Latest Findings of the Regenerative Materials Application in Periodontal and Peri-Implant Surgery: A Scoping Review

Regenerative dentistry represents a therapeutic modern approach involving biomaterials and biologics such as mesenchymal stem cells. The role of regenerative dentistry is promising in all branches of dentistry, especially in periodontology and implantology for the treatment of bony defects around teeth and implants, respectively. Due to the number of different materials that can be used for this purpose, the aim of the present review is to evidence the regenerative properties of different materials both in periodontitis and peri-implantitis as well as to compare their efficacy. Clinical trials, case-control studies, cross-sectional studies, and cohort studies have been considered in this review. The outcome assessed is represented by the regenerative properties of bone grafts, barrier membranes, and biological materials in the treatment of intrabony and furcation defects, peri-implantitis sites, alveolar ridge preservation, and implant site development. Based on the studies included, it can be stated that in the last years regenerative materials in periodontal and peri-implant defects treatments have shown excellent results, thus providing valuable support to surgical therapy. To achieve optimal and predictable results, clinicians should always consider factors like occlusal load control, prevention of microbial contamination, and wound dehiscence. Further evidence is required about the use of enamel matrix derivative in alveolar ridge preservation, as well as of stem cells and bone morphogenetic proteins-2 in furcation defects and peri-implantitis sites. Considering the high amount of research being conducted in this field, further evidence is expected to be obtained soon.


Introduction
Bone formation is a crucial step in the regeneration of alveolar bone around teeth and dental implants. This process is mainly regulated by different cells and molecular mechanisms encompassing matrix interactions. In recent years, regenerative medicine has shown a wide development with more and more in vitro and clinical studies conducted on this topic [1]. Tissue engineering has also been applied to dentistry, especially in the field of periodontology and implantology. Tooth loss as well as hard and soft tissue remodeling are the direct consequences of an inflammatory process [2]. Bone defects in the mouth can significantly vary as regards their size, starting from small intrabody defects related to periodontal/peri-implant disease until more extended lesions, resulting from trauma and neoplastic lesions. The goal of periodontal and peri-implant tissue engineering is to promote the regeneration of the supporting tissues around teeth or implants. Scaffolds, growth factors, and stem cells exert a key role in the regenerative process, with a synergic effect between them [1].
The first approach that has been used for periodontal regeneration is represented by guided tissue regeneration (GTR), which is based on the use of barriers selecting specific cells to promote their colonization of the periodontium after surgery [3]. Moreover, the use of barriers can be combined with the use of bone substitutes, preventing epithelial migration [4]. Accordingly, the colonization of this protected site by periodontal ligament cells should be the expected outcome.
Following this former technology, decades of research have led to the development of several different biomaterials for alveolar bone regeneration which mainly differ in their mechanism of action. Barriers of different types, bone fillers, and biologics are examples of strategies that clinicians can benefit from to obtain periodontal and peri-implant regeneration [1]. As previously stated, barriers cover periodontal defects, protecting them from epithelial downgrowth. Bone fillers are scaffolds or bone grafts replacing the missing bone inside an alveolar defect. Finally, biologics encompass growth factors, mesenchymal cells, or further substances that can be directly administered in the defect, and thus, promote bone regeneration [5,6].
Considering the wide research conducted in the last years in this evolving field, the aim of the present work is to review the evidence on the regenerative properties of different materials both in periodontitis and peri-implantitis as well as to compare their efficacy.

Focused Questions
What are the regenerative properties of bone grafts, barrier membranes, and biological materials in the treatment of periodontal defects? If any, are these properties applicable to peri-implant defects, alveolar ridge preservation, and implant site development? Are the regenerative properties of these materials similar to each other?

Eligibility Criteria
The inclusion criteria applied in this review were: (I) study design-clinical trials, casecontrol studies, cross-sectional studies, and cohort studies, (II) participants-periodontal patients with intrabony and furcation defects, patients with peri-implantitis, patients with extraction socket, and patients with crestal bone defects, (III) interventions-use of bone grafts, barrier membranes, and biological materials for the regenerative treatment of intrabony and furcation defects, peri-implantitis sites, alveolar ridge preservation, and implant site development, and (IV) outcome-regenerative properties of bone grafts, barrier membranes, and biological materials in the treatment of intrabony and furcation defects, peri-implantitis sites, alveolar ridge preservation, and implant site development. Studies that did not meet all the inclusion criteria were not considered. Moreover, the exclusion criteria were: (I) abstract of articles published in non-English languages, (II) duplicate studies, (III) not pertinent studies, (IV) in vitro or animal clinical studies, (V) absence of Ethics Committee approval, and (VI) narrative reviews, scoping reviews, systematic reviews, or systematic and meta-analysis reviews.

Search Strategy
According to the JBI methodology for scoping review, a three-step searching process has been considered consisting of the following phases: (i) preliminary limited search on PubMed (MEDLINE) and Scopus; (ii) selecting key terms from retrieved articles for devising search strategy; (iii) searching reference list of all included articles for additional research [7].
Moreover, the PCC model was applied, which is based on the following three elements: population (people with periodontal/peri-implant disease), concept (regenerative materials in oral surgery), and context (in this case, the review has not been limited to any specific cultural factor or setting). Abstracts of studies that evaluated regenerative properties of bone grafts, barrier membranes, and biological materials in the treatment of intrabony and furcation defects, peri-implantitis sites, alveolar ridge preservation, and implant site development were reviewed.
A literature search was performed in the electronic databases PubMed (MEDLINE) and Scopus, searching the following medical subject heading (MeSH): alveolar ridge augmentations, furcation defects, peri-implantitis, periodontal resorption, regenerative medicine, and tissue engineering. The full electronic search strategy is listed in the Supplementary Materials Section.
In order to review the latest evidence on the topic, only articles published in the years 2000 to 2022 were considered, with a data extraction period of 12 weeks. Three reviewers (M.Pa., M.Pe. and M.M.) performed the search, which was last performed on 4 September 2022. Any contrary opinions were resolved by consulting three other reviewers (F.S., C.M. and A.S.). Relevant articles were reviewed by reading the full texts, recording the results, and identifying any similar studies that met the inclusion criteria. Non-relevant studies were excluded by thoroughly analyzing the titles and abstracts of the articles searched.

Quality Assessment of Included Studies
This review was carried out by assessing the risk of bias by performing quality analysis of the clinical studies through the National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment of Controlled Intervention Studies, for Observational Cohort and Cross-Sectional Studies, for Case Series Studies, and Case Reports Studies [8].

Results
In total, 130 articles were primarily identified using MeSH terms. Subsequently, 41 articles from PubMed and 16 articles from Scopus were removed because the abstracts were published in non-English, and/or duplicate, and/or in vitro or animal clinical studies, and/or irrelevant, and/or lacked ethics committee approval. Consequently, 73 articles were screened and assessed for eligibility. Finally, 25 articles were further excluded as narrative reviews, scoping reviews, systematic reviews, or systematic and meta-analysis reviews. In total, 48 relevant articles were included and assessed in this review. The flowchart of the review process is shown in Figure 1.
Table S1 (Supplementary Materials) shows the studies excluded from this review and the reasons for exclusion .

Risk of Bias
The Cochrane Collaboration tool was applied to assess the risk of bias of the articles included in this review (Table 1), using the judging criteria for risk of bias shown in Table  S2 (Supplementary Materials). A moderate risk of bias is observed in this review.

Discussion
Research performed in vitro and clinical studies regarding regenerative medicine and tissue engineering in dentistry has developed a wide range of performance biomaterials available to the clinician to achieve bone and soft tissue regeneration in the presence of periodontal and peri-implant defects [6].
Some materials have been extensively tested while other materials have reported interesting results in recent years.

Periodontal Application: Intrabony Defects
Regenerative periodontal therapy with EMD in association with autogenous bone graft (ABG) or with bovine-derived bone substitutes in the treatment of intrabony defects (IBDs) in patients with chronic periodontitis results in the former case in improved vertical bone resorption, and in the latter case, in significant clinical attachment level (CAL) gain and probing pocket depth (PPD) reduction, with negligible increase in gingival recession (GR) [9,41].
In addition, combined treatment with PRF and ABG in IBDs results in similar CAL gain, PPD reduction, GR increase, and defect bone level gain compared with the therapeutic combination with EMD and ABG [10]. Combination treatment with PRP and demineralized bone matrix has also resulted in significant improvements in IBDs [42]; however, it has recently been shown that the combination of 1.2 mg of Rosuvastatin, a new synthetic, hydrophilic statin with potent anti-inflammatory and osteogenic differentiation actions, ABG, and PRF reduces PPD, CAL, and defect height and diameter more than the application of ABG and PRF alone [11].
Autogenous bone harvesting can also be performed from a mandibular torus, which can ensure adequate filling of IBDs in periodontal patients, avoiding the second surgical site and showing reduced CAL and complete resolution of tooth mobility [43].
It has been observed how the treatment of IBDs, in patients with aggressive periodontitis, by application of xenogeneic grafts plus modified perforated membranes (MPMs) achieves better results when compared with the application of xenogeneic grafts plus standard collagen membranes (CMs): significant reduction in PPD and, in addition, a significant increase in bone density, which could indicate a greater area of new bone formation [12]. Furthermore, periodontal defect coverage with MPMs is associated with a significant initial increase in bone morphogenetic protein-2 (BMP-2) levels in gingival crevicular fluid, which could improve clinical outcomes of tissue-guided regenerative surgery [13]. Finally, PRF has recently been shown to present comparable results to CM for the treatment of IBDs in patients with aggressive generalized periodontitis and better results regarding the position of the gingival margin [14].
Alloplastic bone grafts have also been tested in the treatment of IBDs: in particular, it has been shown that the application of a premixed composite of bioactive calcium phosphosilicate particles and an absorbable synthetic binder in combination with PRF resulted in a greater CAL increase and PPD reduction than the use of premixed composite alone [15].
The addition of autogenous platelet concentrates (APC) to GTR in deep IBDs does not cause a statistically significant improvement in CAL and the long-term stability of results [16].
Furthermore, the application of an allogenic barrier membrane in the treatment of IBDs allows for a significant reduction in periodontal indexes and radiographic measurement of the bone defect area, achieving results such as the use of a demineralized bone matrix allograft [17].
Recently, stem cells in dentistry have also found great use with excellent results. In the treatment of IBDs, autologous stem cells from dental pulp and periodontal ligament, delivered in a collagen scaffold, significantly improved clinical (PPD and CAL) and radiographic parameters of periodontal regeneration [18,19].
Regarding gene therapy in periodontal defects, the literature to date is very poor. However, the only controlled clinical study by Gonçalves et al. [20] showed that root cementum can modulate the expression of mineral-associated growth factors during periodontal regeneration in IBDs.

Periodontal Application: Furcation Defects
It has been shown that in grade II furcation defects, the combination of PRF with β-tricalcium phosphate allograft (β-TCP) results in significant improvements compared to the use of alloplastic graft alone, showing a more significant reduction in horizontal defect depth and vertical defect depth and improved CAL [21]. In addition, the use of PRP also leads to similar results to the application of PRF, with no significant differences [22]. In contrast, EMD and β-TCP association does not provide a significant advantage compared to isolated approaches in the treatment of grade II furcation defects [23].
Furthermore, the application of freeze-dried demineralized bone allograft (DFDBA) in association with the amniotic allogeneic barrier also results in significant improvement of clinical and radiographic parameters in the treatment of grade II furcations compared to the use of DFDBA alone [24]. Similar results have been obtained by applying concentrated GF with an inorganic bovine bone xenograft [25].
Regarding gene therapy, significant clinical and radiographic results regarding the regenerative potential of BMP-2 impregnated with absorbable collagen sponge and PRF in the treatment of grade II furcation defects have been highlighted, and thus, it has been considered as a potential graft material to be used for the treatment of grade II furcation defects [26].
The association of allogenic cancellous bone grafts and PRF can also be applied in the treatment of grade III mandibular furcation, showing PPD reduction, CAL increase, and radiographic bone filling [33,44]. Among autogenous barrier membranes, the pedicled buccal fat pad (PBFP) can be used to increase the predictability and outcome of root coverage procedures in the treatment of III-class GR with furcation involvement [45].
To date, no clinical trial has been conducted aimed to assay the effect of stem cells in furcation defects.

Implant-Based Application: Treatment of Peri-Implantitis
A 50:50 mixture of ABG and allograft can be successfully used in the treatment of circumferential and semicircumferential bone defects in patients with peri-implantitis; in particular, significant improvement in GR, plaque index (PI), PPD, bleeding on probing (BoP), and CAL at 6 and 12 months has been shown [34].
ABG can also be used in combination with an allogenic graft material, titanium mesh, and acellular dermal matrix, leading to significant improvement regarding mean marginal bone loss and bone gain in peri-implant defects [35]. It was shown that the regenerative approach consisting of the application of deproteinized bovine bone mineral and a collagen membrane after mechanical and chemical decontamination with tetracycline solution in the peri-implant defects showed long-term stability of physiologic PPD, with no clinical signs of peri-implant inflammation and BoP and no radiographic bone loss [46]. Furthermore, after mechanical debridement of the implant surface and application of antimicrobial photodynamic therapy, promising results were achieved in terms of absence of granulation tissue, purulence, progressive bone resorption in the presence of newly formed bone tissue in close contact with the implant surface by the application of 70:30 mixture of ABG and deproteinized bovine bone mineral particles, and the use of titanium mesh and resorbable collagen membrane [47].
Finally, complete bone filling of peri-implant bone defect was observed clinically and radiographically by applying a xenogenic bone substitute with dehydrated and deepithelialized human amnion-chorion membrane [48].
Regarding the application of EMD in the treatment of peri-implantitis, the randomized controlled clinical trial by Isehed et al. [27] observed positive clinical and radiographic results in implant survival at 3 years (100%) and 5 years (85%) after surgical treatment. In addition, bovine-derived hydroxyapatite and EMD have also been tested in patients with peri-implantitis, achieving long-term resolution of BoP and suppuration and significant reduction of PPD [49].
To date, no randomized controlled clinical trials have been conducted to test the effect of stem cells and gene therapy in cases of peri-implantitis. Only a case report by Jensen et al. [50] reported improvement in peri-implantitis by applying BMP-2.

Alveolar Ridge Preservation and Implant Site Development
Autogenous mandibular bone blocks covered with a membrane of bone mineral and bovine collagen can be used to regenerate the alveolar process of patients with edentulous and atrophic ridges, with implant survival rates consistent with those obtained for implants placed in native bone [36].
Furthermore, alveolus preservation by application of demineralized bovine bone mineral particles coated with a porcine-derived non-cross-linked collagen matrix was shown to be an effective technique for maintaining long-term stable hard and soft tissue dimensional volumes [37].
To date, the literature suggests that EMD does not provide significant results in alveolar ridge preservation, while highlighting its role in reducing postoperative pain and swelling following dental extraction [28].
Recently, the application of BMP-2-soaked absorbable collagen sponge or BMP-2dipped tricalcium phosphate and hydroxyapatite particles in alveolar ridge preservation showed significant and similar results [29].
The application of bovine bone combined with a barrier membrane with or without fibroblast growth factor-2 (FGF-2) on dental alveoli can effectively reduce ridge absorption, especially ridge width, while the FGF-2-modified membrane seems to improve the results obtained by using the membrane alone [30]. Similar results in terms of horizontal preservation of the alveolar ridge have been obtained by application of a bovine bone graft covered with anodized titanium foil [51], deproteinized bovine bone mineral with 10% collagen covered with a collagen membrane [38], and xenograft-derived bovine bone mineral and covered with a newly developed dense polytetrafluoroethylene membrane [39].
Particulate ABG and inorganic minerals derived from bovine bone with a 3:7 ratio can be used to perform the sagittal sandwich technique in sinus lift, providing some safety and predictability in the subsequent implant placement [52]. In contrast, the application of allogenic bone blocks grafts to increase pre-implant bone thickness is associated with frequent complications such as graft loss and/or peri-implantitis [53]. Moreover, the cumulative survival rate (CSR) of 192 implants placed in association with guided bone regeneration (GBR) procedures using demineralized bovine bone mineral grafts (DBBM), autologous bone grafts, and a 1:1 ratio mixture of autologous grafts and DBBM (with resorbable or non-resorbable membranes) was compared, achieving satisfactory long-term results with a CSR >90% with all materials used [40].
Recently, it has been shown that the use of composite bone grafts (autogenous bone and xenograft particles) in association with recombinant human platelet-derived growth factor (PDGF) achieves simultaneous vertical ridge augmentation and periodontal regeneration [54]. In addition, both the application of alloplastic poly-lactic-glycolic acid graft coated with calcium β-phosphate (PLGA-β-TCP) and DFDBA particles covered with a rapidly absorbable collagen dressing result in comparable results in terms of maintenance of alveolar bone size, feasibility of implant placement, implant survival, and stability of peri-implant bone level up to 12 months after loading [31].
The application of adipose-derived stem cells derived from buccal fat pad in combination with natural bovine bone mineral can be considered an effective treatment for bone regeneration in large alveolar bone defects, providing implant rehabilitation survival [55].
The prospective case series by Windisch et al. [56] showed efficacy in the survival and predictability of implant rehabilitation following horizontal and vertical GBR using titanium-reinforced high-density polytetrafluoroethylene membranes combined with autogenous bone and particulate bovine-derived xenograft in a 1:1 ratio.
The use of an allograft cellular bone matrix, containing native mesenchymal stem cells and osteoprogenitors, also leads to significant results in bone formation following sinus lift procedures, encouraging faster initiation of implant placement [32].
A summary of the results of studies included in this work is shown in Table 2 Moreover, Table 3 shows a summary of the most relevant growth factors, their origin, composition, mechanism of action, and clinical indications.
This report has some limitations. No information specialists or academic librarians have been included for the conduction of the electronic search. It is possible that the search methodology could have been too specific for a scoping question. Moreover, it did not consider all articles in the literature, with reference to grey literature and non-indexed research. Furthermore, the results may differ according to the population considered. Another limitation could be that the same material used in regenerative dentistry/tissue engineering can be produced by different companies; as this is not always specified in the articles, this aspect should be included, as some differences in the results could occur. Finally, the heterogeneity of commercially available materials, which are often used in combination in the treatment of periodontal and peri-implant defects, complicates the comparison between them. Evaluation of efficacy of premixed composite of bioactive calcium phosphosilicate particles and an absorbable synthetic binder along with PRF produced more favorable results in relative attachment level gain and more reduction in probing pocket depth when compared to premixed composite alone. Scaling and root planing with the removal of granulation tissue and root cementum and soft microbial deposits by cleaning the root surface with a microbrush and saline solution (11 defects-test sites). Scaling and root planing with the removal of granulation tissue and root cementum (11 defects-control sites).
mRNA levels for platelet-derived growth factor-alpha, bone sialoprotein, and basic fibroblast growth factor were higher in the sites where root cementum was kept in place compared to the sites where root cementum was removed completely as part of the periodontal therapy. Root cementum may modulate the expression of growth and mineral-associated factors during periodontal regeneration. The use of autologous PRF or PRP were both effective in the treatment of furcation defects with uneventful healing of sites. EMD + β-TCP + hydroxyapatite does not provide a significant advantage when compared to the isolated approaches. All three tested treatments promote significant improvements and partial closure of class II buccal furcation defects. EMD may be considered an attractive option for this type of defect The unique regenerative potential BMP-2 impregnated with absorbable collagen sponge makes it a potential agent to be used as a graft material for the treatment of grade II furcation defects. Extraction sockets filled with BMP-2-soaked absorbable collagen sponge (32 patients-test group). Extraction sockets filled with β-TCP and hydroxyapatite particles (32 patients-control group).
The delivery systems showed similar efficacy for alveolar ridge preservation without severe adverse events.

References (Authors, Year of Publication and Study Details) Study Methods Results
Stumbras et al., 2021 [30]: 3-month double-blinded randomized controlled clinical trial with 40 post-extraction alveoli in 40 participants following anterior maxillary alveolar ridge preservation.
Alveolar ridge preservation technique in the esthetic zone using natural DBBM covered with resorbable native CM or using FGF-2 beneficial to reduce horizontal and vertical bone changes. Extraction sockets filled with alloplastic graft PLGA coated β-TCP (24 patients-test group). Extraction sockets filled with DFDBA particles covered with a rapidly absorbable collagen dressing (21 patients-control group).
Although a higher proportion of mineralized tissue was associated with the use of DFDBA particles covered with a rapidly absorbable collagen dressing compared to alloplastic graft PLGA-coated β-TCP, both approaches rendered comparable outcomes in terms of maintenance of alveolar bone dimensions.
The high percentage of vital bone content, after a relatively short healing phase, may encourage a more rapid initiation of implant placement or restoration when a cellular grafting approach is considered.
GTR using an allogeneic cancellous bone graft and covered by an absorbable membrane.
GTR using allogeneic cancellous bone graft and absorbable collagen membrane to be a viable option for treating furcation-involved teeth if the defect morphology and the location of the defect are favorable.
GBR technique using 50:50 mixture of ABG and allograft and CMs.
The proposed technique might represent a promising result for treatment of circumferential and semi-circumferential bone defects around implants affected by peri-implantitis.
GBR using titanium mesh, a combination of ABG, allogenic graft material, and acellular dermal matrix. Soft tissue augmentation and vestibuloplasty were performed in the second-stage surgery, if required.
This technique may lead to promising outcomes in cautiously selected patients seeking to retain their failing implants.

References (Authors, Year of Publication and Study Details) Study Methods Results
Chiapasco et al., 2020 [36]: retrospective longitudinal cohort study, with a 3-16-year follow-up on 75 participants with 82 grafted bone defects and 182 implants placed post-regeneration bone.
Reconstructive bone procedure with autogenous mandibular bone blocks and rehabilitated with implant-supported prostheses.
Implants placed in areas reconstructed with mandibular bone blocks presented survival rates consistent with those obtained for implants placed in native bone.
Alveolar socket preservation with DBBM particles covered with a porcine-derived non-cross-linked collagen matrix.
Alveolar socket preservation using DBBM in combination with a porcine-derived non-cross-linked collagen matrix proved to be an effective technique to maintain stable dimensional volumes of both hard and soft tissues. Manavella et al., 2018 [38]: retrospective cohort study, with a 12-month follow-up on 11 severely resorbed alveolar sockets in 11 participants.
Ridge augmentation procedure with DBBM with 10% collagen covered with a CMs.
A ridge preservation technique performed with DBBM, and a CMs was able to improve ridge shape and dimensions in compromised alveolar sockets.
Alveolar socket preservation with non-resorbable dense polytetrafluoroethylene membranes.
The use of the examined new non-resorbable dense polytetrafluoroethylene membranes consistently led to the preservation of hard tissue in the extraction sites. Beretta et al., 2015 [40]: retrospective long-term follow-up study, with a 78-month follow-up on 61 participants with 192 implants placed after guided bone regeneration.
All the procedures performed with different bone grafts and type of membranes guaranteed optimal results in CSR (>90%).
Yoshikawa et al., 2020 [41]: case report, with an 18-month follow-up on a 57-year-old man participant with generalized chronic periodontitis.
Surgical periodontal therapy with using EMD and ABG. Periodontal regenerative therapy using EMD with ABG resulted in improvement in vertical bone resorption. Thakkalapati et al., 2015 [42]: case report, with a 2-year follow-up on a 30-year-old female patient with one-wall intrabony osseous defect.
Open flap debridement and placement of combination of autologous PRP and DBBM.
Radiographic evidence of bone formation was observed as early as 3 months with almost complete fill by 6 months post-operatively. The results were maintained over a period of 2 years. Pal et al., 2018 [43]: case report, with a 1-year follow-up on a male participant with a mandibular torus and intrabony defect at the mandibular right central incisor.
ABG was obtained from a mandibular torus and utilized to fill the IBD.
The mandibular torus provided sufficient graft material and eliminated the need for a second surgical site. A follow-up at 1 year revealed reduction in clinical attachment loss and complete resolution of tooth mobility.

References (Authors, Year of Publication and Study Details) Study Methods Results
Zhou et al., 2020 [44]: case report, with a 12-month follow-up on a 56-year-old and 34-year-old female patients with mandibular grade III furcation involvement.
Open flap debridement with allogenic bone graft and PRF.
Successful periodontal regeneration of grade III furcation defects can be achieved by using PRF in combination with bone allograft. Panda et al., 2016 [45]: case report, with a 6-month follow-up on a 36-year-old male participant with class III gingival recession defect along with furcation involvement.
Open flap debridement with PBFP.
PBFP may be considered as a reliable modality for root coverage of severe GR defects, which could not be repaired by other conventional procedures. Bassi et al., 2015 [46]: case report, with a 17-year follow-up on a 48-year-old female patient with peri-implantitis affecting the mandibular right second molar.
Open flap debridement with DBBM and a CM. The treatment seemed to show improved clinical results up to a relevant follow-up period.
Poli et al., 2020 [47]: case series, with a 9-month follow-up with reentry on 6 participants with peri-implantitis affecting maxillary or mandibular area.
Open flap debridement, antimicrobial photodynamic therapy with a solution of phenothiazine chloride dye consisting of methylenthioniniumchlorid photo-activated with 100-mW diode Laser (660 ± 10 nm) and regeneration with 70:30 mixture of ABG and DBBM particles, titanium mesh, and resorbable CM.
At the reentry surgery, no evidence of granulation tissue, purulence, or progressive bone resorption was found. Newly formed bonelike tissue hardly distinguishable from the existing bone was found in intimate contact with the implant surface at most of the implant sites. A modest amount of augmented bone was obtained at only one mandibular site, resulting in persistent dehiscence-type defects associated with a supracrestal component. Bhide et al., 2022 [48]: case report, with a 2-year follow-up on a 68-year-old male participant with peri-implantitis affecting the endosseous implant that replaced the maxillary left first molar.
GBR performed using DBBM covered with a dehydrated human deepithelialized human amnion-chorion membrane.
Posttreatment clinical assessment suggested that the patient responded well to surgical regenerative therapy, with the reestablishment of healthy peri-implant soft tissues. It is possible to treat peri-implantitis successfully and obtain stable long-term results with a GBR approach utilizing a DBBM covered with a dehydrated human deepithelialized human amnion-chorion membrane.
Park et al., 2018 [49]: case report, with a 27-month follow-up on a 52-year-old male patient with peri-implantitis affecting mandibular right second premolar area.
Open flap debridement with bovine-derived hydroxyapatite and EMD.
The area showed maintenance of graft material with increased radiopacity around the dental implant.
Sinus floor grafting with BMP-2 in an absorbable collagen sponge carrier.
Sinus floor grafting to salvage trans-sinus implants or to prevent peri-implantitis/sinusitis is suggested by the successful use of BMP-2 in an absorbable collagen sponge carrier. Sinus augmentation using particulate ABG and inorganic bovine bone-derived mineral (3:7 ratio). Implants were placed on baseline residual alveolar ridge height.
Implant placement after two-stage sinus grafting utilizing the sagittal sandwich technique is a relatively safe and predictable procedure with minimal complications and marginal bone loss after 10-year follow-up.
Blume et al., 2021 [53]: case report, with a 6-month follow-up on a 19-year-old male patient with a complex maxillary defect.
Reconstruction of a complex maxillary defect using allogeneic bone block.
The present case report demonstrates a limited resorption of the allogeneic bone block and further emphasizes the practicability of determining bone resorption by the here introduced method.
Urban et al., 2022 [54]: case report, with a 3-month follow-up on a 55-year-old male participant with peri-implantitis around an implant in the maxillary left central incisor position and with severe bone loss on the mesial aspect of the maxillary left lateral incisor.
Ridge augmentation using composite bone graft (ABG + xenograft particles), and a PDGF. Tissue augmentation with connective tissue grafts. Peri-implant keratinez mucosa augmentation using labial gingival graft strip and a xenogenic collagen matrix.
Simultaneous vertical ridge augmentation and periodontal regeneration can be achieved to manage a challenging clinical situation.
Khojasteh et al., 2019 [55]: case report, with a 10-month and 6-month follow-up, respectively, on a 19-year-old female and 22-year-old male participants with large alveolar defects.
GBR using adipose-derived stem cells, originated from buccal fat pad, loaded with natural bovine bone mineral.
The application of adipose-derived stem cells isolated from buccal fat pad in combination with natural bovine bone mineral can be considered an efficient treatment for bone regeneration in large alveolar bone defects.
Vertical GBR consisting of a split-thickness flap and using titanium-reinforced high-density polytetrafluoroethylene membrane combined with particulated ABG and bovine-derived xenograft in 1:1 ratio.
Vertical GBR consisting of a split-thickness flap and using titanium-reinforced non-resorbable membrane in conjunction with a 1:1 mixture of particulated ABG and bovine-derived xenograft may lead to a predictable vertical and horizontal hard tissue reconstruction. Future research prospects could include further randomized controlled clinical trials that should be conducted to evaluate the effects of stem cells and gene therapy in the treatment of furcation defects and peri-implantitis. In addition, further studies will be needed to evaluate the possible interactions of regenerative materials with peri-implant probiotic therapy, considering the different populations of microorganisms at peri-implant sites [83] and the supposed competitive role of probiotics against peri-implant pathogens [84]. Though this research has been focused on clinical trials, systematic reviews based on in vitro studies could also be valuable to transfer basic research into clinical application.

Conclusions
In the last few years, several randomized clinical trials have been carried out to evaluate the outcomes of regenerative materials in periodontal and peri-implant defects treatments, obtaining excellent results, and thus, providing valuable support to surgical therapy. The clinician must always consider occlusal load control, prevention of microbial contamination, and wound dehiscence to achieve optimal and predictable results using such materials.
Further evidence is required about the use of EMD in alveolar ridge preservation, and clinical studies are needed regarding the utility of stem cells and BMP-2 in furcation defects and peri-implantitis sites. However, since the advances made in materials science and tissue engineering in recent years have been considerable, it is fair to expect that in a short time, these issues will also be bridged.