Adjunctive antimicrobial photodynamic therapy versus scaling and root planing alone for stage III-IV periodontitis: a systematic review and meta-analysis

INTRODUCTION

Periodontitis is a chronic multifactorial inflammatory disease initiated by a dysbiotic subgingival biofilm and sustained by an exaggerated host response, which progressively destroys the periodontal ligament, the root cementum and the alveolar bone and constitutes one of the leading causes of tooth loss in adults.(1) Severe periodontitis affects approximately 11% of the adult population worldwide, which makes it one of the most prevalent chronic diseases of humanity, and its functional and nutritional consequences extend well beyond the oral cavity, because tooth loss compromises mastication, speech and quality of life. The 2017 World Workshop replaced the former diagnostic labels of chronic and aggressive periodontitis with a staging and grading system that links severity and complexity to treatment. In this framework, stages III and IV identify the severe forms: probing depths of 6 mm or more, interdental attachment loss of at least 5 mm, radiographic bone loss extending to the middle or apical third of the root, and, in stage IV, the loss of five or more teeth attributable to periodontitis together with the need for complex rehabilitation.(2,3) It is precisely in these stages that non-surgical therapy becomes least predictable. Subgingival instrumentation can remove biofilm and calculus from the accessible root surface, but its mechanical access is limited at the base of deep pockets, in furcation entrances and in root concavities, so residual deposits and bacterial recolonization are common and the treatment outcome is determined in part by the initial probing depth.(4,5) Deep residual pockets that persist after instrumentation are the sites at which the disease is most likely to progress, and they are also the sites at which an adjunctive local decontamination would be expected to add the most. The persistence of deep pockets after therapy is a recognized risk factor for further attachment loss, which explains the sustained search for adjunctive interventions able to decontaminate the sites that instruments cannot reach.

Antimicrobial photodynamic therapy is a local, non-invasive intervention that rests on three elements: a photosensitizer, a light source of a matching wavelength and molecular oxygen. The photosensitizer is placed into the periodontal pocket and, once activated by light, transfers energy to oxygen to generate reactive species, mainly singlet oxygen, that oxidize bacterial membranes, proteins and nucleic acids.(6-9) Because the cytotoxic effect is confined to the illuminated and sensitized area, aPDT does not select for antimicrobial resistance and spares the surrounding tissues, which distinguishes it from locally delivered and systemic antibiotics.(10) The photosensitizers most used in periodontics are the phenothiazine dyes methylene blue and toluidine blue, activated in the red spectrum between roughly 630 and 670 nm, and indocyanine green, activated in the near infrared around 810 nm; the parameters of dye concentration, pre-irradiation time, light dose, mode of delivery and number of sessions vary widely between studies, and this variability is itself considered one of the reasons for the inconsistent results. Numerous randomized trials have tested aPDT as an adjunct to scaling and root planing, but the published systematic reviews reach discordant conclusions. Some report a small but statistically significant additional reduction in probing depth at three months, whereas others find no clinically relevant benefit and discourage the routine use of the technique.( 11-15) The S3-level clinical practice guideline of the European Federation of Periodontology, based on a meta-analysis of single-application protocols, does not recommend adjunctive aPDT for the treatment of stage I-III periodontitis.(16)

Most of these syntheses pooled trials diagnosed under the pre-2017 labels, which do not map directly onto the current staging system, and none focused specifically on stages III and IV, the population in which an adjunctive decontamination strategy is most needed.(17,18) The reviews also differ in their inclusion of single versus repeated applications, in the photosensitizers admitted, and in whether they meta-analyzed only probing depth or also attachment, all decisions that influence the conclusions. An updated synthesis restricted to the current staging framework, and separated by outcome and by time point, is therefore warranted. The aim of this systematic review and meta-analysis was to evaluate whether, in adults with stage III-IV periodontitis, adjunctive antimicrobial photodynamic therapy improves probing depth reduction and clinical attachment gain compared with scaling and root planing alone.

METHODS

RESULTS

Study selection

The searches identified 204 records, of which OpenAlex contributed 110, PubMed 54 and Crossref 40. No language restriction was applied at the search stage, although the screening and the full-text assessment were conducted on the English-language records that the sources returned. After 52 duplicates were removed, 152 records were screened and 105 were excluded on title and abstract, most because they were not randomized trials, because they addressed another population, or because they evaluated an intervention other than photodynamic therapy. Full text was sought for 47 reports; 32 could not be retrieved because no legitimate open-access copy was available, and 15 reports were assessed for eligibility. Five reports were excluded at this stage: one because its data were not of primary origin and its reference list was unrelated to the study, one because it was a before-after design without a concurrent control group, one because it enrolled stage I-II periodontitis, and two because they lacked a scaling-and-root-planing-alone arm. This left 10 studies included in the review (Figure 1).

Probing depth reduction

Six trials contributed probing depth data at three months. The pooled mean difference favored adjunctive aPDT by 0.77 mm (95% CI 0.46 to 1.09; p < 0.001), with moderate heterogeneity (I2 = 64%). The per-study differences ranged from 0.23 mm in Kataria 2019 and Annunziata 2023 to 1.47 mm in Mallineni 2020, and no study favored the control group; Gupta 2026 and El Mobadder 2023 contributed intermediate estimates.(21-26) Secondary outcomes pointed in the same direction: Najm 2024 reported higher odds of pocket closure with the photosensitizers than with instrumentation alone, and Annunziata 2023 found a significantly greater reduction in initially deep pockets at six months in the aPDT group. Adverse events were absent or limited to transient discomfort in the trials that reported them (Figure 2; Table 3).

Study	n (SRP/aPDT)	SRP alone	SRP + aPDT	MD (95% CI)
Kataria 2019	30 / 30	2.11 (1.19)	2.34 (1.10)	0.23 (-0.35 to 0.81)
Mallineni 2020	15 / 15	0.73*	2.20*	1.47 (0.88 to 2.06)
Annunziata 2023	12 / 12	1.54 (1.10)	1.77 (0.77)	0.23 (-0.53 to 0.99)
Gupta 2026	15 / 30	0.67*	1.47*	0.80 (0.35 to 1.25)
El Mobadder 2023	16 / 16	2.26*	2.90*	0.64 (0.17 to 1.11)
Najm 2024	102 / 230	1.80 (0.80)	2.80 (0.99)	1.00 (0.80 to 1.20)
Pooled (random)				0.77 (0.46 to 1.09)

Note: Change values are mean (SD) in millimetres; a positive change indicates reduction. aPDT = antimicrobial photodynamic therapy; SRP = scaling and root planing; MD = mean difference. Changes marked with an asterisk were computed from baseline and endpoint values with the SD of the change imputed (correlation 0.5). Source: Own elaboration.

Clinical attachment gain

Five trials contributed clinical attachment data at three months. The pooled mean difference was 0.72 mm in favor of adjunctive aPDT, but the confidence interval crossed zero (95% CI −0.29 to 1.74; p = 0.163) and heterogeneity was high (I2 = 89%). Four of the five point estimates favored the aPDT group, but the confidence intervals of all the individual studies except Mallineni 2020 crossed zero, so the pooled estimate does not meet a conventional threshold of significance. The largest estimate came from Mallineni 2020, in which the baseline attachment level was unbalanced between the quadrants, and Gupta 2026 was the only trial whose point estimate favored the control group (Figure 3; Table 4).

Study	n (SRP/aPDT)	SRP alone	SRP + aPDT	MD (95% CI)
Kataria 2019	30 / 30	1.71 (1.24)	2.09 (1.34)	0.38 (-0.27 to 1.03)
Mallineni 2020	15 / 15	0.53*	3.60*	3.07 (2.16 to 3.98)
Annunziata 2023	12 / 12	1.08 (0.90)	1.29 (0.89)	0.21 (-0.51 to 0.93)
Gupta 2026	15 / 30	1.67*	1.21*	-0.47 (-1.26 to 0.33)
El Mobadder 2023	16 / 16	1.83*	2.37*	0.54 (-0.18 to 1.26)
Pooled (random)				0.72 (-0.29 to 1.74)

Note: Change values are mean (SD) in millimetres; a positive change indicates gain. aPDT = antimicrobial photodynamic therapy; SRP = scaling and root planing; MD = mean difference. Changes marked with an asterisk were computed from baseline and endpoint values with the SD of the change imputed (correlation 0.5). Source: Own elaboration.

DISCUSSION

The pooled results indicate that adjunctive antimicrobial photodynamic therapy adds a small, statistically significant reduction in probing depth of about 0.8 mm at three months over scaling and root planing alone, but does not produce a demonstrable gain in clinical attachment. The probing depth benefit is consistent in direction across the studies, yet its magnitude is modest and sits close to the threshold usually considered clinically relevant for pocket closure. The attachment result, in turn, suggests that the extra millimetre of probing depth reduction may reflect a change in gingival position and inflammation rather than a true gain of connective tissue attachment. The clinical translation of this finding is therefore limited: a patient treated with aPDT would, on average, close a deep pocket by a fraction of a millimetre more than a patient treated with instrumentation alone, which may or may not alter the need for additional therapy.

These findings agree with earlier syntheses in the direction of effect but not in its strength. Sgolastra et al. and Atieh reported a significant additional probing depth reduction of a similar order at three months, whereas Azarpazhooh et al. found no significant difference at six months.(11-13) The divergence between the three-month and the six-month estimates in the older literature deserves attention: it suggests that any early advantage of aPDT tends to fade once the benefits of the mechanical debridement itself have matured, which is consistent with a superficial and transient antimicrobial effect rather than a regenerative one. The EFP S3 guideline, grounded on a meta-analysis of single-application protocols, concluded that the benefit did not justify a recommendation, and Salvi et al. reached the same position for untreated periodontitis.(14,16) More recent reviews restricted to indocyanine green or methylene blue protocols again describe significant but small gains in probing depth, which matches the present estimate, while acknowledging that the evidence is heterogeneous and that the clinical relevance is uncertain.(15,18,31,32) The recurrent absence of a clear attachment gain is therefore not an artifact of this review but a consistent feature of the aPDT literature, and it should temper any claim that the therapy regenerates the periodontium. In other words, the technique behaves in the literature as a decontaminating adjunct that slightly improves pocket depth in the short term, not as a regenerative or attachment-gaining intervention, and its place in therapy should be framed accordingly.

The choice of three months as the primary time point also deserves comment. Three months is the standard re-evaluation interval after subgingival instrumentation, at which the mechanical effect has largely matured, and it was the only time point available in enough trials to allow pooling. The six-month data were reported by too few of the pooled studies to be combined, but the direction of the individual results suggests that any early advantage narrows over time. This temporal pattern, together with the null six-month findings of the older reviews, supports the view that aPDT shortens the recolonization window rather than producing a lasting structural gain.( 12,14)

Individual trials outside the pooling window illustrate both sides of this literature. Braun et al., Betsy et al., Joshi et al., Hill et al., Sukumar et al., AlSarhan et al., Gandhi et al., Monzavi et al. and Moreira et al. reported superior probing depth or attachment outcomes with aPDT,(33-41) whereas Christodoulides et al., Polansky et al. and Preshaw et al. found no advantage over instrumentation alone.(42-44) The discrepant trials are instructive because they used protocols very close to those of the positive studies, and yet failed to reproduce the benefit; the null trial of Preshaw et al. is particularly relevant because it was multicentre and examiner-blinded, two design features absent from most of the positive studies.(44) This pattern raises the possibility that part of the positive signal in the smaller, unmasked trials reflects detection bias, a concern that is reinforced by the risk-of-bias assessment of the present review.

The discrepancy between studies is better explained by protocol differences than by any single factor. Photosensitizers and wavelengths vary widely, the number of sessions ranges from one to several, and some trials irradiate only the deepest sites while others treat the full mouth.(8) The concentration and pre-irradiation time of the dye, the light dose and the mode of delivery all influence the yield of reactive oxygen species, and the surfactant formulations used in some protocols were introduced precisely because the aggregation of methylene blue in aqueous solution reduces its phototoxicity. Smoking also modulates the response: trials in smokers report weaker effects, as in the home-device trial of Vakaki 2025 and in the earlier comparison of smokers and never-smokers by Theodoro et al..(30,45) The deep-pocket subgroup of Annunziata 2023, in which a significant benefit emerged only at six months, further suggests that the population and the timing of the evaluation determine whether an effect is detectable.( 23)

Heterogeneity in the present meta-analysis was moderate for probing depth and high for attachment gain. The main sources were the unit of analysis, which alternated between patients and sites, the different photosensitizers and light doses, and the baseline imbalance in attachment level in Mallineni 2020, which inflated the attachment estimate. The attachment pooling should therefore be read with caution, and the probing depth estimate, although more robust, should not be extrapolated beyond the short term. The split-mouth design, used by most of the included trials, minimizes inter-patient variability but does not eliminate the possibility of contamination between treated and control sites within the same mouth, and it complicates the estimation of the standard deviation of the change when only endpoint values are reported. A further source of divergence from other reviews is that this one admitted only photodynamic protocols, that is, those combining a photosensitizer with light, and excluded laser-only or photobiomodulation studies, whose mechanisms and dose-response differ and which are sometimes pooled together with aPDT in the broader literature.( 14)

From a mechanistic perspective, the modest clinical effect is plausible. aPDT reduces the bacterial load and inactivates lipopolysaccharide, but its action is superficial and transient, and it cannot remove the calculus or correct the anatomy that sustains the pocket; it therefore complements, rather than replaces, mechanical debridement.(7,8) This may explain why the effect is more visible in deep pockets, where instrumentation is least complete, than in shallow sites, and why repeated applications or longer wavelengths, which penetrate more deeply, are the protocols most often associated with a benefit. It also explains why the technique has not been associated with the harms of systemic antimicrobials, such as bacterial resistance or gastrointestinal effects, a property that remains its main appeal.(6,46) The absence of a corresponding attachment gain is consistent with this account: a reduction in inflammation and in pocket depth can occur through tissue shrinkage and reduced edema without the formation of new connective tissue attachment, and the latter would be required for a durable structural improvement.

This review has limitations that concern both the evidence and the review process. The number of trials is small, most were single-centre with short follow-up, and risk of bias was high or unclear in the majority; larger, registered and blinded trials are required before the technique can be recommended routinely. The populations were heterogeneous in smoking status and disease severity, and the trials that did not state the stage were classified as stage III-IV on the basis of probing depth thresholds, which may have misclassified some populations; future trials should report the stage explicitly and analyze patients, not sites, as the unit, because site-level analyses overstate precision. Only three bibliographic sources were searched, and only open-access full texts could be evaluated, so eligible trials without an accessible full text were excluded at retrieval; a broader search including the grey literature and subscription databases, together with author contact, would reduce this risk. The change standard deviations of several trials were imputed with an assumed correlation, which may distort the weights; reporting the standard deviation of the change, or the individual patient data, would remove this assumption. The three-week trials and the home-applied device were excluded from the pooling because their time point or delivery differed from the in-office protocols, and their separate description shows that the short-term effect does not guarantee a durable one. Finally, the outcome is surrogate and short-term; whether the additional probing depth reduction is maintained, and whether it translates into fewer residual pockets or less need for surgery, remains unknown and should be the target of future trials. The certainty of the evidence was not formally graded, and the small number of studies precluded the subgroup analyses, by photosensitizer or by smoking status, that would have clarified the sources of heterogeneity; a future update should register its protocol, apply GRADE and plan those subgroups in advance.

The safety profile of the intervention is favorable, and this is the main respect in which aPDT differs from systemic antibiotics. None of the included trials reported serious adverse events attributable to the therapy, and the complaints recorded were limited to transient discomfort, warmth and a sensation of excess saliva with the home device, which led to discontinuation in a minority of users.(30) This is consistent with the mechanistic premise that the phototoxic effect is confined to the sensitized and illuminated pocket and that the reactive species are short-lived.(7,8) Safety, however, does not by itself justify use, because the clinical benefit that would balance the cost and the additional chair time is still uncertain.

The comparison with established adjuncts also helps to calibrate expectations. The additional probing depth reduction observed here is of the same small order as that reported for locally delivered antimicrobials, and smaller than the gains usually attributed to systemic antimicrobials in severe disease, although the protocols, populations and time points differ enough that any direct numerical comparison would be misleading.(46,47) What distinguishes aPDT is not the size of its effect but its favorable resistance profile, which may make it attractive for patients in whom systemic antimicrobials are undesirable or contraindicated. This consideration, rather than a superiority in efficacy, is probably the most defensible basis for offering the therapy today.

The clinical meaning of the pooled probing depth difference deserves explicit comment. A mean difference of 0.77 mm is smaller than the measurement error usually attributed to manual periodontal probing, which is in the order of one millimetre, and is therefore unlikely to be perceived by the clinician in an individual patient. Its relevance depends on whether it concentrates in the deepest pockets, where a fraction of a millimetre can decide whether a pocket closes or remains patent, rather than being distributed uniformly across all sites. The subgroup data available in Annunziata 2023 and the pocket-closure analysis of Najm 2024 suggest that this may be the case, but the pooled estimate itself cannot confirm it.(23,25) An effect of this size also cannot support claims of regeneration, and the null attachment result reinforces that interpretation.

Small-study effects are a further reason for caution. The trials in this review were, with one exception, small and single-centre, and the forest plots show that the most precise estimates are those closest to zero, whereas the larger point estimates came from the smallest studies. A formal assessment of publication bias was not possible with fewer than ten studies, but the pattern is compatible with an overestimation of the effect in the small, unmasked trials, and it strengthens the case for interpreting the pooled estimate as an upper bound rather than a precise measure.

Finally, the generalizability of these findings to stage III-IV disease specifically is imperfect. Only Annunziata 2023 stated the stage explicitly among the pooled trials, and only Vakaki 2025 recruited exclusively stage III-IV patients; the remaining studies enrolled periodontitis described by probing depth thresholds that map onto, but do not prove, stages III-IV. A review that restricted itself to trials reporting the stage would have been unfeasible, but the consequence is that the pooled estimate applies to severe periodontitis broadly rather than to a verified stage III-IV population. This distinction should be borne in mind when the results are applied to individual patients.

For clinical practice, the results suggest that aPDT can be offered as an adjunct when a marginal improvement in probing depth in deep pockets is sought, but it should not replace subgingival instrumentation or be presented as an alternative to established adjuncts such as locally delivered or systemic antimicrobials, whose evidence base is more consistent.(46,47) Clinicians who elect to use it should define the photosensitizer and light parameters explicitly, treat only the sites with residual deep pockets, and re-evaluate at three and six months to judge whether the additional gain justifies the chair time and the device cost. For research, the priorities are a consensus protocol with defined light and photosensitizer parameters, examiner blinding, patient-level analyses, and outcomes that reflect pocket closure and the need for additional therapy rather than millimetre changes alone.

CONCLUSIONS

In adults with stage III-IV periodontitis, adjunctive antimicrobial photodynamic therapy produced a modest additional reduction in probing depth at three months compared with scaling and root planing alone, with moderate heterogeneity across the trials. The technique did not provide a statistically significant gain in clinical attachment, and the attachment estimate was driven by a single unbalanced trial. The available evidence is small, at moderate to high risk of bias, and therefore insufficient to support a routine recommendation in stage III-IV periodontitis. Any clinical use of the technique should be reserved for deep pockets in which a marginal additional decontamination is desired, and should be weighed against the limited and short-term nature of the benefit.

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