The Effectiveness of a Bioactive Healing Abutment as a Local Drug Delivery System to Impact Peri-Implant Mucositis: A Prospective Case Series Study

Modern dental therapy makes use of prosthetic implant reconstructions, which are supported or retained on dental implants. The most frequent, long-term complications associated with these prosthetic implants include mucositis and peri-implantitis. Since mucositis is the initial inflammation of tissues supporting the dental implant, the management of this condition is thus crucial. The aim of the present study was to assess the effects of the placement of bioactive healing abutment for 48 h, in patients diagnosed with peri-implant mucositis. Moreover, the quantitative and qualitative shift in the bacterial profile of the biofilm present in the peri-implant pockets, was assessed by means of RT-PCR genotyping. Each patient was examined using a commercially available PET test protocol: the first sample was taken upon diagnosis (after which the bioactive healing abutment, with clindamycin at a dose of 30 mg, was used for 48 h and replaced with the prosthetic superstructure used so far by a patient); the second sample was taken two weeks after removal of the bioactive healing abutment. The effects of the intervention were clinically assessed using the PET test after the two weeks. A significant reduction in mucositis was observed following treatment, as measured by periodontal indices: modified Sulcus Bleeding Index—mBI (p < 0.001), modified Plaque Index—PLI (r = 0.69, Z= −4.43; p < 0.001) and probing depth—PD (Z = −4.61; p < 0.001). Significant differences in the occurrence of periopathogenic bacteria were also observed: Aggregatibacter actinomycetemcomitans (p < 0.014; Z = −2.45; r = 0.38), Treponema denticola (p < 0.005; Z = −2.83; r = 0.44), Tannerella forsythia (p < 0.001; Z = −4.47; r = 0.69) and Porphyromonas gingivalis (p < 0.132; Z = −1.51).


Introduction
Dental implants are commonly used in prosthodontics to restore single or multiple missing teeth, rehabilitate the stomatognathic system in edentulous patients and to restore the aesthetics of the dental arches [1]. The long-term, single-implant restoration survival rate in a fifteen-year period has been shown to range from between 89-94% [2][3][4].
Non-surgical therapy alone does not appear to be effective in a large proportion of cases. Although published cases have shown promising additional benefits when using systemic antibiotics as an adjunct to non-surgical treatments for peri-implantitis, no randomized clinical trials have been conducted to evaluate the effects of systemic antibiotics, including metronidazole, in addition to conservative treatment of peri-implantitis. Moreover, the justification for the use of systemic antibiotics in the periprocedural period during implantation is being questioned due to the possibility of general complications in the patient, the development of drug-resistant strains and the questionable effectiveness in reducing the number of complications [20,25,26]. The current state of medical knowledge prompts the search for modern treatments for peri-implantitis and peri-implant mucositis based on the local application of bacteriostatic and bactericidal drugs [24].
To date, studies aimed at non-surgical methods of eradication or at least remission of peri-implant inflammation have been based on the use of local drug application via implant pockets or medical devices [24]. Implant pocket drug delivery seems to be imprecise in dosage and unpredictable in pharmacodynamics and pharmacokinetics. Medical devices such as bioactive healing abutment can be substantively justified but, so far, their effectiveness has been tested only in vitro [24,27]. Locally delivered antibiotics, together with mechanical debridement, are indicated for non-responding sites of focal infection or in localised recurrent disease. Topical application of the drug, as compared to systemic administration, in the management of periodontal and peri-implant diseases shows a much more favorable effect on the MIC (minimally inhibitory concentration) and is characterized by low-level antibiotic resistance [28]. clindamycin is a bacteriostatic antibiotic of the lincosamide group. It is active against most bacterial strains that play an important role in the etiology of peri-implant and periodontal diseases. When administered in general, it may encounter bacterial resistance and produce some adverse effects. When administered topically, it can reach higher concentrations, which even results in a bactericidal effect, avoiding general health complications. The mechanism of its action is based on the inhibition of bacterial protein biosynthesis, by binding to the 50S ribosome subunit, followed by blocking the A site and 16-L protein [29]. Systemic administration of clindamycin provides a bone concentration of 1/3 that of the serum level. When applied topically, in higher concentrations, clindamycin is bactericidal. Furthermore, systemic use of clindamycin may lead to the development of acute pseudomembranous colitis [30].
The authors searched the PubMed, ProQuest and Web of Science databases using the keywords: clindamycin, bioactive healing abutment, peri-implantitis and peri-implant mucositis and found no publications from human clinical trials. This study is the first attempt to examine the effects of bioactive healing abutment and clindamycin on the reduction of bacteria residing in the peri-implant tissue in humans.
The aim of the study was to conduct a preliminary clinical and microbiological evaluation of the use of an innovative bioactive healing abutment, of its own design, as a tool for the local administration of biologically active agents in the vicinity of a dental implant. The authors wanted to assess the potential impact of clindamycin secreted from this bioactive healing abutment on the condition of periodontal tissues in patients with diagnosed peri-implant mucositis.

General Statements
The study was classified as an observational prospective case series study, according to the taxonomy of Grimes and Schulz clinical trials [31]. To ensure the quality of these studies, the STROBE reporting guidelines recommended by the 7th European Periodontology Workshop were used, and all proposals for a set of outcome domains for clinical research in implant dentistry for peri-implant health (marginal bone level, tissue inflammation-Bleeding On Probing (BOP) with modified Sulcus Bleeding Index (mBI) and probing depth have been investigated [32]. The study was conducted with the consent of the Bioethics Committee at the Medical University of Warsaw no KB/211/2020 and was conducted in

Participants
The participants were 41 generally healthy, non-smoking participants, who were not taking any medications on a regular basis-20 female (48.8%) and 21 male (51.2%)-aged from 39 to 76 years old (M = 55.46; SD = 10.11). Twelve participants received implants in the aesthetic region (29.3%), the other 29 received implants in the premolar and molar areas (70.7%).

Case Qualification
All patients admitted to the study had permanent prosthetic restorations on one to six intraosseous titanium implants in the past. All prosthetic superstructures were made in the form of single crowns screwed on implants or block crowns screwed on implants. All implants were inserted into a fully healed alveolar bone and loaded in a delayed protocol. The time that had passed since the implementation of the permanent prosthetic superstructure ranged from between 26 to 54 months.
A homogenous study group was obtained, consisting of individuals with high socioeconomic status.
The initial recruitment of patients for the study was based on a clinical evaluation performed during the routine follow-up of patients after implant treatment. In most cases (18 persons-60%), patients did not report any subjective symptoms. Peri-implant mucositis was observed in relation to 22 implants (53.66%), the development of which went unnoticed by the patient. All implants were bone level internal connection with a hexagon shape and 3.75 diameter platform.
After the interview was completed, all cases were assessed both periodontally and radiologically. As part of the radiological examination, CBCT (cone beam computed tomography) segmental scans were taken and bone loss was assessed at four points (medial, linguistic, distal and buccal), by two independent examiners. Cases in which bone loss was observed were excluded from the study design.

Periodontal Examination
Periodontal examination included: modified Plaque Index (mPlI), modified Sulcus Bleeding Index (mBI) and Pocket Depth (PD) measurements, as described by Mombelli et. al. [33]. Periodontal examinations were performed by two independent investigators and the results were given as the mean of the studies.
A KerrHawe Click-Probe was used. Peri-implant mucositis diagnosis was based on the presence of peri-implant inflammation symptoms, including redness, swelling and bleeding on probing without additional bone loss in comparison to the last examination.
The calibration process in periodontology consisted of two parts: examiner alignment and examiner assessment, according to the standard protocol. The mutual agreement was assessed by a pilot study prior to the main periodontal examination. Since the pilot measurements were completed, the obtained discrepancies were at ∆ > 1. The κ statistics were used to assess the examiners' agreement. We calculated that κ >0.8 in all selected to the study indices. Since the two examiners specialized in periodontology, the risk of bias was further lessened.  were used to assess the examiners' agreement. We calculated that κ >0.8 in all selected to the study indices. Since the two examiners specialized in periodontology, the risk of bias was further lessened.  After the diagnosis of peri-implant mucositis, the bacterial profile of the biofilm present in the peri-implant pockets was assessed by means of real-time PCR genotyping (MIP-Pharma). A commercially available PET test kit (MiP Pharma GmbH), in accordance with the described manufacturer protocol we used. Samples were collected by a paper filer and real-time PCR with a fluorescent probe was then performed. In the next step, the prosthetic crown was unscrewed from the implant. The prosthetic superstructure was sent for decontamination and sterilization. The implant socket was then rinsed with saline until any debris was removed and spontaneous bleeding ceased. The bioactive healing abutment (patent no PL238183) described by Iwańczyk, Wychowański et al. [27] was then fixed with the torque of 10 N/cm to the implant affected by the peri-implant mucositis. The BHA was made of grade 5 titanium alloy (Ti6Al4V). The BHA resembled the typical healing abutment and was fixed by screwing to the implant-prosthetic platform. The innovation is bases on the hollow structure inside the abutment that communicate with the peri-implant pockets via release holes. The BHA chamber may be refilled with the active substance thanks to the removable cover mounted on its top.

Study Design
The chamber of bioactive healing abutment was filled with clindamycin on a collagen carrier and closed with the lid. Figure 2 below shows a schematic outline of the technical data of the bioactive healing abutment. After the diagnosis of peri-implant mucositis, the bacterial profile of the biofilm present in the peri-implant pockets was assessed by means of real-time PCR genotyping (MIP-Pharma). A commercially available PET test kit (MiP Pharma GmbH), in accordance with the described manufacturer protocol we used. Samples were collected by a paper filer and real-time PCR with a fluorescent probe was then performed. In the next step, the prosthetic crown was unscrewed from the implant. The prosthetic superstructure was sent for decontamination and sterilization. The implant socket was then rinsed with saline until any debris was removed and spontaneous bleeding ceased. The bioactive healing abutment (patent no PL238183) described by Iwańczyk, Wychowański et al. [27] was then fixed with the torque of 10 N/cm to the implant affected by the peri-implant mucositis. The BHA was made of grade 5 titanium alloy (Ti6Al4V). The BHA resembled the typical healing abutment and was fixed by screwing to the implant-prosthetic platform. The innovation is bases on the hollow structure inside the abutment that communicate with the peri-implant pockets via release holes. The BHA chamber may be refilled with the active substance thanks to the removable cover mounted on its top.
The chamber of bioactive healing abutment was filled with clindamycin on a collagen carrier and closed with the lid. Figure 2 below shows a schematic outline of the technical data of the bioactive healing abutment.

Preparation of the Insert for the Bioactive Healing Abutment
Dalacin C, 300 mg capsules (Pfizer, Brussels, Belgium), saline and natural collagen-Collacone (Botiss, Zossen, Germany) were used to prepare the cartridge. A total of 30 mg of clindamycin, in the form of Dalacin C 300 mg capsules, was weighed using SBS-LW-200N laboratory balance (Steinberg Systems, Dusseldorf, Germany). The weighed clindamycin was made into a paste using saline on the glass. The prepared paste was used to moisten the fragment of collagen (Collacone, Botiss, Zossen, Germany) located in the bioactive healing abutment chamber. After closure of the lid, the patient was allowed to leave the clinic and then returned after two days.

Preparation of the Insert for the Bioactive Healing Abutment
Dalacin C, 300 mg capsules (Pfizer,Brussels, Belgium), saline and natural c Collacone (Botiss, Zossen, Germany) were used to prepare the cartridge. A tota of clindamycin, in the form of Dalacin C 300 mg capsules, was weighed using 200N laboratory balance (Steinberg Systems, Dusseldorf, Germany). The clindamycin was made into a paste using saline on the glass. The prepared paste to moisten the fragment of collagen (Collacone, Botiss, Zossen, Germany) loca bioactive healing abutment chamber. After closure of the lid, the patient was a leave the clinic and then returned after two days.
The bioactive healing abutment was then unscrewed and the implant s rinsed with saline and the previously sterilized old prosthetic superstructure The second real-time PCR (MIP-Pharma PET) was performed two weeks after superstructure restoration. At the same visit, the second periodontal examin performed including Plaque Index (mPlI), modified Sulcus Bleeding Index ( Pocket Depth (PD) assessment. All patients who took part in the study remain constant medical supervision and had the opportunity to obtain appropriate a should the need have arisen.

Statistical Analysis
In order to address the research questions, we carried out statistical analy obtained database using IBM SPSS Statistics v.25 software (Armonk, New York United States). We calculated basic descriptive statistics using Shapiro-W Wilcoxon's tests and Mann-Whitney tests. An alpha value threshold of 0.05 (p < used. The Shapiro-Wilk test was statistically significant, meaning that the distr all variables was significantly different from the normal distribution. Both skew kurtosis were high, therefore non-parametric tests were used. Statistical power o The bioactive healing abutment was then unscrewed and the implant socket was rinsed with saline and the previously sterilized old prosthetic superstructure was fixed. The second real-time PCR (MIP-Pharma PET) was performed two weeks after prosthetic superstructure restoration. At the same visit, the second periodontal examination was performed including Plaque Index (mPlI), modified Sulcus Bleeding Index (mBI) and Pocket Depth (PD) assessment. All patients who took part in the study remained under constant medical supervision and had the opportunity to obtain appropriate assistance, should the need have arisen.

Statistical Analysis
In order to address the research questions, we carried out statistical analysis on the obtained database using IBM SPSS Statistics v.25 software (Armonk, New York, NY, USA). We calculated basic descriptive statistics using Shapiro-Wilk tests, Wilcoxon's tests and Mann-Whitney tests. An alpha value threshold of 0.05 (p < 0.05) was used. The Shapiro-Wilk test was statistically significant, meaning that the distribution of all variables was significantly different from the normal distribution. Both skewness and kurtosis were high, therefore non-parametric tests were used. Statistical power of the tests used was calculated using the G*Power 3.1.9.4 program. We assumed dependent sample analysis (Wilcoxon tests), moderate effect size, p value at the level of 0.95 (α = 0.005) sample size n = 41 and the estimated power of a test was 0.92. As can be observed in the results, in many cases, we observed high effect sizes-if analyzed with such input, the power of a test was 0.999.

Results
Using the proposed protocol of administration of clindamycin from a bioactive healing abutment in patients with peri-implant mucositis, the authors obtained statistically significant results in relation to the observed some clinical symptoms: level of bleeding gums (mBI); the level of plaque deposit (mPLI), occurrence of both redness and swelling of the gums and probing depths by implants.
Significant differences in the frequency of occurrence of different bacteria strains were observed following treatment. These differences concern the occurrence of: Aggregatibacter actinomycetemcomitans Treponema denticola, Tannerella forsythia and Peptostrep. (Micromonas) micros. The size of all the observed effects was high or very high.
A significantly lower number of bacteria, both total number of bacteria and the number of bacteria in each strain, was observed after the treatment in relation to Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Peptostrep. (Micromonas) micros, Fusobacterium nucleate, Eubacterium nodatum, Porphyromonas gingivalis, Treponema denticol and Capnocytophaga gingivalis strains.

Bleeding Gums-Modified Sulcus Bleeding Index-mBI
We found a statistically significant frequency reduction in the level of bleeding gums following treatment mBI, Z = −5.39; p < 0.001. As can be seen in Table 1, better results were observed in 36 patients while there were no differences in only five of the patients. The size of the observed effect was very high, r = 0.84.

Plaque Deposit-Modified Plaque Index-mPLI
A significant reduction in the level of plaque deposit was observed following treatment mPLI, Z = −4.43; p < 0.001. As can be seen in Table 2, mPLI were better in 27 patients, while there were no significant differences observed before and after treatment in 12 of the patients, and slightly worse plaque deposit observed in 2 patients. The size of the observed effect was very high, r = 0.69.

Redness, Swelling and Exudation
A significant reduction in the occurrence of both redness and swelling was observed following in treatment. As can be seen in Table 3, we observed improvement in redness in 41 patients in swelling in 36 patients. The size of both effects were very high. Exudation was not observed upon both measurement I and II.

Depth of Pockets Formed by Implants
A significant reduction in probing depths by implants was observed following treatment, Z = −4.61; p < 0.001 ( Figure 3). Improvements were observed in 24 of the patients, while there was no change in the remaining 17 patients. The size of the observed effect was very high, r = 0.72.

Redness, Swelling and Exudation
A significant reduction in the occurrence of both redness and swelling was observed following in treatment. As can be seen in Table 3, we observed improvement in redness in 41 patients in swelling in 36 patients. The size of both effects were very high. Exudation was not observed upon both measurement I and II.

Depth of Pockets Formed by Implants
A significant reduction in probing depths by implants was observed following treatment, Z = −4.61; p < 0.001 ( Figure 3). Improvements were observed in 24 of the patients, while there was no change in the remaining 17 patients. The size of the observed effect was very high, r = 0.72.

Occurrence of Bacterial Strains
Significant differences in the frequency of occurrence of different bacteria strains were observed following treatment (Table 4). Aggregatibacter actinomycetemcomitans was absent following treatment (at measurement II) in six patients out of the nine patients in which this pathogen was present before treatment (at measurement I). Treponema

Occurrence of Bacterial Strains
Significant differences in the frequency of occurrence of different bacteria strains were observed following treatment (Table 4). Aggregatibacter actinomycetemcomitans was absent following treatment (at measurement II) in six patients out of the nine patients in which this pathogen was present before treatment (at measurement I). Treponema denticola, Tannerella forsythia and Peptostrep. (Micromonas) micros were all absent following treatment in 8 out of 19 patients, 20 out of 27 patients and Peptostrep. in 17 out of 40 patients, respectively. The size of all the observed effects was high or very high. Nearly statistically significant difference in Eubacterium nodatum was observed following treatment. This pathogen was absent at measurement II in three out of five patients. Size of this effect was moderate. Other results were not statistically significant. Porphyromonas gingivalis was absent following treatment (at in measurement II) in 8 out of 12 patients in which this pathogen was present before treatment (at measurement I). Interestingly, this pathogen was observed in three patients following treatment (at in measurement II), while it was absent in these patients prior to treatment (at measurement I). Capnocytophaga gingivalis was absent following treatment in 1 out of 31 patients, while Prevotella intermedia was not observed in any of the patients, both before and after treatment.

Number of Bacteria Detected in Peri-Implant Soft Tissues
A significantly lower number of bacteria, both total number of bacteria and the number of bacteria in each strain, was observed after the treatment. The size of the observed effect was very high with regards to the total number of bacteria and for the number of bacteria of Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Peptostrep. (Micromonas) micros, Fusobacterium nucleatum and Eubacterium nodatum strains, high in Porphyromonas gingivalis, Treponema denticola strains. The effect size was moderate with regards to the number of bacteria of the Capnocytophaga gingivalis strain. Results are shown in Table 5. The total number of bacteria before (measurement I) and after treatment (measurement II) with a bioactive healing abutment containing clindamycin are presented in Figure 4.

Number of Bacteria Detected in Peri-Implant Soft Tissues around Front and Posterior Implants
A significantly lower number of Fusobacterium nucleatum and Capnocytophaga gingivalis was observed in patients with frontal teeth implants at measurement I ( Table 6). The size of the observed effect was moderate for the Fusobacterium nucleatum strain and high for the Capnocytophaga gingivalis strain. Table 6. Number of bacteria detected in peri-implant soft tissues of patients, depending on the position of the implant, before (measurement I) and after treatment (measurement II) with a bioactive healing abutment containing clindamycin.

Number of Bacteria Detected in Peri-Implant Soft Tissues around Front and Posterior Implants
A significantly lower number of Fusobacterium nucleatum and Capnocytophaga gingivalis was observed in patients with frontal teeth implants at measurement I ( Table 6). The size of the observed effect was moderate for the Fusobacterium nucleatum strain and high for the Capnocytophaga gingivalis strain. There were no statistically significant differences in both total number and the number of bacteria per strain. There were also no significant differences in the total number of bacteria or the number of bacteria per strain following treatment (at measurement II).

The Difference in the Number of Bacteria before and after Treatment
We also calculated the difference in the number of bacteria between measurements (i.e., before and after treatment). A significant decrease in the number of Fusobacterium nucleatum and Capnocytophaga gingivalis was observed in patients with front teeth implants. The size of the observed effects was moderate. Other differences were not statistically significant (Table 7). Table 7. The difference in the number of bacteria between measurements (i.e., before and after treatment with a bioactive healing abutment containing clindamycin) in patients with front and side teeth implants.

The Case Presentation
The case study referring to the peri-implant mucositis of 12 implant treatments in the described research scheme is shown in Figures 5 and 6.

Discussion
This is the first study to present a novel method of mucositis treatment in patients after implantoprosthetic proceedings. To date, there has been no constructed study on animals concerning the use of the bioactive healing abutment containing an antibiotic. The differences in bacterial contamination between animals and humans seems to constitute an insurmountable obstacle at present. An animal's tooth size is significantly different to

Discussion
This is the first study to present a novel method of mucositis treatment in patients after implantoprosthetic proceedings. To date, there has been no constructed study on animals concerning the use of the bioactive healing abutment containing an antibiotic. The differences in bacterial contamination between animals and humans seems to constitute an insurmountable obstacle at present. An animal's tooth size is significantly different to that of a human, and the diet and chewing function seems to be the next obstacle to providing a reliable animal model to study the action of the bioactive healing abutment. In order to obtain the most reliable data, the study was conducted on humans after obtaining approval from the bioethics committee, as a follow-up of the in vitro study [26].
The use of the bioactive healing abutment resulted in a reduction in the levels of clinical indices of inflammation, measured using mBI, mPI and PD indicators. Moreover, a decrease in redness and swelling of the gums around the implants was observed. In the genetic study, a significant reduction in the total number of bacteria was observed, as well as a significant reduction in the number of Aggregatibacter actinomycetemcomitans (Aa), Treponema denticola (Td), Tanerella forsythia (Tf) and Peptostreptococcus micros (Pm). A decrease in the number of Porphyromonas gingivalis (Pg) was also observed, although it was not significant. Most of these bacteria belong to the red complex, according to Socransky [34]. The presence of these bacteria is associated with inflammation of periodontal tissues, which clinically manifests itself as bleeding on probing. The red complex bacteria produce specific invasins and are able to relocate, which enables them to penetrate the gum tissue and makes them difficult to remove through standard debridement methods. In addition, gram (-) bacteria, with Aa being one of them, activate the inflammasome complex, which through the action of NLRP proteins leads to an increase in the secretion of pro-inflammatory cytokines [35]. Hence, there is a theoretical basis for the use of clindamycin in bioactive healing abutment in order to reduce the number of bacteria and in doing so, the local inflammatory reaction [36]. Practical studies, with clindamycin's use as a pharmacologically active agent placed in bioactive healing abutment have been carried out only in vitro [27].
The causes of mucositis and peri-implantitis are diverse. The most common causes include improper hygiene measures, residual bacterial biofilm around the implants, reduced width of keratinized gums, occlusal overload and local factors related to the design of implants, including material imperfections such as microleakage and misfit of the abutment [37]. In the long run, most of the above-mentioned factors lead to the colonization of the implant structures by particularly pathogenic bacteria such as Aa and Pg. The bacterial biofilm leads to the development of mucositis. If left untreated, the inflammation spreads to the bone that is supporting the implant and, consequently, peri-implantitis develops [38]. Many previous efforts to prevent peri-implantitis were based on the modification of the implant surface by: modified sandblasting and an acid etching technique (mod-SLA), coating with hydroxyapatite or polyglycolactonic acid (PLGA) and covering the implant surface with recombinant human bone morphogenetic protein (rhBMP-2) solution. These methods influenced the process of osseointegration of the implant, which is crucial in the healing phase, but did not constitute a line of defense against bacterial colonization, and thus did not protect against the development of mucositis or peri-implantitis.
Earlier attempts related to the local use of antibiotics in the treatment of peri-implantitis involved performing an open-flap debridement, and then a drug was applied to the prepared surface of the implant and to the position of the bone lesion. The results obtained indicated a reduction in inflammation, which led to a reduction in the loss of dental implants due to peri-implantitis [39]. Peri-implantitis is an advanced form of inflammation of the tissues around the implant. In modern treatment, we rely on the early diagnosis of mucositis and the implementation of mucositis treatment methods, as it is a reversible inflammation of soft tissues that does not yet affect bone structure. Therefore, controlling mucositis is a form of peri-implantitis prevention. The treatment of peri-implantitis is long, costly, burdensome for the patient and the prognosis is uncertain. Moreover, the effectiveness of regenerative methods used in the treatment of peri-implantitis depends on many factors, such as: age, disease burden, general medications used, and on local factors including bone defect conformation and tobacco smoking. Hence, regimens for the treatment of mucositis and the prevention of peri-implantitis have been developed for years.
In the year 2000, the cumulative interceptive supportive treatment (CIST) protocol was published [40]. In the case of mucositis, this protocol recommended mechanical debridement and antiseptic cleansing. Only in the case of pocket depths (PD) of >5.0 mm and radiologically confirmed bone loss of 2.0 mm, local or general antibiotic therapy and/or regenerative surgery were advised. The described CIST protocol did not assume the use of an antibiotic in the treatment until the condition developed into what we now call peri-implantitis. Moreover, in the case of inflammation of the soft tissues around the implants (PD ≤ 3.0 mm and BOP (+) positive), only local measures of the peri-implant pocket treatment were implemented. To our knowledge, bacteria such as Aa, Pg, Tf and Td secrete a number of collagenases and invasins, the activity of which leads to the lysis of extracellular matrix, and finally the penetration of these bacteria into the gum tissue. Clindamycin is characterized by a high rate of gingival infiltration [41]. It is active against gram (+) and (-) bacteria, especially against anaerobic bacteria present in the tissue of infected gums. Topical application of clindamycin promotes rapid achievement of high active concentrations at the site of administration and reduces the risk of developing antibiotic resistance. Moreover, there is no risk of developing C. difficile colitis, which is common when clindamycin is administered orally.
In most cases, the authors noted a significant decrease in the number of individual bacterial strains in the peri-implant pockets of patients after the application of clindamycin with BHA. The registered growth of P. gingivalis in three tested people may be the result of some hygienic negligence, pharmacodynamics of clindamycin release or drug resistance of bacterial strains. The resistance of some strains of periopatogens on clindamycin should be considered [42]. The significant advantages of using the described method of mucositis treatment include the fact that the described method of treatment is not bothersome for the patient. The application of the drug in bioactive healing abutment takes place during one dental appointment. In addition, there is no need for surgery, and fixing the bioactive healing abutment itself does not require anesthesia or incision of the gum. The procedure is quick and relatively cheap. The most important feature obtained in the proposed treatment protocol is the long-lasting elimination of periopathogenic bacteria, as the second measurement was performed two weeks after the removal of the bioactive healing abutment. Limitations of the study include the inability to control drug release over time, and the lack of established guidelines for oral hygiene in patients with mucositis.
Modern strategies for the clinical and microbiological management of the oral microbiota include personalized protocols with a proactive approach. These algorithms include a combination of minimally invasive instrumentation, to avoid tissue reorganization, and the topical use of probiotics and paraprobiotics to enhance these treatments. Proactive actions act only on the risk factors, and rebalancing the bacterial biota present within the gingival sulcus and cervical fluid. These strategies are willingly accepted by the patients due to their atraumatic character as well as avoidance of the use of antibiotic. The proposed bioactive healing abutment may be a useful active agent delivery toll to peri-implant sulcus in these modern periodontal treatment strategies [43][44][45][46].
The release time of the active agent varies with the drug used, the carrier used as well as the number and size of releasing holes and the clinical conditions. In the presented in-vivo study, periodontium is an important factor influencing the release of antibiotic. The probing depth of the peri-implant pocket, periodontal phenotype and gingival fluid flow, as an inflammatory exudate may be important variables. The above factors constitute the further limitations of the study and the need for in vitro and in vivo study to optimize the drug release curve.
Another limitation of our study was the performance of only bacteriological and clinical examinations of the peri-implant tissues, without the examination of cytokine and enzyme levels. Our results, therefore, reflect the sum of the actions (bacteriostatic, bactericidal and anti-inflammatory) of clindamycin on the peri-implant tissues and do not assess the contribution of individual components to the final effect.
The case series is the first report to present the method. It has to be proven by carrying out a research design that includes the control group as a cohort study or even experimental study. Hence, there is a need for further research on a larger group of patients, longer follow-ups and other types of research projects.

Conclusions
The use of a bioactive healing abutment decreases of the numbers of anaerobic gram (-) bacilli, which play a key role in the development of peri-implant mucositis and in the etiology of peri-implantitis, thus reducing the clinical parameters of peri-implant mucositis in a short time period.
Systematic monitoring of patients with dental implants can help detect the asymptomatic onset of peri-implant inflammation and BHA may in the future be a valuable tool in the hands of medical practitioners to treat this pathology.
Further research should be conducted in order to confirm the results obtained in the present study, as well as the faith of implants especially due to the recurrence of the peri-implant mucositis and the risk of peri-implantitis development around these implants.
The bioactive healing abutment may be a useful drug/active substance delivery toll to perform minimally invasive oral microbiome management protocols in modern periodontal proactive action strategies to balance oral dysbiosis.

Institutional Review Board Statement:
The study was conducted in accordance with the Declaration of Helsinki and approved by the Bioethics Committee at the Medical University of Warsaw, no. KB/211/2020.