeth, of which 28 tests and 27 controls), extracted for different reasons. The articles provided a broad range of outcome variables to assess the regenerative potential of platelet concentrate and its possible benefits to the treatment.
| Author, publication year | Tooth type/reason for extraction | Outcome variables | Evaluation methods | Effect of platelet concentrate |
|---|---|---|---|---|
| A nitua , 1999 | Various tooth types/untreatable tooth with vertical fracture or severe periodontal disease | Soft tissue healing Hard tissue healing | Clinical assessment Histological analysis |
Positive (in PRGF group better epithelialization, more mature bone and better organized trabeculae than controls) |
| S ammartino et al., 2005 | Mandibular third molars/impaction | Soft tissue healing Hard tissue healing |
Clinical assessment of periodontal parameters in the distal site of adjacent 2nd molars Radiological analysis (panoramic and periapical x-rays) Histological analysis only in test sites |
Positive (in test sites PD and PAL improved more than control sites; no difference for gingival recession and bleeding) |
| G ürbüzer et al., 2008 | Mandibular third molars/impaction | Hard tissue healing | Static phase scintigraphic evaluation of early osteoblastic activity (as compared with activity from normal calvaria bone) | None |
| V ivek and S ripathi R ao , 2009 | Mandibular third molars/impaction | Soft tissue healing Hard tissue healing Post-op quality of life |
Clinical assessment Soft tissue healing index of L andry et al. Radiological analysis (periapical X-rays) VAS for pain evaluation |
Positive (in PRP group less pain, better soft tissue healing and accelerated bone formation) |
| A lissa et al., 2010 | Various tooth types/mostly caries (60.9%) and endodontic failure (21.7%) | Incidence of complications Soft tissue healing Hard tissue healing Post-op quality of life |
VAS for pain evaluation; 1-week questionnaire for swelling, bruising, bleeding, bad taste, food stagnation, satisfaction, analgesics taken Socket complications: alveolar osteitis, infection, inflammation Soft tissue healing index of L andry et al. Radiological analysis (periapical X-rays) |
Positive (in PRP group less pain and analgesic consumption in the first 2–3 days, less complications and improved hard and soft tissue healing) |
| G ürbüzer et al., 2010 | Mandibular third molars/impaction | Hard tissue healing | Static phase scintigraphic evaluation of early osteoblastic activity (as compared with activity from normal calvaria bone) | None |
| M ozzati et al., 2010 | Mandibular third molars/impaction | Post-op quality of life Tissue markers of wound healing and inflammation |
Evaluation of pain on a VAS scale and facial swelling Real-time PCR for IL-1β, IL-6, IL-10, TGF-β, BMP-4, BMP-7, PPAR-β, collagen type I and type III |
Positive (reduced post-op pain and swelling; accelerated inflammatory response) |
| R utkowski et al., 2010 | Mandibular third molars/impaction | Post-op quality of life Hard tissue healing |
Self-evaluation (pain on a VAS scale, temperature, oedema, bleeding and numbness) Observer evaluation (dehiscence, bleeding, inflammation, facial oedema and pain on a VAS scale) Radiographic bone density change with CT Scan (on three patients), plus periapical X-rays |
Positive for bone density in the early 2 weeks but null for post-op pain, bleeding, numbness |
Soft tissue healing
The extent of soft tissue healing 1 week after tooth removal was evaluated in two studies using the healing index of L andry et al. , assessing colour of tissues, epithelialization of wound margins, presence of bleeding on palpation, granulation and suppuration. A significant difference favouring the use of platelet-rich plasma (PRP) was found in both studies.
Hard tissue healing
In two studies, G ürbüzer et al. evaluated bone healing using bone scintigraphy, finding a positive but not significant effect of platelet concentrates on osteoblastic activity after 4 weeks of healing.
In the study by A lissa et al. , two methods of radiographic assessments were carried out. A subjective radiographic evaluation 3 weeks after surgery revealed a significant difference between test and control group favouring the use of PRP. The automated texture analysis of radiographs with specific software revealed a general trend for PRP-treated sockets to have more, longer, wider and closer trabeculae and a higher bone volume than the control sockets, but these differences did not reach statistical significance.
Postoperative quality of life
Pain levels were assessed daily during the first week after surgery, by means of a visual analogue scale (VAS). M ozzati et al. and A lissa et al. recorded less pain in platelet concentrate-treated sockets at the seventh postoperative day and at the first, second and third days, respectively, whilst no statistically significant difference was found between test and control sites in two other studies .
Platelet concentrates were also correlated with reduced analgesic consumption, fewer bad tastes or bad smells in the mouth and food stagnation in the operation area, less incidence of complications and less swelling .
Other variables
M ozzati et al. in a split-mouth study comparing PRGF to control, evaluated the changes of the tissue levels of several cytokines involved in the inflammatory process, as well as growth and differentiation factors level, in the first week post-extraction, using real-time polymerase chain reaction (rtPCR). PRGF was more effective on all parameters examined, suggesting it is related to an acceleration of the healing process.
Methods for platelet concentrates preparation
Table 3 summarizes the main characteristics of the procedures for preparing the platelet concentrate in the included studies. A variety of techniques has been adopted. Few studies reported the actual increase of platelet concentration obtained after centrifugation.
| Author, publication year | Centrifugation system, manufacturer | Volume of blood drawn, ml | Anticoagulant solution | Centrifugation parameters: No. speed, time | Increase of platelet concentration from baseline | Activator |
|---|---|---|---|---|---|---|
| A nitua , 1999 | PRGF System ® , BTI Biotechnology Institute, Vitoria, Alava, Spain | 10–20 | 10% trisodium citrate | 1×, 160 g; 6 min | 2–3 fold | Calcium chloride |
| S ammartino et al., 2005 | NR | 40 | 10% trisodium citrate | 1×; 1200 rpm; 15 min | NR | Batroxobine + calcium gluconate |
| G ürbüzer et al., 2008 | Curasan PRP Kit, Curasan, Pharma Gmbh AG, Lindigstrab, Germany Bench-top centrifuge (Heraeus Labofuge 300, Thermo Scientific, Frankfurt, Germany) |
16 | Citrate phosphate dextrose | 1°: 2400 rpm; 10 min 2°: 3600 rpm; 15 min |
6.8 ± 2.3 (SD) fold | Calcium chloride |
| V ivek and S ripathi R ao , 2009 | NR | 10 | 10% trisodium citrate | 1°: 1000 rpm; 10 min 2°: 1500 rpm; 10 min |
NR | Calcium chloride |
| A lissa et al., 2010 | PCCS™ II, 3i Implant Innovations, Palm Beach Gardens, Florida, USA Bench-top centrifuge (IEC Model I-703A, International Equipment Company, Needham Heights, MA, USA) |
27 | Citrate dextrose | 1×; 3200 rpm; 12 min | NR | Autologous thrombin |
| G ürbüzer et al., 2010 | Bench-top centrifuge (Universal 320, Hettich, Tuttlingen, Germany) | 10 | None | 1×; 400 g (2030 rpm); 10 min | NR | None |
| M ozzati et al., 2010 | PRGF System ® , BTI Biotechnology Institute, Vitoria, Alava, Spain | 10–20 | 10% trisodium citrate | 1×; 1800 rpm; 8 min | NR | Calcium chloride |
| R utkowski et al., 2010 | NR | 9 | 10% trisodium citrate | 1×; 1150 g; 10 min | NR | NR |
Quality assessment
Table 4 shows the results of the quality assessment for the included studies. Seven studies were classified at moderate risk of bias, one study at high risk and one study at low risk.
| Author, publication year | Study type | Sample size calculation | Concealed allocation of treatment | Complete-ness of data reported | Randomization method | Clear inclusion and exclusion criteria | Compara-bility of groups at entry | Calibration/blinding of assessors | Risk of bias |
|---|---|---|---|---|---|---|---|---|---|
| A nitua , 1999 | RCT (pa) | 0 | 0 | 1 | 1 | 1 | 1 | 1 | M |
| RCT (sm) | 0 | 0 | 1 | 1 | 1 | 0 | 1 | M | |
| S ammartino et al., 2005 | CCT (sm) | 0 | NA | 1 | NA | 1 | 1 * | 1 | M |
| G ürbüzer et al., 2008 | RCT (sm) | 0 | 0 | 1 | 1 | 1 | 1 † | 1 | M |
| V ivek and S ripathi R ao , 2009 | CCT (sm) | 0 | NA | 1 | NA | 1 | 0 | 0 | H |
| A lissa et al., 2010 | RCT (pa) | 1 | 1 | 1 | 1 | 1 | 1 | 1 | L |
| G ürbüzer et al., 2010 | RCT (sm) | 0 | 0 | 1 | 1 | 1 | 1 † | 1 | M |
| M ozzati et al., 2010 | RCT (sm) | 0 | 0 | 1 | 1 | 1 | 1 † | 0 | M |
| R utkowski et al., 2010 | CCT (sm) | 0 | NA | 1 | NA | 1 | 0 | 1 | M |
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