Randomized and Controlled Clinical Trial of Bone Healing After Alveolar Ridge Preservation Using Xenografts and Allografts Versus Plasma Rich in Growth Factors

The implant is currently accepted as the preferred treatment option for tooth replacement, and long-term success after implant therapy requires maintaining a sufficient amount of alveolar bone volume. More recently, dental implantology has shifted from implant placement in a fully healed bone to treatment protocols that reduce overall treatment time, such as immediate implant placement.¹  In their systematic review, Tan et al²  assessed postextraction alveolar ridge dimensional changes.²  In that review, different studies showed that vertical hard-tissue resorption was 11%–22% with horizontal bone loss of 29%–63%, whereby two-thirds of the tissue was lost during the first 3 months after tooth extraction.^3–6  Bone resorption is greater on the buccal bone plate and results in the palatal/lingual shift of the alveolar crest, especially in the thin periodontal biotype.⁷  The more pronounced resorption of the buccal alveolar plate could be related to its lower thickness and the fact that it is composed mostly of bundle bone.^8–10  Bundle bone is a tooth-dependent structure and is lost after tooth removal. Thus, several alveolar ridge-preservation techniques have been proposed for preserving the alveolar ridge dimensions.^3,4  Both alveolar ridge preservation and the quality of regenerated bone are factors that may affect the long-term success of implant-supported rehabilitation.¹¹  Although the dimensions of alveolar bone are important for a proper 3-dimensional position of the implant, the quantity of newly regenerated bone is related to successful osseointegration and long-term stability of dental implants.^11,12 

Many different bone-grafting materials have been proposed for alveolar ridge preservation.^13–15  Jung et al¹⁶  suggested a clinical decision tree for alveolar ridge preservation in the esthetic zone and proposed preservation of the extraction socket in clinical cases with more than 50% of the buccal bone present. Meanwhile, in cases of severe bone loss (more than 50%), researchers have suggested performing a guided bone-regeneration procedure. With regard to the definition of terms, there are 2 different approaches to maintaining the alveolar ridge profile: maintaining alveolar ridge dimensions (socket preservation) and increasing the ridge volume (guided bone regeneration).¹⁷  Although there are many studies investigating postextraction dimensional changes of the socket and the quality of regenerated bone, the ideal bone socket preservation technique is still unknown. Ideal bone-grafting material should possess properties of osteoinduction, osteoconduction, and osteogenesis. However, only autologous bone demonstrates all of these properties. However, limitations such as the risk of donor site morbidity, limited availability, and unpredictable resorption¹⁸  have led to a search for alternatives in bone regeneration.

One alternative to promote bone healing is the use of biological mediators such as autologous platelet concentrates. The activation of platelets and leukocytes results in the massive release of autologous growth factors and cytokines, which accelerates cell growth and differentiation.^19,20  Many studies have stated that plasma rich in growth factors (PRGF) improves the tissue-healing process.^19–22  Some authors have proposed the elimination of leukocytes from platelet concentrates, which help to eliminate metalloproteinases that are destructive for growth factors.^21,22  The technology behind PRGF is different from other platelet products that have proposed the absence of leukocytes.²²  Because PRGF is a source of growth factors, it can serve as a scaffold to stimulate tissue healing at the same time.²³  Using PRGF also initiates the formation of the cross-linked fibrin network, which maintains and facilitates the application of bone-grafting materials. Furthermore, it stimulates neoangiogenesis and tissue formation.²⁴ 

However, there is a lack of randomized clinical trials comparing the use of platelet concentrates without leukocytes to other biomaterials for alveolar ridge preservation in the anterior maxilla.

Hence, the aim of this study is to assess new bone formation during alveolar ridge preservation with PRGF, human heterologous bone substitute, and anorganic bovine bone. This has been controlled by spontaneous alveolar bone healing after tooth extraction. The null hypothesis of this study is that the formation of new mineralized tissue after 3 months of healing will not be affected by the type of biomaterial/graft used to fill the extraction socket.

A randomized controlled parallel-design study was conducted between January 1, 2018, and June 2019 at the Department of Maxillofacial Surgery, Lithuanian University of Health Sciences, Lithuania. The trial followed the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) statement.²⁵  The risk of therapy and the study protocol were discussed with all patients prior to enrollment. The patients were fully aware of the study procedures and signed the informed consent before starting the study. The study followed the principles outlined in the Helsinki Declaration of 1975, as revisited in 2000, on clinical research involving human subjects. The study received the approval of the Lithuanian bioethics committee (protocol no. BE-2-27).

Inclusion criteria consisted of the following:

• age ≥18 and ≤65 years,

• good general health,

• successful delivery of signed informed consent,

• extraction of at least 1 asymptomatic single rooted tooth in the anterior maxilla, and

• the presence of more than 50% of the buccal bone height.

Exclusion criteria were as follows:

• uncontrolled diabetes,

• irradiation in head and neck area,

• immunodeficiency diseases,

• systemic health problems,

• pregnant and lactating women,

• history of bisphosphonate therapy,

• smoking more than 10 cigarettes per day, and

• presence of uncontrolled or untreated periodontal disease, periapical lesions, and soft-tissue pathology.

A total of 48 patients were assessed for eligibility, of whom 3 refused to participate in the study and were excluded. A total of 45 patients participated in the study and underwent extraction of 1 tooth the in esthetic area in the maxillae. After 12 weeks of healing, 3 patients (1 patient in each of the BBM/CM, FDBA/CM, and PRGF groups, respectively) missed the appointment, whereas 2 patients allocated to the control group had an insufficient amount of alveolar ridge for bone biopsy. A total of 40 patients were included (Figure 1). Computer-generated randomization schedules were generated following the block randomization method. The randomization codes were placed in sealed, nontransparent envelopes. Patient allocation to each group was revealed by an independent researcher (different from the surgeon), and blood samples were taken only from patients randomized to the PRGF group. The surgeon (A.S.) was unblinded to the allocated treatment only after finishing tooth extraction. The follow-up period was 12 months. Analysis of the variables of the study was carried out by the investigator, who was different from the individual who performed the interventions and was unaware of the treatment assignments.

A silicone key was prepared before tooth extraction. Local anaesthesia was achieved with articaine hydrochloride with epinephrine (1:100 000), and a single rooted tooth in the upper anterior maxilla was extracted using a minimally invasive flapless technique. For that procedure, the periotome tip was placed at the periodontal ligament space to mobilize the tooth.²⁶  Forceps were then used to remove the tooth out of the alveolar socket. The alveolar socket was properly curetted to remove granulation tissue, and the socket walls were inspected with a periodontal probe. If the socket walls were preserved (presence of more than 50% of the buccal bone height), the allocated treatment was applied. Afterward, the extraction sockets were randomly allocated to the following 4 treatment groups:

• Group I (control group): extraction socket healed by spontaneous healing

• Group II: extraction socket filled with natural bovine bone mineral (BBM; Cerabone, Botissdental GmbH, Berlin, Germany) and covered with resorbable native collagen membrane (Jason, Botissdental GmbH, Berlin, Germany) (BBM/CM)

• Group III: extraction socket filled with freeze-dried bone allograft (FDBA; Maxgraft, Botissdental GmbH, Berlin, Germany) and covered with resorbable native collagen membrane (Jason, Botissdental GmbH, Berlin, Germany) (FDBA/CM)

• Group IV: extraction socket filled with PRGF alone (Endoret, BTI Biotechnology Institute, Vitoria, Spain)

No extraction socket preservation was performed in the control group, and gingival tissues were sutured using a monofilament 5/0 Nylon suture to stabilize the blood clot. No attempt was undertaken to approximate the gingival margins.

Alveolar ridge preservation groups were treated as follows. In the BBM/CM and FDBA/CM groups, bone-grafting material was prepared according to the manufacturer's instruction, and the bone substitute was mixed with sterile saline solution and kept for 30 seconds. The socket was filled with bone substitute to the level of the bony plates. Native collagen membrane was adapted to the soft-tissue borders and was fixed with a single interrupted sutures.

For the PRGF group, the socket was filled with 2 PRGF clots prepared from F2 and covered with an autologous fibrin membrane prepared from F1. Finally, cross stitches were applied. The PRGF was prepared following the manufacturer's instructions (BTI Biotechnology Institute S.L, Vitoria, Spain). Citrated venous blood (4 tubes of 9 mL) was centrifuged in a BTI System IV centrifuge. Then, the plasma was fractioned to obtained fraction 1 (F1), the plasma column above the F2, and the fraction 2 (F2) defined as the 2 mL of plasma just above the buffy coat. For the activation of the coagulation cascade, 20 μL of 10% calcium chloride per each 1 mL of plasma was added.

All patients were instructed to rinse their mouth twice daily with 0.12% chlorhexidine–digluconate for the first 2 weeks postoperatively and refrained teeth brushing in the operated area. Removable prosthesis was not worn for the first 2 to 3 weeks. This prosthesis was corrected to avoid any pressure to the extraction socket. The sutures were removed after 14 days.

After 12 weeks of healing, the implant was placed. After local anaesthesia, the mucoperiosteal flap was raised and the regenerated bone identified. Guided by the silicone key, a bone core biopsy of regenerated tissue was taken at the central part of the extraction socket using a trephine drill (internal diameter 2.5–3.0 mm, 4- to 5-mm depth). The biopsy was placed into 4% buffered formalin. Subsequently, implant site preparation was completed, and the implant (Straumann; Straumann Group, Basel, Switzerland) was inserted according to the manufacturer's instruction.

After sample fixation in 4% buffered formalin, the samples were dehydrated in ascending concentrations of ethanol. Undecalcified samples were included in methyl methacrylate type resin and were subsequently cut with a motorized microtome. Finally, histological sections (5 μm in thickness with the same length as the biopsy) were prepared from the most central part of the biopsy and stained with hematoxylin–eosin and May Grünwald–Giemsa stains. Images were captured with the light microscope operating with and objective of 5×. A mosaic plug in of Image J software (National Institutes of Health, Bethesda, Md) were then used to generate an image of the entire histological section. The histomorphometric analysis was performed by an independent researcher (with more than 5 years of experience) blinded to the treatment groups and using Image J software (National Institutes of Health). The variables were the newly formed mineralized tissue, the newly formed nonmineralized tissue (NMT), and residual bone-grafting material. For the histological description, the biopsies were examined using a light microscope working with the objectives of 10×, 20×, or 40×.

The sample size was calculated based on a previous controlled clinical trial²³  in which a difference in new bone formation of 27% between extraction sockets healed spontaneously and those treated with PRGF. Considering a normal distribution with a standard deviation of 20%, to achieve such differences by means of a Student t test, with a power of 80% and a significance level of 5%, and assuming that the ratio of patients assigned to the PRGF group and to the control group was 1:1, in addition to 10% of dropouts, a total of 11 patients assigned to the control treatment and 11 patients assigned to the control group would be necessary. To achieve this, 22 more patients (11 for each group) were recruited for the BBM/CM and FDBA/CM groups.

An independent statistician performed the statistical analysis. Patient characteristics were compared between the study groups by 1-way analysis of variance (ANOVA) for continuous variables (post hoc analysis was performed with least significant difference [LSD]) and a chi-square test for categorical variables. The histological variables were assessed with 1-way ANOVA test and LSD as the post hoc test. The statistical significance was set at P < .05. All statistical analyses were performed using the SPSS v21.0 (SPSS Inc, Chicago, Ill).

The study population was composed of 48 patients. Eight patients were not eligible for participation: 3 patients missed the appointment at 12 weeks after tooth extraction, 2 patients had insufficient alveolar width for bone biopsy, and 3 failed to deliver the signed informed consent. Figure 1 shows the study flow chart. Table 1 presents the demographic data of the participants and extracted teeth.

Forty of the randomized 45 patients completed the study according to the study protocol. Two participants who were randomized to the spontaneous healing group (control) did not have enough alveolar width for a bone core biopsy to be taken, and 3 patients were not able to place the implant within the 12-week time frame after tooth extraction. In total, 40 bone core biopsies were taken with 10 regenerated bone biopsies in every group. No signs of complications were recorded, and none of the extraction sockets lost bone graft material. After 3 months of healing, bone samples were obtained and dental implants inserted in the optimal 3-dimensional position.²⁷ 

All samples were analyzed under light microscopy measuring remaining bone graft, NMT, and newly formed mineralized tissue ratios. Results of the histomorphometrical analysis are listed in Table 2. Representative histological images of each section are presented in Figure 2.

Histomorphometrically, the percentage of newly formed mineralized tissue was the highest in the PRGF group and amounted to 75.5% ± 16.3%. The mean amount of newly formed mineralized tissue in the control group (spontaneous healing) was 46.5% ± 15.2%. Meanwhile, the area of new mineralized tissue for the bone-grafting materials and ranged from 7.2% ± 8.6% for the FDBA/CM group and 20.3% ± 21.9% for the BBM/PRGF group.

Residual bone graft material occupied 45.0% ± 19% of the sample volume in the BBM/CM group as compared with the 38.5% ± 26.4% in the FDBA group. This difference was not statistically significant.

The average percentage of nonmineralized tissue ranged from 53.5% ± 15.2% in extraction sockets healed spontaneously (control group) as compared with 24.4% ± 16.3% in the PRGF group. The NMT occupied 34.7% ± 10.5% and 54.3% ± 18.5% of the biopsy in the BBM/CM and FDBA/CM groups, respectively (Figures 3 and 4).

Once the statistical analysis was performed, we observed significant differences between groups in new mineralized tissue formation (P = .000) and new nonmineralized tissue formation (P = .001). Thus, the null hypothesis (ie, the received treatments did not affect the outcome) could not be accepted. More exactly, after the application of the post hoc test, statistical differences were observed between the different groups in terms of new mineralized tissue formation: control/PRGF (P = .009), control/(BBM/CM) (P = .005), control/(FDBA/CM) (P = .002), PRGF/(BBM/CM) (P = .000), and PRGF/(FDBA/CM) (P = .000) groups. The new mineralized tissue formation was in the following order in the studied sample: PRGF > control > BBM > FDBA. The differences between the bone substitute groups were not statistically significant.

With regard to the nonmineralized tissue formation, the differences were statistically significant between the control/PRGF (P = .001), control/(BBM/CM) (P = .005), PRGF/(FDBA/CM) (P = .002), and (FDBA/CM)/(BBM/CM) (P = .016) groups. The differences were not statistically significant for control/(FDBA/CM) (P = .934) and PRGF/(BBM/CM) (P = .125). The new NMT formation was in the following order: control = FDBA/CM > BBM/FDBA > PRGF.

This randomized controlled clinical trial has assessed the efficacy of different biomaterials in alveolar ridge preservation as compared with PRGF and spontaneous healing in extraction socket management. The results of this randomized controlled clinical trial (RCT) indicate that PRGF is associated with significantly more new mineralized tissue formation than blood clot, heterologous bone graft, and xenograft. Extraction socket grafting with a bone substitute significantly reduced the amount of newly formed mineralized tissue. However, a regenerated bone core biopsy was not taken for 2 patients who were allocated to the control group because of insufficient alveolar ridge width. The more pronounced bone resorption in spontaneously healing sites was caused by bone remodeling, which starts rapidly after tooth extraction.^7,28–30  A systemic review²  that analyzed dimensional alveolar ridge changes after tooth extraction demonstrated 29%–63% of horizontal and 11%–22% of vertical bone loss within 6 months after tooth extraction. Therefore, to reduce alveolar ridge dimensional changes, the alveolar ridge preservation technique has been proposed.^3,4  With respect to implant outcomes in grafted sockets, a recently performed meta-analysis³¹  concluded that implants placed into grafted sockets have a similar survival rate and lower marginal bone loss as compared with nongrafted sites.

To promote bone and soft-tissue regeneration, a variety of growth factors or bone morphogenetic proteins (BMPs) have been used. BMPs stimulate the differentiation of osteoprogenitor cells into osteoblasts and are essential in bone formation.^32,33  However, BMPs are difficult to use because of possible immunologic response, high cost, and insufficient scientifically based evidence.^34,35  To overcome these limitations, autologous platelet-derived growth factors (PDGFs) that are involved in tissue regeneration were used. The application of autologous platelet concentrates is a common treatment in dentistry. Previously published studies revealed its role in reducing tissue inflammation, promoting tissue regeneration, and increasing vascularization of bone tissue.³⁶  A great amount of growth factors is released from platelets after their activation, including PDGF, transforming growth factor (TGF)–β, vascular endothelial growth factor, and epidermal growth factor (EGF). Growth factors are a set of biologically active proteins that play an important role in the coordination of tissue regeneration: PDGF is known to have a strong mitogenic effect on stem cells and osteoblasts and accelerates bone maturation,^37,38  TGF is responsible for extracellular matrix development,³⁹  VEGF stimulates angiogenesis and blood vessel ingrowth,⁴⁰  and EGF stimulates fibroblasts and osteoprogenitor cell differentiation into osteoblasts.⁴¹  Furthermore, fibrin facilitates cell attachment, spreading, and proliferation and serves as a conductive scaffold for defect bridging. It also actively participates in angiogenesis through the stimulation of endothelial cell spreading, proliferation, and capillary tube formation.⁴²  All of these biological factors have a positive effect on the regenerative capacity of the organism and bone regeneration. A recently performed systematic review analyzing the effect of leucocytes included in platelet concentrates concluded that leucocytes are responsible for the prolonged inflammation phase and less effective cell migration, proliferation, and differentiation.⁴³  PRGF technology proposes the elimination of leukocytes with the aim of avoiding proinflammatory effects caused by white blood cells.²²  A positive effect on the bone regeneration and vascularization process using PRGF was demonstrated in a study performed by Anitua et al,²⁰  which showed an increase in newly formed mineralized tissue formation and enhanced vascularization process (116 blood vessels per 1 mm² of connective tissue in the PRGF group vs 7 blood vessels in the control group).

Histological analysis showed the presence of new bone formation in all biopsies. Histomorphometric evaluation revealed a significant difference between the extraction sockets preserved with PRGF and spontaneously healed sockets (control group). Our study demonstrated 75.5% ± 16.3% of newly formed mineralized tissue in the PRGF group vs approximately 46.4% ± 15.2% in the control group. These results were in agreement with a study by Hauser et al,⁴⁴  in which extraction sockets preserved with platelet-rich fibrin demonstrated improved bone healing as compared with sockets without preservation. A systemic review⁴⁵  analyzing the effect of autologous platelet concentrates for alveolar socket preservation demonstrated that PDGFs improved bone healing but also the acceleration and gain of soft tissue. Temmerman et al⁴⁶  reported that the use of leukocytes and platelet-rich fibrin significantly increased the percentage of newly formed mineralized bone (94.7%) as compared with natural healing (63.3%) 3 months after tooth extraction. Carmagnola et al⁴⁷  investigated sockets healed spontaneously 1 year after extraction and revealed fully healed mineralized bone and bone marrow. These findings suggest that PRGF accelerates bone healing and, within 3 months after tooth extraction, could mineralize and regenerate bone, whereas spontaneous healing takes 1 year. A recently published animal clinical study reported that 56.4% of newly formed bone in extraction sockets healed spontaneously after 16 weeks of healing,⁴⁸  which is comparable to the finding of our study.

Recently performed RCTs using allografts for extraction socket preservation revealed a great regenerative potential and resulted in 38.42% of newly formed mineralized tissue in sites treated with demineralized FDBA.¹¹  Meanwhile, in the same study, the use of mineralized FDBA for postextraction sockets resulted in 24.63% of newly formed bone 5 months after grafting. Another RCT analyzing FDBA with 38 extraction sockets showed favorable and similar regenerated bone results after 6 months.¹  In contrast to the previous mentioned RCTs, the present study revealed less pronounced bone regeneration and a lower percentage of newly formed bone in defects treated with FDBA. This lower percentage of regenerated bone might be explained by the shorter healing time, which was 3 months in the present study. The importance of healing time was reported by Canullo et al,⁴⁹  who compared extraction sockets treated with calcium sulphate after 2 months and 4 months of healing with a new mineralized tissue formation from 15% to 77.4%, respectively.

However, more research is needed to compare the importance of platelet concentrate in combination with bone graft substitute or how biomaterial alone is less efficient without autologous platelet concentrate.

A large number of studies have evaluated the quality of regenerated bone in sockets treated with xenogenic bone graft materials.^50–52  Gholami et al⁵⁰  used xenografts for extraction socket preservation and demonstrated 27.35% of newly formed mineralized tissue after 7.5 months. Another study assessing newly formed bone regeneration with 2 different xenogenic bone graft materials revealed bone regeneration of 28.5% to 31.4% after 6 months.⁵¹  Another RCT assessing bone healing after 5 months in extraction sockets treated with xenograft revealed 22.2% of newly formed mineralized tissue.⁵²  The present RCT assessed bone regeneration after 3 months of extraction socket healing. Considering newly formed mineralized tissue, similar bone regeneration to that of previous studies has been observed in extraction sites treated with BBM alone. Although the quality of regenerated bone is important for successful implant placement, the dimensional stability of regenerated bone is also crucial for primary implant stability.^53,54  To assess the stability of the grafted socket, newly formed mineralized tissue, newly formed nonmineralized tissue, and the remaining bone graft material were measured.

Residual bone graft material was greater in the BBM/CM group (45.0% ± 19%) as compared with the FDBA/CM group (38.5% ± 26.4%). This result is comparable with the findings of a previous study⁵⁵  in which the percentage of remaining bovine-derived xenograft was 40.18% at 4 months after preservation of the extraction socket. Similar results regarding residual bone graft particles of FDBA were reported in a clinical study¹¹  in which the remaining bone graft was 25.42% at 4 months after grafting.

The present study has some limitations. The sample size (10 patients per study arm) was smaller than the sample size calculated previously (11 patients per study arm). However, despite the small number of patients included, post hoc analysis indicated a statistical power of more than 90%. A possible drawback of this study is the comparison of 4 different groups instead of a comparison using a split-mouth model. In addition, all treatment and clinical recordings were performed by a single investigator. However, the study could have benefited from reduced variability. Patient-related outcomes (quality of life, pain) and soft-tissue healing were not assessed. The present study failed to identify an influence of buccal bone defect, and the alveolar walls were preserved in all extraction sites. This allowed us to standardize the study and to reach a homogenous result. However, intact postextraction sockets do not reflect the real influence of biomaterial with regard to bone regeneration in extraction sockets with defected bony walls. In addition, harvesting the regenerated bone using a trephine drill may have affected the histologic sample near the boundaries; therefore, the use of a silicone key limited the identification of nonregenerated bone. A further limitation of this study is the early evaluation period at 3 months following tooth extraction. However, a systematic review performed by Tan et al²  showed that the greatest dimensional changes in the alveolar ridge occurred in the first 3 months. Animal studies¹⁰  confirmed that the most pronounced alveolar bone reduction occurs in the first 2–3 months after tooth extraction. This study revealed that 3 months is an adequate period for regeneration of alveolar bone in spontaneously healing sites or in sites treated with PRGF. Because of the requirements of the treatments studied here (PRGF clot from the patient's own blood and an inorganic biomaterial), it was not possible to blind the patients or the practitioner during treatment application. The main limitation of this study is the small sample size, which might not be large enough to represent the study population. Thus, future multicentric RCTs are needed to confirm the results reported here.

A possible drawback of this study could be the lack of evaluation of dimensional changes in the alveolar ridge. Most clinical studies have focused on dimensional changes of the alveolar ridge after extraction socket preservation.^8,9,13,47,51  Although the dimensions of the alveolar ridge remain an important factor in determining the longevity of an implant, the quantity of newly regenerated bone is related to successful osseointegration and the long-term stability of dental implants^11,12 ; therefore, it is important to investigate the quality of regenerated bone. With regard to regenerated bone, this study raises some questions. How much newly formed bone is needed to achieve successful osseointegration of the dental implant? Will the sockets treated with bone graft material and that have less vital bone regenerated have a higher percentage of newly formed bone when residual biomaterial is replaced? Moreover, additional studies are needed to assess the impact of the differences observed in this study on the longevity of dental implants.

Additional research to assess the efficacy of these treatments in the dimensional alterations of the alveolar ridge following tooth extraction is needed. Also, it remains unknown how the combination of bone graft material and PRGF affects bone healing in the extraction socket. A systematic review analyzing regenerative bone potential after sinus floor elevation demonstrated that a combination of bone graft material with PRGF enhances bone regeneration and vascularization.⁵⁶  Although these limitations have to be taken into account during the interpretation of the data and in the design of future studies, the large statistical differences observed in this study and the measures followed to avoid performance and detection bias (blinding of the dentist during tooth extraction and blinding of the evaluator) proposed that the application of PRGF for alveolar preservation is a promising therapy that merits a deeper investigation in the future.

The use of PRGF for extraction socket preservation in the esthetic area increased bone regeneration and the amount of newly formed bone. The present RCT demonstrated significantly greater new bone formation in ridge preservation with PRGF as compared with spontaneous healing and sites grafted with BBM whether FDBA covered with collagen membrane. Histologically, sites treated with FDBA have a smaller percentage of residual bone graft substitute. However, future multicentric RCTs are needed to confirm the efficacy of PRGF in alveolar preservation in the esthetic area by measuring both histological and radiologic outcomes.

Abbreviations

ANOVA:

analysis of variance

BBM:

natural bovine bone mineral

BMPs:

bone morphogenetic proteins

CM:

collagen membrane

EGF:

epidermal growth factor

FDBA:

freeze-dried bone allograft

LSD:

least significant difference

PDGF:

platelet-derived growth factor

PRGF:

plasma rich in growth factors

NMT:

newly formed nonmineralized tissue

RCT:

randomized controlled clinical trial

TGF:

transforming growth factor

We acknowledge Irena Nedzelskiene, consulting biomedical statistician, Department of Dental and Oral Pathology, Lithuanian University of Health Sciences.

There are no conflicts of interest.