The current literature was reviewed to evaluate the effect of autologous plasma concentrates on the preservation of extraction sockets. A comprehensive literature search was performed from October 2013 to February 2014 in the MEDLINE/PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Four studies, published between the years 2010 and 2013, met the eligibility criteria and were included in the review. There were 102 extractions (55 tests, 47 controls) in 82 patients. There was considerable heterogeneity between studies with regard to the design, follow-up time, surgical techniques, and method of preparation of plasma concentrates, and therefore the data could not be analyzed quantitatively. The use of plasma concentrates seems to accelerate healing and soft tissue epithelialization in extraction sockets and reduce postoperative pain and discomfort. However, there is no evidence to date to confirm that plasma concentrates improve hard tissue regeneration.
Socket preservation procedures should be performed at the time of extraction to minimize resorption of external tissues and maximize bone formation inside the socket. The preservation of the ridge after tooth extraction is fundamental to the success and predictability of treatments that include dental implants. Tissue loss after extraction is physiological, progressive, and more marked during the first 3–6 months, and is followed by less intense resorption thereafter. Two recent systematic reviews on dimensional changes in soft and hard tissues showed that changes in thickness are usually greater than those in height. In addition, the buccal wall is usually more affected than the lingual wall, and the mandible tends to undergo greater resorption than the maxilla.
Several grafting techniques and materials combined or not with biological barriers have been suggested to reduce ridge changes after extractions. Although several of these techniques and materials may limit or reduce resorption, the quality of the newly formed tissue inside the extraction socket may vary widely.
Recently, the use of plasma-rich growth factor (PRGF) has been recommended for tissue regeneration in oral surgeries. Some studies have described the potential of plasma concentrates rich in growth factors to stimulate soft and hard tissue repair and regeneration and to reduce inflammation and the consequent pain and discomfort. Important factors and cytokines, such as platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), and platelet-derived endothelial growth factor (PDEGF), are released during the preparation of plasma concentrates. These factors, also found in tissues during natural healing, are responsible for the regulation of cell events, such as induction, proliferation, differentiation, chemotaxis, and the synthesis of the extracellular matrix, which accelerates mitosis, osteoblast proliferation, vascularization, and collagen synthesis. As plasma concentrates are autologous and easily obtained at a relatively affordable cost, they have been used increasingly for the preservation of extraction sockets.
A systematic review of the literature on the effects of autologous platelet concentrates for alveolar socket preservation was conducted.
Materials and methods
Development of a protocol
The method used in this systematic review was adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the guide prepared by Needleman. Clinical questions were formulated and organized according to the PICO framework for evidence-based practice.
The focused question was ‘What is the effect of autologous platelet concentrates for alveolar socket preservation using autologous plasma concentrates when compared with natural (spontaneous) socket healing?’
The search strategy was based on the PRISMA guidelines ( www.prisma-statement.org ). A broad electronic search was performed from October 2013 to February 2014 in the database of the National Library of Medicine, Washington, DC (MEDLINE/PubMed) and the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant publications in indexed journals. The electronic search followed the strategy shown in Table 1 .
|Focus question||What is the effect of autologous platelet concentrates for alveolar socket preservation using autologous plasma concentrates when compared with spontaneous socket healing?|
|Population||(1) MeSH terms: extraction socket OR tooth extraction socket OR post-extraction socket OR alveolar socket
Text words: fresh extraction socket
|Intervention||(2) MeSH terms: socket preservation OR extraction socket preservation OR platelet growth factors OR platelet rich plasma OR platelet rich fibrin
Text words: PRP OR PRF OR L-PRP OR L-PRF OR PRGF
|Outcomes||(3) MeSH terms: extraction socket healing OR wound healing OR bone healing OR tissue healing OR dimensional change
Text words: dimensional changes OR socket dimensional changes
|Search combination||1 AND 2 AND 3|
|Electronic databases||MEDLINE/PubMed and Cochrane Central Register of Controlled Trials (CENTRAL)|
|Inclusion criteria||• RCTs, CCTs, and prospective cohort studies with a control group
• Studies that conducted quantitative or qualitative analysis of bone changes and soft tissues by means of clinical or radiographic follow-up for at least 2 months
• Population: partially edentulous humans
• No restriction on age or number of patients
• Healthy individuals (no systemic diseases)
• Intervention: treatment to preserve the extraction socket using autologous plasma concentrates (PRP or PRF)
• Comparison: no biomaterial in the control group; only clot in the socket
• Outcome: dimensional changes of soft and hard tissues
|Exclusion criteria||Studies in animals, case reports, case series, retrospective studies, technique descriptions, and narrative reviews, as well as studies that included the extraction of third molars or the immediate placement of implants|
Screening and selection
Human studies (partially edentulous patients), published in English, including randomized clinical trials (RCTs), controlled clinical trials (CCTs), and prospective cohort studies with a control group, were included in this review. In addition, studies that conducted quantitative or qualitative analysis of bone and soft tissue changes by means of clinical or radiographic follow-up for at least 2 months were also included in the present study.
Studies in animals, case reports, case series, retrospective studies, technique descriptions, and narrative reviews, as well as studies that included the extraction of third molars or the immediate placement of implants, were excluded.
The screening of titles and abstracts for potential inclusion in the review was undertaken by the two reviewers independently. Selected full studies were read carefully and analyzed for the eligibility criteria (inclusion/exclusion) and planned data extraction. Differences between reviewers were resolved by discussion and consensus.
Assessment of heterogeneity
The heterogeneity of the primary results of the studies included in this review was evaluated according to the following factors: study design, follow-up time, number, age, and gender of participants, extraction site, extraction method and intervention, evaluation method, and statistical analysis.
The methodological quality of each study was assessed according to the criteria suggested by Van der Weijden et al., which combine the criteria described in the PRISMA statement, the CONSORT statement, the MOOSE statement, and the STROBE statement, and those in the studies conducted by Moher et al., Esposito et al., and Needleman. The following criteria were used to define the risk of bias: (1) randomized distribution; (2) inclusion and exclusion criteria to select patients; (3) examiner and patient randomization; (4) balanced experimental groups; (5) identical treatment in all groups, except for the intervention; and (6) information about follow-up. When all criteria were met, the risk was classified as low, if any one of these criteria was not met, the risk was classified as moderate, and if two or more criteria were not met, the risk was classified as high.
After analysis of the selected studies, data on dimensional (vertical and horizontal) changes of the soft and hard tissues were collected. Mean results and their standard deviations were recorded when available in the studies. Other data, such as postoperative complications, healing, and analysis of newly formed tissues, were also collected.
The analysis of the studies included revealed great heterogeneity in design. Therefore, a quantitative analysis followed by meta-analysis could not be conducted. A descriptive analysis was thus performed.
The initial search yielded 259 titles in MEDLINE/PubMed and 42 in the Cochrane Central Register of Controlled Trials ( Fig. 1 ). After the first evaluation, 14 potential studies were selected. Of these 14 studies, 10 were excluded because they did not meet the eligibility criteria. Reasons for exclusion are shown in Table 2 . Four prospective studies published between 2010 and 2013 were included in this systematic review.
|Reason for exclusion||Authors|
|Extraction of impacted mandibular third molars||Sammartino et al.
Gürbüzer et al.
Gawande and Halli
Vivek and Sripathi Rao
Gürbüzer et al.
Mozzati et al.
Rutkowski et al.
Célio-Mariano et al.
|Growth factors associated with autologous bone or others biomaterials||Anitua|
|No control group||Simon et al.|
Assessment of heterogeneity
Preliminary examination of the selected studies revealed considerable heterogeneity. The study characteristics are shown in Table 3 .
|Authors, year||Title||Design and evaluation time||Subjects (sites), gender, mean age (range)||Interventions (sites)|
|Alissa et al. , 2010||The influence of platelet-rich plasma on the healing of extraction sockets: an explorative randomised clinical trial||RCT
|n = 23 (23)
8 M/15 F
30.5 (20–52) years
|Farina et al. , 2013||Plasma rich in growth factors in human extraction sockets: a radiographic and histomorphometric study on early bone deposition||CCT
|n = 28 (36)
13 M/15 F
55.2 (34–74) years
|Suttapreyasri and Leepong , 2013||Influence of platelet-rich fibrin on alveolar ridge preservation||CCT
|n = 8 (20)
3 M/5 F
22.6 (20–27) years
|Hauser et al. , 2013||Clinical and histological evaluation of post-extraction platelet-rich fibrin socket filling: a prospective randomized controlled study||RCT
|n = 23
9 M/14 F
47 (22–75) years
|Anti-inflammatory as needed||Clinical and radiographic||Incidence of socket complications
Post-operative quality of life
Soft tissue healing
Hard tissue healing
|This study suggested that PRP may have some additional benefits in reducing healing complications and improving healing of soft tissue of extraction sockets. It remains unclear whether the use of PRP in post-extraction sites can promote bone healing.|
|Chlorhexidine gluconate 0.12% for 7 days||Micro-CT and histological||Hard tissue healing||The plasma rich in growth factors (PRP) treated group did not show any enhancement in early (4 and 8 weeks) bone deposition compared to the control group.|
|NR||Clinical, model casts, and radiographic||Soft tissue healing
Hard tissue healing
|The preliminary results of this study demonstrated neither better alveolar ridge preservation nor enhanced bone formation of PRF in the extraction socket. The use of PRF revealed limited effectiveness by accelerated soft tissue healing in the first 4 weeks.|
|Anti-inflammatory (number of days not reported)||Micro-CT, nano-indentation test, clinical, and radiographic||Hard tissue healing||The results of this study indicated that the use of PRF membranes to fill the socket after tooth extraction leads to improved alveolar bone healing with a better preservation of the alveolar crest width.|
Assessment of quality
The analysis of quality is shown in Table 4 . Two studies had a high level of evidence and low risk of bias. One study had a moderate risk of bias and the other study a high risk of bias.
|Validity/quality criteria||Alissa et al.||Farina et al.||Suttapreyasri and Leepong||Hauser et al.|
|Representative population group||Yes||Yes||Yes||Yes|
|Eligibility criteria defined||Yes||Yes||Yes||Yes|
|Blinded to the patient||ND||No||No||ND|
|Blinded to the examiner||Yes||Yes||ND||Yes|
|Blind during statistical analysis||ND||ND||ND||ND|
|Reported loss to follow-up||Yes||Yes||ND||Yes|
|No. (%) of dropouts||7 (30.4%)||0||0||1 (4.34%)|
|Treatment identical, except for intervention||Yes||Yes||Yes||Yes|
|Sample size calculation and power||Yes||ND||ND||ND|
|Point estimates presented for primary outcome||Yes||Yes||Yes||Yes|
|Measures of variability for the primary outcome||Yes||Yes||Yes||Yes|
|Intention to treat analysis||ND||ND||ND||ND|
|Study design||RCT (parallel)||CCT (parallel)||CCT (split-mouth)||RCT (parallel)|
|Calibration of examiner||ND||ND||ND||ND|
|Reproducibility data shown||No||No||No||No|
|Reason for extraction||Root fracture, caries, periodontal disease, endodontic failure, orthodontic reason||Root fracture, caries, periodontal disease, endodontic failure||Requiring extraction||Root fracture, caries, periodontal disease, endodontic failure|
|Estimated potential risk of bias||Low||Moderate||High||Low|
Study design and study population
Two studies were RCTs and two were CCTs ; three were parallel-group studies, and one had a split-mouth design. The duration of follow-up was at least 2 months in all studies. The number of participants ranged from eight to 28 ; their mean age was 38.8 years (range 20–75 years), and 40.2% ( n = 33) were male. There were 102 extractions (55 tests and 47 controls) in 82 subjects.
Extraction and intervention type and reason
One study performed extractions with flaps. Another study performed two types of extraction, one with and one without a flap. For all studies, the authors reported that the sockets were debrided carefully after extraction to remove granulation tissue before closing or using plasma concentrates. All sockets corresponded to molars or premolars that had an indication for extraction. Antibiotics were not prescribed in any study. Two studies used platelet-rich plasma (PRP) in the test group, and two used platelet-rich fibrin (PRF).
Evaluation method and study outcome
The patients in the studies included in this review underwent clinical, histological, and radiographic tests. The evaluation methods used and results are shown in Table 5 .
|Authors||Outcome||Measurement method||Effect of PRP/PRF a||P -value b|
|Alissa et al.||Incidence of socket complications||Criteria of Cheung and Griffin||Sig.||0.06|
|Postoperative quality of life||Health-related quality of life questionnaire||Non-sig.||0.22|
|Soft tissue healing||Healing index of Landry et al.||Sig.||0.03|
|Hard tissue healing||Standardized peri-apical radiographs||Sig.||0.01|
|Farina et al.||Bone volume||Micro-CT||Non-sig.||0.792|
|Tissue mineral content||Micro-CT||Non-sig.||0.662|
|Tissue mineral density||Micro-CT||Non-sig.||0.429|
|Mean number of CD68+ stained cells||Histomorphometric||Non-sig.||0.792|
|Mean area of CD68+ staining||Histomorphometric||Non-sig.||0.662|
|Mean number of von Willebrand factor-positive stained cells||Histomorphometric||Non-sig.||0.792|
|Mean area of von Willebrand factor positive staining||Histomorphometric||Non-sig.||0.792|
|Mean osteocalcin staining score||Histomorphometric||Non-sig.||0.247|
|Suttapreyasri and Leepong||Dimensions of the socket orifice (M–D)/(B–L)||Periodontal probe||Non-sig.||>0.05|
|Alveolar ridge contour change||Model casts||Sig.||0.031|
|Radiographic resorption of marginal bone levels (M–D)||Standardized peri-apical radiographs||Non-sig.||>0.05|
|Hauser et al.||Bone volume to total volume||Micro-CT||PRF-flapless Sig.
|Trabecular number||Micro-CT||PRF-flapless Sig.
|Trabecular thickness||Micro-CT||PRF-flapless Non-sig.
|Trabecular separation||Micro-CT||PRF-flapless Sig.
|Elastic modulus||Nano-indentation test||PRF-flapless Sig.
|Working energy||Nano-indentation test||PRF-flapless Sig.
|Tissue hardness||Nano-indentation test||PRF-flapless Non-sig.
|Alveolar width at 4 mm apical to the crest||Calliper||PRF-flapless Sig.
|Alveolar height (M–D)||Standardized peri-apical radiographs||PRF-flapless Sig.
Soft tissue healing
Soft tissue healing was evaluated in two studies. One study used the soft tissue healing index described by Landry et al., which includes tissue colour, bleeding, alveolar ridge epithelialization, and the presence of granulation tissue or suppuration. A statistically significant difference favouring the use of PRP was found ( P = 0.03). The other study evaluated soft tissue healing by measuring the width of the socket ridge mesiodistally (M–D) and buccolingually (B–L) using a periodontal probe. Immediately after extraction, mean measures in the PRF group were M–D 4.79 ± 0.59 mm and B–L 7.38 ± 1.12 mm, and in the control group were M–D 4.70 ± 1.09 mm and B–L 7.61 ± 1.12 mm. Eight weeks after extraction, ridge healing was slightly better in the PRF group (M–D 1.76 ± 1.36 mm, B–L 3.31 ± 0.9 mm) than in the control group (M–D 2.17 ± 1.65 mm, B–L 3.92 ± 0.64 mm), however this was not statistically significant.
Postoperative health-related quality of life index
One study used a questionnaire in the first week after extraction to evaluate patient perceptions of pain, oral function, general activities, and other symptoms. Pain was statistically less intense in the first 3 days in the PRP group. Moreover, the patients in the test group needed less analgesic medication than those in the control group in the first week. Patients treated with PRP also reported less bad taste in the mouth, less halitosis, and a lower accumulation of food in the operated region because there was a biological barrier in the socket. However, other events under analysis, such as speech, sleep, and daily activities, were not statistically different between the groups.
Hard tissue healing
One study analyzed horizontal changes before and after 8 weeks of follow-up using a calliper clamp positioned in the oral region of the socket at about 4 mm below the gingival margin. The PRF-flapless group had less bone resorption (0.06 mm) than the PRF-flap group (0.42 mm) or the control group (0.43 mm; P < 0.05). The analysis of vertical changes using standardized peri-apical radiographs revealed that the control group had a greater bone loss ( P < 0.05) in the mesial (M −0.77 ± 0.17 mm) and distal (D −2.07 ± 0.81 mm) regions than the PRF-flapless (M −1.21 ± 0.40 mm; D −0.76 ± 0.25 mm) and PRF-flap (M −0.86 ± 0.34 mm; D −2.15 ± 1.05 mm) groups, which indicated that PRF prevented bone resorption. Alissa et al. evaluated standardized peri-apical radiographs using specialized software (Win TAS software, Steve Paxton, UK) and reported that there was more trabecular bone and greater bone volume in the test group (PRP) than in the control group at the 3-month follow-up, which indicated that PRP had a positive effect. Suttapreyasri and Leepong also evaluated vertical bone resorption in the mesial and distal regions using peri-apical radiographs, but did not find any statistical differences between the PRF (M 0.70 mm; D 1.23 mm) and the control (M 1.33 mm; D 1.14 mm) groups at 8 weeks of follow-up ( P > 0.05).
Horizontal changes of combined hard and soft tissues
One study assessed the horizontal changes in soft and hard tissues of the socket ridge by analyzing study models. In both groups evaluated, the contraction of buccal tissues started in the first week after extraction, whereas changes in lingual tissues started only in the second week. Buccal changes were more marked than lingual changes. Eight weeks after extraction, buccal (B) and lingual (L) tissues in the PRF group (B 1.96 ± 1.10 mm; L 1.59 ± 0.64 mm) had fewer dimensional changes than those in the control group (B 2.59 ± 0.7 mm; L 1.78 ± 0.47 mm).
One study conducted an immunohistochemical analysis of vascular and endothelial cells (von Willebrand factor), osteoblast activity, and immunological cells. Although the test group had a greater number of CD68+ cells (giant multinucleated cells, macrophage fusion) and a higher von Willebrand factor, the difference between groups at 8 weeks was not statistically significant. The amount of osteocalcin, a protein associated with osteoblast activity, was similar in the test and control groups at all follow-up times.
The volume and amount of newly formed bone were analyzed using micro-CT in two studies. Farina et al. did not find any statistically significant differences in bone volume or the amount and density of mineral tissue between the test and control groups at 8 weeks. In contrast, Hauser et al. found significantly greater bone volume in the PRF-flapless group than in the PRF-flap and the control groups. The authors also found that the PRF-flap group had lower bone volume than the other groups.
Methods for platelet concentrate preparation
The studies used different methods to prepare plasma concentrates. Table 6 summarizes the methods used in the studies included in this review.