Surgical regenerative therapy for peri-implantitis—a comprehensive review and what is the current histological evidence?

Introduction

Dental implants have evolved into a pivotal choice for contemporary oral restoration based on high survival rates and long-term predictable outcomes. Meanwhile, increasing technical and biological complications, ranging from soft tissue inflammation to severe peri-implant bony destruction which cause implant failure, pose a significant threat to patients’ oral health. The 2017 World Workshop defined peri-implantitis as a “plaque-associated” pathologic condition occurring in the tissue around dental implants, characterized by inflammation in the peri-implant mucosa and subsequent progressive loss of supporting bone (1-3). A systematic review with meta-analysis estimated the prevalence of peri-implantitis to be 22% (range from 1% to 47%) (4). Although the etiology posed by biofilm is widely recognized, the consensus on the best methods for thorough surface decontamination, peri-implant tissue pathology, and sustainable regenerative outcome over time remains the main issue for research (3,5).

This article delves into an array of treatment strategies for peri-implantitis, with a particular emphasis on surgical regenerative therapies, proposing a practical step-by-step review. It also reviews the application of laser technology and various biomaterials, highlighting not only surface decontamination but also biomodulation of peri-implant soft tissue responses and the promotion of regeneration. Last but not least, promising outcomes supported by recent histological studies will be reviewed and discussed. By adhering to the key principles proposed in this article, clinicians may achieve higher success rate of surgical regenerative therapies for peri-implantitis. This article would also like to call for further research that supports evidence-based approach.

Peri-implantitis diagnosis and classification

Peri-implantitis is clinically defined by signs of inflammation around the implant, radiographic bone loss after initial healing, and increased probing pocket depth (PPD) compared to post-prosthetic placement measurements (6). In cases without prior radiographs, a radiographic bone level (RBL) of ≥3 mm, along with bleeding on probing (BoP) and PPD ≥6 mm, also indicates peri-implantitis (6). Froum et al. have contributed a straightforward classification system that not only aids clinicians in assessing the severity of peri-implant diseases but is also patient-friendly in terms of comprehension (7). Building upon this, Decker et al. introduced a prognostic model that integrates systemic and local characteristics to predict future stability of implant and peri-implant tissues. This model categorizes prognosis into four systems: favorable, questionable, unfavorable, and hopeless (8).

When addressing the treatment of peri-implantitis, it is essential to conduct a thorough assessment of both hard tissue topography and soft tissue phenotype. Peri-implant bone loss is a critical factor in determining severity and its prognosis in the previously-mentioned system, especially if more than 50% of bone loss has already occurred, prognosis may be considered poor (9). Focusing on the configuration of hard tissue defects, Monje et al. have refined the classification (10), reporting that peri-implantitis often presents with circumferential bone loss (55.3%, Schwarz et al., 2007; 30%, García-García et al., 2016) (11,12) and buccal dehiscence (25% buccal dehiscence combined with circumferential defect, García-García et al., 2016) (12), commonly resulted in a combined defect with both intra-bony and supra-bony components. A more contained bony defect generally shows higher regenerative potential yet the predictability is much lower compared to periodontal regeneration.

The peri-implant soft tissue phenotype, including keratinized mucosa width (KMW), mucosa thickness (MT), and supra-crestal tissue height (STH) defined by Avila-Ortiz et al., are also key factors influencing peri-implant disease prevalence and treatment success (13). Systematic reviews have confirmed that the presence of at least 2 mm KMW is associated with lower peri-implantitis rates and less inflammation, while thick MT (≥2 mm) contribute to better aesthetic outcomes and patient satisfaction (14,15). Understanding both hard and soft tissue conditions are crucial, as they play a significant role in guiding the decision-making process for subsequent management and treatment strategies in peri-implantitis.

Treatment strategy of peri-implantitis

In 2018, Sinjab et al. proposed a comprehensive decision-making framework for managing peri-implant diseases (16). The decision tree assists clinicians in the diagnostic process, suggesting appropriate interventions, ranging from non-surgical methods for minor issues to more involved procedures for severe cases. These include resective and reconstructive therapies for hard tissues and implants, and soft tissue augmentation to improve tissue volume and quality. Effective management of the peri-implant phenotype is critical for both aesthetic outcomes and long-term stability. Despite such guidelines, treatment outcomes for peri-implant diseases, which aim at achieving complete tissue reconstruction and arresting disease progression, often remain unpredictable. The uncertainty frequently leads clinicians deliberating between surgical and non-surgical options, as well as between resective and reconstructive (regenerative) therapies.

Non-surgical therapy

The objective of non-surgical treatment for peri-implantitis primarily focuses on removing biofilm and granulation tissue, as well as resolving mucosal inflammation. Clinically, this involves mechanical debridement, chemical detoxification, and antibiotic intervention systemically or locally (16-19). According to Herrera et al. (20), the endpoints of non-surgical therapy include residual PPDs at the implant level of ≤5 mm, no BoP at more than one site, and no suppuration. However, a retrospective study indicated that non-surgical treatment have not shown the same level of efficacy in reducing bone loss progression as surgical intervention (21). Surgically treated implant sites demonstrated a mean bone loss of 1.4±2.4 mm prior to surgical intervention. After therapy, there was only a minor change of 0.2±1.0 mm observed, even with a longer follow-up duration (7 vs. 41 months). It revealed the limitation of non-surgical treatments in achieving complete resolution of moderate/severe peri-implantitis, and confirmed the effectiveness of surgical treatments in significantly reducing bone loss progression (21). This result has also been corroborated by other studies that surgical procedures are considered more efficacious in the treatment of peri-implantitis (22,23).

Despite its limitations (24), some researches have shown that non-surgical treatment could achieve disease stabilization in more than 40% of cases (25,26). In consequence, the non-surgical treatment has been recommended prior to the surgical phase for peri-implantitis management (19,20). Figures 1,2 illustrate clinical cases of non-surgical therapy for peri-implantitis.

Figure 1 Non-surgical therapy for peri-implantitis with stable conditions. (A) Pre-operative, the upper anterior area showed active BoP after charting (PPD >7 mm), with noticeable redness and swelling of the buccal marginal mucosa around the implant (i11), indicating acute inflammation. Non-surgical therapy involved mechanical and chemical surface decontamination using scalers, curettes, saline irrigation, and povidone-iodine application. Additionally, Er:YAG laser treatment and local minocycline delivery (Periocline^®) were used, along with systemic antibiotics (amoxicillin 500 mg, q8h for 7 days). (B) One month post-operative, inflammation around i11 had partially subsided. (C) Six months follow-up, no BoP with limited PPD (<5 mm) was observed around i11, and the peri-implant tissue appeared healthy and stable, though part of the implant abutment was exposed. The X-ray suggested possible bone remineralization on the mesial side of i11. (D) One year follow-up, the peri-implant tissue remained stable, with more evident bone remineralization. The patient was not concerned about esthetics and insisted on not replacing the prosthesis. Continued professional maintenance was carried out. BoP, bleeding on probing; PPD, probing pocket depth; q8h, every 8 h.

Figure 2 Non-surgical therapy for peri-implantitis with limitations. (A) Pre-operative, mechanical, and chemical surface decontamination methods were used during non-surgical treatment, including the use of scalers and curettes, irrigation with normal saline, and application of povidone-iodine. Additionally, Er:YAG lasers and local delivery of minocycline (Periocline^®) were utilized in conjunction with systemic antibiotics (amoxicillin 500 mg, q8h, 7 days) for infection prophylaxis as part of the treatment protocol. (B) Four weeks post-extraction, healing of #15 extraction site was uneventful, and the buccal sinus tract and swelling had subsided. Peri-implant tissue was relatively stable and more implant threads exposed. (C) Twelve weeks post-operative, BoP was noted around i17 again, indicating the limitation of non-surgical treatment in completely reducing inflammation of peri-implant tissues. Repeated non-surgical therapy was required. (D) Initial radiographic film. (E) Twelve weeks post-operative radiographic film. q8h, every 8 h; BoP, bleeding on probing.

In Figure 1, a 74-year-old male patient reported frequent gum swelling in the upper anterior area for years, with recent onset of pain. Clinical and radiographic evaluations revealed that the dental implant (i11) exhibited deep PPD of up to 7 mm at distal buccal side, active BoP, and radiographic bone loss. the implant (i11) was diagnosed with moderate peri-implantitis, and assigned a questionable prognosis (8). Although surgical intervention may have been indicated due to the severity of the peri-implant disease, the patient, a heavy smoker who was afraid of surgery and unwilling to remove the over-contoured implant crown, opted for a conservative non-surgical treatment plan for i11. The clinical photos and radiographs over 1 year demonstrated stable conditions with minimal bone loss progression, indicating the effectiveness of the non-surgical treatment. However, close monitoring and continuous maintenance are recommended, given the patient’s smoking habits and poorly designed prosthesis, which pose challenges to long-term stability.

In Figure 2, a 59-year-old female presented with persistent swelling and pus discharge in the upper right area for several months. Clinical and radiographic evaluations revealed that tooth 15 (#15) had a PPD exceeding 10 mm, active BoP, and vertical mobility. Additionally, three implants (i14, i16, i17) showed pus drainage and at least 7 mm PPD circumferentially with over 50% supra-bony bone loss but no mobility. The natural tooth (#15) was diagnosed with severe periodontitis and deemed hopeless (27); the dental implants (i14, i16, i17) were diagnosed with advanced peri-implantitis, carrying a prognosis ranging from unfavorable to hopeless (8). According to the serious condition and heavy smoking habit for decades, yet desiring to maintain the current state as much as possible, the treatment plan proposed the following: (I) extraction of #15 due to recurrent pain and a buccal sinus tract with consistent pus drainage. (II) Non-surgical therapy for the implants (i14, i16, i17) to slow disease progression, and thereby prolong their lifespan. Pre- and post-treatment comparisons confirmed that non-surgical treatment could initially control inflammation but was not effective in halting disease progression. Surgical intervention, such as resective or regenerative therapy, should be considered. Based on the radiograph, i14 may be suitable for a regenerative therapy, and i16 and i17 are more indicated for resective therapy. However, the peri-implant tissue deficiency and the patient as a heavy smoker without any intention for smoking cessation, preclude the decision for an immediate surgical intervention. An active maintenance program with repeated non-surgical treatment may be a better option.

Indications for resective vs. reconstructive (regenerative) therapy

When the endpoints of non-surgical therapy cannot be achieved, a surgical approach for peri-implantitis treatment needs to be considered (20). In such cases, the decision between resective and reconstructive (regenerative) therapies often poses a clinical dilemma. Based on defect’s morphology and severity previously mentioned, supra-bony defects are typically managed with open flap debridement or resective surgery, sometimes incorporating implantoplasty (10,16). Implantoplasty serves the purpose of removing debris and the infected layer of titanium, thereby creating a surface less prone to bacterial adhesion and plaque retention. However, there are some concerns about generating alloy particles and reducing implant wall thickness and fracture resistance (28-30). While current systematic reviews suggest that implantoplasty is not associated with significant mechanical or biological complications in the short- to medium-term (31), it is essential to assess the necessity of implantoplasty in resective surgery beforehand. This is particularly crucial in areas where patients can maintain good oral hygiene and for implants with a smaller diameter (3–3.5 mm) (28).

On the other hand, reconstructive approaches are recommended for intra-bony defects, leveraging the space formed by the surrounding bone walls. Although surgical regenerative therapy for peri-implantitis has been recommended for intra-surgical defects with at least 3 mm of depth (20,32), which is derived from the concept of periodontal defects around natural teeth (33), we suggest that as long as a bony defect is formed and clinically assessed to be a contained defect, regenerative approaches should be considered. These approaches have been statistically supported to result in better outcomes. Reconstructive surgery, in particular, has demonstrated a mean improvement in marginal bone levels of 1.7 mm and more radiographic defect fill at 12 months follow-up [weighted mean difference (WMD) =57%] (34). Additionally, a systematic review examining changes in peri-implant soft tissue levels following surgical treatment of peri-implantitis indicated that reconstructive surgery leads to less mucosal recession compared to other therapies (WMD =−1.35 mm, P=0.038) (35).

Despite limited comparisons and ongoing debates over whether radiographic outcomes accurately reflect actual tissue regeneration, current studies suggest that reconstructive surgical interventions are preferable to resective procedures when both are indicated. These interventions are more effective at maintaining stable mucosal margins while improving clinical symptoms of peri-implantitis (35). However, the choice of technique should be tailored to the specific clinical scenario and patient needs. Figure 3 illustrates a regenerative approach in treating peri-implantitis. A 57-year-old female presented complaining of persistent swelling and pain in the upper left area. Clinical examination and radiographic evaluations revealed severe bone loss affecting over two-third of the root of tooth 26 (#26) with grade III furcation involvement, which remains vital, and the presence of both intra-bony and supra-bony defects around implant 25 (i25), with a 10 mm PPD at distal side. Prognosis of both i25 and #26 were questionable due to severe bone and attachment loss with proximity. Given the patient’s absence of systemic condition, lack of drug allergies, and good adherence to non-surgical treatment, further surgical regenerative therapy was proposed and accepted by the patient. Pre- and post-operative comparisons showed successful defect fill with only mild gingival recession, despite the through-and-through furcation in the mesial-buccal root of #26. 10 months later, clinical examination showed a 5 mm PPD on the distal side of i25 with no BoP, which meets the endpoint for peri-implantitis treatment (20). This confirmed that the surgical intervention effectively halted disease progression and successfully reconstructed peri-implant hard and soft tissues over a follow-up period of nearly 1 year.

Figure 3 Clinical photos and radiograph of surgical regenerative peri-implantitis treatment. (A) Pre-operative, the upper left area exhibits mild gingival swelling and active BoP after non-surgical treatment. (B) Flap access, the buccal and palatal flaps were reflected, revealing a circumferential defect around i25 and exposure of the mesial furcation of #26. The bone loss over the distal surface of the implant involves 1/2 to 1/3 of the threads exposed, suggesting a moderate to advanced lesion. (C) Debridement, mechanical and chemical surface decontamination methods were used, including the use of scalers and curettes, irrigation with normal saline, and application of povidone-iodine. Additionally, Er:YAG lasers were utilized as part of the treatment protocol. (D,E) Biomaterials and defect filling, EMD was applied for peri-implant tissue modulation, while a combination of FDBA and xenograft grafting particles filled the defect using the sandwich technique proposed by Wang et al. (36). (F) Suturing, coronal advancement, and primary closure were achieved using 4-0 PTFE suture, and antibiotics prescription (amoxicillin 500 mg, q8h, 7 days) for infection prophylaxis. (G) Twelve weeks post-operative, with professional maintenance and follow-up, the clinical examination and radiographic film revealed successful defect fill with only mild gingival recession. (H) Twenty-four weeks post-operative. (I) Ten months post-operative, clinical examination showed stable conditions, and the radiographic film revealed increased bone density in the bone graft filling area. BoP, bleeding on probing; EMD, enamel matrix derivative; FDBA, freeze-dried bone allograft; PTFE, polytetrafluoroethylene; q8h, every 8 h.

Surgical steps for regenerative therapy

We have synthesized a sequence of surgical steps for peri-implantitis regenerative therapy, outlined as a comprehensive approach in Table 1. This protocol draws from a wealth of articles and extensive clinical practice to offer a summarized collection of procedures designed to enhance the likelihood of successful outcomes (Figure 3). Each step is carefully tailored based on existing evidence and expert consensus to address the challenges presented by peri-implantitis. Subsequent sections will expound on these seven pivotal steps of the treatment rationale.

Case selection and flap access

Successful regenerative therapy for peri-implantitis begins with proper case selection. High-risk factors such as a history of periodontitis, poor oral hygiene, smoking, and systemic diseases (e.g., poorly controlled diabetes, cardiovascular disease, immunosuppression) must be identified and addressed (3,20,37-40). Additional factors include a lack of keratinized mucosa, previous implant failures, and poorly designed prostheses which may require modification or removal and should also be evaluated before treatment (3,37). Implants with mobility or poor positioning are contraindicated for regenerative treatment and may require removal (3,16,41,42).

Preoperative management, including non-surgical therapies with or without antibiotics to reduce contaminants and inflammation, is beneficial to the following surgical steps. Although high-dose antibiotics before surgery significantly lower the failure rates of dental implant placement (43-45), it does not show consistent benefit in treating peri-implantitis. Two meta-analysis studies and a randomized controlled trial (RCT) have indicated that systemic antibiotics provide no assistance in post-operative reductions of PPD and BoP (46-48). However, antibiotics may be considered in acute inflammatory conditions or peri-implant abscesses where they can provide significant clinical benefits, such as resolving infection and preserving tissue integrity, which are essential for preparing the site for potential surgery.

Surgical defect access by incision and flap reflection should allow for complete exposure of the affected implant surface, ensuring successful decontamination and adequate blood supply for healing. When facing deep circumferential or vertical defect, sharp dissection of the attached granulation tissue is often necessary. Removing ill-fitting prosthetics, particularly for bone-level implants (two-piece implants) can improve access, lower inflammatory markers (e.g., IL-1β, IL-6, TNF-α), and facilitate primary closure, which leads to more predictable treatment outcomes (49).

Surface decontamination

The next crucial step, surface decontamination, remains a contentious topic in current research on peri-implantitis, because of the conflict purposes of removing biofilm and preserving implant surface characteristics. Although no definitive evidence suggests that any single treatment is most effective for managing peri-implant disease, it was observed that osseointegration can be attained subsequent to the decontamination of the affected implant (50). Given the substantial evidence supporting the bacterial etiology of peri-implantitis, eliminating the biofilm from contaminated implant surfaces is essential for achieving disease resolution (1,3,51). There is a strong desire for dentists to discover a readily available, easy-to-use, and cost-effective method for detoxifying an implant surface, including mechanical methods, chemical agents, lasers, and other approaches.

Mechanical methods

Mechanical debridement, using curettes, ultrasonic scalers, and titanium brushes, is the first option for biofilm removal from implant surface. Studies have shown that titanium brushes are superior to plastic curettes, improving PPD, gingival index, and reducing radiographic bone loss, with a significant PPD reduction of 4.87 mm observed over a 12-month (52,53). However, it’s important to recognize that even titanium instruments can cause treatment traces and surface roughness, which may potentially alter the implant surface characteristics (54-56).

Abrasive particle blasting systems have also shown promise in peri-implantitis treatment, which effectively removed up to 98.8% of bacterial endotoxins in vitro, with some studies reporting 100% bacteria elimination (57-59). Despite worries about implant surface damage from air abrasion, biocompatible powders seem to not negatively impact cellular responses (58,60). In vivo studies suggest these treatments can reduce BoP, yet risks like subcutaneous emphysema from prolonged use raise caution (61,62). Accordingly, a careful application of titanium instruments and/or blasting systems is recommended in areas with intra-bony defects, in order to minimize the risk of surface damage and maximize regenerative potential.

Chemical agents

Different chemical agents are commonly used in clinical practice for implant surface decontamination. Chlorhexidine (CHX) is widely used at 0.12% and 0.2% concentrations. However, recent studies point out that utilization of 0.12% CHX for peri-implant mucositis treatment did not outperform the placebo group (63). In addition, CHX at a high concentration (2%) can be cytotoxic to fibroblasts, inhibit cell migration, and compromise titanium surface biocompatibility (64,65). Citric acid, recognized for its antibacterial properties, can alter titanium surface roughness and potentially harm surrounding tissues by dissolving the oxide layer (66,67). Due to its potential toxicity and adverse effects on cell proliferation at concentrations above 4%, its use might not be recommended (68,69). Sodium hypochlorite (NaOCl) is recognized for its broad-spectrum antibacterial effects and non-toxicity, making it the most common irrigation solution in endodontics (70). A pilot study demonstrated that a 0.25% NaOCl oral rinse on peri-implantitis lesion could reduce PPD by 1.1 mm and the gingival bleeding index by 0.8 within 3 months (71). Despite its cost-effectiveness, limitations of NaOCl are its inability for smear layer removal (70), and carries a risk of iatrogenic mucosal burns.

Hydrogen peroxide, known for its strong oxidizing properties and antimicrobial activity, shows significant bactericidal effect against bacteria adhering to titanium implants in pilot studies (72,73). However, an ex vivo study demonstrated it is ineffective in removing mature biofilm from infected implant surfaces (74).

A 10% povidone-iodine, offering superior antibacterial action against Porphyromonas gingivalis (75), can eliminate 65% of biofilm-forming cells within 5 minutes (76). Although it may cause solution sensitivity and reversible yellow discoloration, these effects can be mitigated by using low concentrations for short durations (77,78). A 10% povidone-iodine is sufficient and recommended for effective surface decontamination with caution of allergic reaction.

Lasers

Over the past decades, the exploration of laser therapy in the management of peri-implantitis has expanded significantly. The efficacy of laser therapy encompasses not merely the decontamination of the implant surface, in which it successfully removes microbial contamination while maintaining surface microstructure. It also targets peri-implant defects by removing granulation tissue, detoxifying the defect area, and crucially, performing bio-stimulation to enhance healing and hemostasis, thereby promoting regeneration. This multifaceted approach is an effect that other surface decontamination methods cannot accomplish (79). Specifically, Nd:YAG, Er,Cr:YSGG, and Er:YAG lasers have been examined for their effectiveness in reducing peri-implant inflammation and bacterial decontamination (80-83). A 12-month controlled trial using the Nd:YAG laser showed significant improvements in PPD and RBLs compared to mechanical debridement alone (84). The Er,Cr:YSGG laser also demonstrated superior resolution of inflammation relative to traditional mechanical methods (85). Long-term studies, particularly with the Er:YAG laser, which is highly absorbent in periodontal tissues and offers precise control over pulse duration, have indicated sustained improvements in PPD, BoP, and RBL over 30 months follow-up period (86). These findings suggest that lasers could play a crucial role in managing peri-implantitis, allowing clinicians to select the appropriate laser based on the specific clinical needs, particularly balancing between ablation efficiency and thermal effects (87).

Despite these encouraging outcomes, the studies point out the limitations in laser-related research as well. There are only a few RCTs and comparative clinical trials, often with short follow-up periods and small sample size. Additionally, variations in study designs and implant systems used complicate the results. We need more comprehensive and standardized protocols to improve treatment efficacy and enhance tissue response to laser therapy (84,86,88).

Defect filling and membrane barrier

Surgical regenerative interventions for peri-implantitis primarily rely on the concepts of guided bone regeneration (GBR) procedures, focusing on the reintegration of the implant surface and bone reconstruction. Therefore, the biomedical materials and characteristics employed in GBR surgeries over the past decades can serve as conceptual foundations for regenerative treatments in peri-implantitis (89). To accomplish successful regeneration in peri-implantitis, two of the most commonly discussed factors are the defect configuration and its inherent limitations, as well as the choice between particulate bone grafts and/or bone substitutes, with or without barrier membranes.

As mentioned previously, a more contained bony defect may have greater peri-implant regenerative potential, though its predictability is often less certain than periodontal regeneration. According to Monje et al., bone configurations such as Classes Ib, Ic, IIIb, and IIIc are more likely to result in successful reconstructive outcomes, particularly with circumferential defects (Class Ic) (11,90). Larger bone defects, however, may require a combination of resective and reconstructive surgery for optimal results.

According to the literature, clinicians can choose bone graft materials based on their characteristics and clinical needs (91,92). Autogenous bone grafts, considered the gold standard for their osteogenic, osteoinductive, and osteoconductive properties, offer the highest potential for bone regeneration. However, their limited availability and the need for a secondary surgical site are notable drawbacks (93). Allografts provide good osteoconductive properties, but their osteoinductive potential may vary depending on the processing method. While studies have demonstrated favorable clinical outcomes using allografts in peri-implantitis cases, concerns about long-term stability, immunological aspects, and risks of disease transmission, making them unacceptable in some countries (92,93).

Xenografts, usually derived from bovine or porcine, are widely used due to their biocompatibility and slow resorption rate. They mainly serve as a scaffold, facilitating new bone formation. Clinical trials have shown that xenografts can effectively maintain ridge dimensions and support re-osseointegration, particularly when combined with barrier membranes (93-95). Synthetic bone grafts, such as hydroxyapatite, beta-tricalcium phosphate, and titanium granules, are alternative without disease transmission risks. However, their slow or non-resorption can hinder new bone growth (93). A 7-year follow-up study revealed unpredictable results when using porous titanium granules for peri-implant osseous defect treatment (96).

The choice of graft material remains controversial, and selection should be based on the specific properties of each material to optimize regenerative outcomes in peri-implantitis treatment. For instance, the “Sandwich” bone augmentation technique, leveraging the unique properties of various materials, was introduced to enhance bone augmentation results (36). This method involves layering bone grafts to mimic the natural composition of bone (36). Recent human histological studies have shown promising outcomes when combining different graft materials (97,98), warranting further consideration and research.

Membrane barriers are a crucial component in GBR procedures, particularly in the treatment of peri-implantitis and other bone defects. Two randomized clinical trials have examined the adjunctive effect of barrier membrane in peri-implantitis reconstructive therapy, especially resorbable collagen membrane due to its high biocompatibility, predictability, and maneuverability. While reconstructive surgery improved clinical measurements for peri-implantitis defects, the application of a barrier membrane to bone substitute did not significantly benefit in containable defects and was associated with post-surgical complications like soft tissue dehiscence and exposure of graft materials (99,100). Given these findings, there is an urgent need to refine surgical techniques or explore new biomaterials to reduce membrane exposure risks. Establishing a reasonable threshold for membrane exposure to access its effectiveness in peri-implant tissue may serve as an initial research goal-point for reconstructive therapy. Moreover, the effect of barrier membranes on bone formation and re-osseointegration, especially in cases of partial wound exposure, is still an under-explored area that requires further investigation (35,101).

Adjunctive approaches and biologics

Understanding that peri-implantitis is influenced not only by plaque but also by the host’s immune response, utilizing biologics to modulate inflammation in peri-implant soft and hard tissues and create an environment conducive to regeneration is crucial. Although current clinical practice guidelines, due to limited evidence, indicate that no specific surgical technique or biomaterial has proven superior (20), recent reviews emphasize the use of reconstructive techniques and biologics to enhance hard tissue regeneration, improve healing potential, and accelerate wound closure (35,90). This discussion will focus on the application of growth factors and platelet-rich fibrin (PRF), long used in periodontitis treatments, in the surgical regenerative therapy for peri-implantitis.

Growth factors: enamel matrix derivative (EMD) and recombinant human platelet-derived growth factor BB (rhPDGF-BB)

Research on EMD provides a comprehensive understanding of its application in various treatment strategies (102). For treating peri-implantitis, one study showed that EMD application on titanium surfaces significantly increased gingival fibroblast diffusion and promoted collagen-1 synthesis, as well as enhanced VEGF-A and fibronectin mRNA levels (103). A randomized clinical trial discovered that using EMD as an adjunctive to mechanical debridement significantly improved BoP and PPD, and reduced IL-6 and IL-17 levels in peri-implant crevicular fluid (PICF) post-operatively (104). Other clinical studies have also demonstrated a positive relationship between EMD use and increased marginal bone levels (105), with average PPD reduction from 4.9 to 2.7 mm, and BoP decrease from 90% to 20% (106). In essence, EMD shows promise in the treatment of peri-implantitis, particularly in surgical interventions. However, there is a clear need for more comprehensive research to confirm these findings and establish standard treatment guidelines (107).

One the other hand, current research on the effects of rhPDGF-BB on peri-implantitis treatment is relatively sparse. rhPDGF-BB is known to stimulate cell proliferation, migration, and angiogenesis, which are critical processes in tissue regeneration (108). Its application in periodontal therapy has shown promising results in enhancing soft and hard tissue healing, making it a molecule of interest for peri-implantitis treatment and deserving of further investigation.

PRF

Since the 1970s, medical applications have utilized platelet-rich plasma (PRP) for its wound healing properties, leverages platelets’ role in coagulation and their secretion of crucial growth factors like PDGF, TGF-β, VEGF, TNFα, IGF-1, and interleukins (IL-1, IL-4, IL-6). PRF evolves from PRP, combining platelets, leukocytes, red blood cells, a dense fibrin matrix, and growth factors into a scaffold for tissue regeneration. This structure ensures a sustained release of growth factors (109). Efficacy of PRF was investigated in treating peri-implantitis bone defects combination of GBR. Compared to controls undergoing flap curettage and GBR, the PRF group reported less pain and bleeding post-surgery, with significantly improved bone density at 60- and 120-day follow-up period. Though longer-term studies with larger samples are needed, this research suggests PRF, alongside GBR, significantly enhances bone defect repair in peri-implantitis while minimizing patient discomfort (110,111).

Professional maintenance and outcome assessment

Following dedicated peri-implant treatment, professional maintenance plays a vital role in preventing peri-implantitis recurrence, with a recommended recall interval of 6 months or less based on patient risk factors, including compliance and prosthetic design (112). Recent systematic reviews and consensus report even suggest that peri-implant maintenance therapy (PIMT) should be provided every 3–4 months for the first 12 months after surgical treatment of peri-implantitis (1,20,113), significantly reducing failure rates by up to 90% compared to neglecting maintenance (P=0.001) (114). A cross-sectional study involving 206 implants in 115 patients over 36 months clearly showed a statistically significant association between patient compliance and peri-implant conditions (P=0.04). At least two PIMTs per year are essential for preventing peri-implantitis, and factors such as history of periodontal disease and smoking habits can significantly lower patients’ adherence to the maintenance treatments (115). Therefore, individualized professional PIMT strategies are needed to prevent further peri-implant disease.

Prompt intervention is essential for any recurrence of inflammation, with a preference for non-surgical treatments as previously mentioned. Moreover, educating patients on proper implant care, including effective brushing and flossing techniques, is key for improving treatment outcomes. Emphasizing smoking cessation is equally important, as smoking significantly reduces implant success rate (40).

In summary, regular professional maintenance significantly lowers the risk of implant failure, illustrating its indispensable role in securing long-term implant success. The ongoing discussion will explore how professionals can perform outcome assessments within maintenance therapy to enhance treatment success rates and prolong the lifespan of dental implants.

Clinical and radiographic evaluation

The primary clinical criteria for diagnosing peri-implantitis progression involve changes in crestal bone level and the presence of BoP or suppuration, often accompanied by deepening peri-implant pockets (51). Traditional parameters like modified gingival index or BoP have been questioned its validity around dental implant due to the likelihood of pin-point bleeding spot in healthier peri-implant tissue—a bleeding tendency scale may be more helpful (116). Additionally, the accuracy of probing can also be affected by factors like prosthesis design, mucosal mobility, implant thread irregularity, bone defects, and measurement errors. Radiographic assessment is needed together with clinical examination to make a more definitive diagnosis and treatment outcome (6,117).

Radiographic evaluations, including periapical and bitewing X-rays, are essential for assessing bone levels, particularly when inflammation is present (1,6). However, their two-dimensional nature may underestimate bone loss, as studies have shown intraoperative peri-implant bone levels are statistically more apical than the radiographic findings (12,118). This underscores the importance of proactive intervention upon observing bone loss in X-ray images during periodical examinations. For cases requiring additional diagnostic detail, dental cone beam computed tomography (CBCT) offers superior three-dimensional imaging of both hard and soft tissues, aiding in the assessment of implant apical engagement or residual buccal/lingual bone plate height, which may impact implant stability and the outcome of reconstructive surgery. Despite its advantages, CBCT does have limitations, such as metal artifacts and concerns about radiation exposure (119,120). Therefore, Intraoral radiographs remain the primary tool for routine evaluation of peri-implant lesions (6,20).

Soft tissue stability is another key factor for implant health (35,121). Recent research suggests that a soft tissue thickness of 2mm or more around implants enhances aesthetic outcomes and long-term stability. Soft tissue augmentation using connective tissue grafts (CTGs) or acellular dermal matrices (ADMs) can effectively increase mucosal thickness (15,122). Besides, maintaining at least 2 mm of KMW is vital for reducing peri-implantitis risk, plaque accumulation, soft-tissue inflammation, discomfort on brushing, and marginal bone loss (14,20).

A comprehensive peri-implantitis assessment involves precise clinical and radiographic analysis. Concurrently, gauging peri-implant soft tissue phenotype, modifying mucosal thickness and KMW if needed, plays a significant role in reducing PPD and maintaining peri-implant health and stability over time.

Histological evidence for peri-implantitis regenerative therapy

In major studies on peri-implantitis treatment, success has often been gauged by radiographic signs of bone fill and close bone-to-implant contact (BIC) upon clinical reentry. However, these indicators fall short of proving re-osseointegration, which requires histological evidence of direct new BIC on surfaces previously decontaminated. Animal studies over the past decades have shown that re-osseointegration is achievable (50,81,123,124). For instance, Persson et al. conducted a preclinical study on dogs, revealing that re-osseointegration failed to occur on implant surfaces exposed to bacterial contamination, but did consistently occur where a pristine implant component was placed in the bone defect after surgical debridement (50). Similarly, another canine study by Nevins et al. elaborated the effectiveness of the Er:YAG laser in halting the inflammatory process around contaminated implants and promoting new BIC, indicating that the Er:YAG laser creates a favorable environment for re-osseointegration (81,124). A systematic review of surgical regenerative therapy for induced peri-implantitis in animals showed promising results, aligning with recent preclinical studies (124-127). However, translating these findings to humans has been challenging due to biological limitations and ethical concerns.

Notably, Fletcher in 2017 reported the first known case demonstrating human histologic evidence of re-osseointegration around an implant affected by peri-implantitis (94). The treatment involved removing the restoration for primary closure, followed by comprehensive debridement using cost-effective materials such as plastic curettes, dilute NaOCl, hydrogen peroxide, and sterile saline, and then GBR with calcium sulfate, bovine bone, and a porcine collagen barrier. Six months later, significant bone fill has occurred within the walls of the intra-bony defect, and out of the eight initially exposed implant threads, direct BIC was observed in the bottom three threads. One should also note that, as observed in the longer-term clinical trial, transition of quality radiographic bone fill at the interface indicative of re-osseointegration may take up to 1–2 years (86). The histological findings indicated nearly 100% new bone integration in the three threads with no inflammatory cells evident near or away from the implant (94). The study suggests that re-osseointegration is achievable in humans, even on previously contaminated implant surfaces. Furthermore, this process can be accomplished using cost-effective and readily available tools and substances.

Subsequent articles, including a human autopsy case in 2018 and two clinical studies on electrolytic cleaning or Er,Cr:YSGG laser debridement with regenerative therapy, have further supported the possibility of re-osseointegration in humans (97,98,128). Despite challenges such as incomplete defect fill and soft tissue ingrowth and recurrent peri-implantitis, these studies demonstrated promising results in terms of bone gain, reduced PPD, and less BoP, with varying degrees of re-osseointegration observed (98,128).

These findings highlight the potential for re-osseointegration in treating peri-implantitis in humans, even with different but accessible and cost-effective techniques. More studies have been published and details are outlined in Table 2 for histological evidence of peri-implantitis regenerative therapy.

Some scholars advocate using the term “reconstructive therapy” for peri-implantitis as more appropriate since limited evidence for regenerative outcome. However, one must differentiate a regenerative treatment outcome from its treatment intention. Not every periodontal regenerative therapy can achieve regenerative outcome since no histology can be scrutinized. Therefore, we describe in most cases as radiographic bone fill but not regeneration due to a lack of histological evidence. In the case when a regenerative therapy for peri-implantitis was provided, we can never determine its regenerative outcome without histological evidence. In this sense, the use of regenerative therapy for peri-implantitis can be reasonable given the current abundant animal and precious human histological evidence to support this attempt. Further research is needed to strengthen this evidence.

Biomarkers

Recent studies have explored the use of biomarkers in diagnosing and monitoring peri-implantitis, trying to distinguish healthy peri-implant conditions from disease states (129). A systematic review summarizes the latest research on biomarker concentrations in the saliva and PICF of patients with healthy implants, peri-implant mucositis, and peri-implantitis. It found significantly higher concentrations of IL-1β, RANKL, sRANKL, IL-6, TNF-α, TNFSF12, MMP2, and MMP8 in the peri-implantitis group compared to the healthy group (130,131). A 5-year retrospective study also suggested that elevated levels of active MMP8, detected 6 months after implant loading, could be a strong predictor of peri-implantitis onset, even preceding clinical and radiographic signs (132).

Given the limitations of probing depth in measuring peri-implant defect and monitoring disease status, biomarkers are increasingly utilized to monitor the disease progression and treatment outcome (133). For example, a clinical trial assessing adjunctive Er:YAG laser therapy in regenerative treatment demonstrated significant downregulation of IL-1β and VEGF in PICF, with sustained effects for up to 6 months (134). This highlights biomarkers’ value in determining disease stability, since probing depth alone has limited sensitivity and accuracy in representing status.

Additionally, next-generation sequencing technology has revealed the immunolandscape of the peri-implant granulation tissue. The deconvoluted immune cell profile can predict the regenerative treatment outcome and thus provide risk assessment for personalized treatment strategies and maintenance program (135). These studies provide valuable insights into the use of biomarkers for the assessment of peri-implant disease activity and provide higher resolution for outcome measurement and future research methods.

Conclusions

This comprehensive review underscores the vital role of surgical regenerative therapies in managing peri-implantitis, a condition that significantly impacts dental implant longevity and patient well-being. Through a detailed examination of various treatment strategies, including the use of advanced laser technology and innovative biomaterials, we may be able to effectively halt disease progression and promote regeneration to reestablish implant re-osseointegration. The evidence presented, particularly from human histological studies, supports the feasibility of regenerative therapy. Furthermore, an increasing number of clinical trials and studies are demonstrating the efficacy of regenerative approaches in restoring the structure, health, and function of peri-implant tissues.

However, it is crucial to acknowledge the limitations of this review, which primarily arise from the selection and scope of the manuscripts included. The variability in study designs and the scope of data reviewed may influence the generalizability of the findings. As such, while the potential for regenerative approaches to restore the structure, health, and function of peri-implant tissues is promising, current evidence underscores prevention as the cornerstone of managing peri-implantitis. While further research is needed to refine the treatment approach and re-define predictability, the outlook for surgical regenerative therapy in managing peri-implantitis is still warranted.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-36/prf

Funding: This manuscript was partially supported by the Yushan Fellow Program by the Ministry of Education (MOE) (No. 112-2001-012-400) to C.W.W.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-36/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All clinical procedures described in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients for the publication of this article and accompanying images.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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