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Introduction

Diabetes-related foot ulcers (DFU) are a common, highly severe, complication of long-term diabetes, associated with high rates of amputation and mortality.¹ The cumulative incidence of the first ulcer is estimated at 5.65%,² contributing to a significant global impact. Each year, around 18.6 million people worldwide are affected by this condition,³ highlighting the magnitude of the problem and the urgent need for therapeutic approaches that accelerate healing, reduce further consequences (such as infection, extended hospital stays, and amputation) and improve quality of life.

One therapeutic approach that has gained prominence in the management and treatment of DFU is antimicrobial Photodynamic Therapy (PDT). PDT combines a topical photosensitiser with light sources — such as LASER or light-emitting diodes (LED) — which, in the presence of tissue oxygen, generate reactive oxygen species. This reaction produces a beneficial cytotoxic effect, reducing bacterial load and promoting tissue repair.⁴

Studies indicate that PDT is significantly more effective in treating DFU than standard treatment alone.^5,6 A cost-benefit study in Italy reported that the use of PDT in people with DFU had a positive budget impact, reducing the time to achieve outpatient healing by 50%, as it promoted improvements in the tissue repair process.⁷

A study applying PDT to leg ulcers, including DFU, compared outcomes between an intervention group and a control group, each with 10 participants. Most ulcers contain polymicrobial flora, notably Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacteriaceae, and Streptococcus pyogenes. In the group treated with PDT, there was a reduction in microbial load in eight out of 10 patients. In contrast, only five patients in the control group showed reduced microbial load.⁸

An umbrella review is warranted to synthesise existing systematic reviews, providing a consolidated evidence base to guide clinical practice.^9,10 Searches in PubMed, Web of Science, and Scopus revealed no prior umbrella reviews on PDT for DFUs. This umbrella review aimed to evaluate and summarise scientific evidence on the efficacy of PDT in bacterial control and tissue repair in people with DFU. Additionally, it contributes to support the development of effective clinical guidelines and treatment strategies to improve outcomes for people with diabetes-related foot ulcers.

Methods

This umbrella review followed JBI guidelines⁹ and was registered in the Open Science Framework (DOI: 10.17605/OSF.IO/8Y5B7). The process included defining the title and authors, formulating the research question, establishing inclusion criteria, developing and applying search strategies, selecting studies, assessing methodological quality, extracting data, and synthesising findings. The review question was structured using the PICO framework: People (patients with diabetes-related foot ulcers); Intervention (antimicrobial PDT); Control (conventional treatment); Outcomes (bacterial control and tissue repair). The resulting question was: “What are the effects of antimicrobial PDT on bacterial control and tissue repair in people with diabetes-related foot ulcers?”.

Eligible studies were systematic reviews with meta-analyses assessing PDT for DFU treatment and reporting effects on tissue repair, with or without microbial control. No language or publication date restrictions were applied. Duplicates were excluded. Search strategies combined Medical Subject Headings (MeSH) and keywords, linked with Boolean operators “AND” and “OR” and adapted for each database. Searches were conducted in MEDLINE (via PubMed), Web of Science, CINAHL, Scopus, Science Direct, and Embase, accessed through the Lakehead University library portal. Table 1 details the search strategies and databases.

 

Table 1. Search strategies and databases

 

The first author with experience conducting review studies exported the documents in Research Information Systems (RIS) format to Rayyan QCRI® software. Initially, duplicate scientific articles were excluded, followed by the screening of titles and abstracts by two independent researchers (Brandao and Pereira). Each disagreement was resolved during the study selection process, through consensus decision meetings between the two reviewers.

The quality methodology assessment of systematic reviews was a crucial step to ensure the reliability and validity of the included evidence. This study was assessed using JBI’s critical appraisal checklist, widely recognised for its methodological rigor in evaluating systematic reviews.¹¹ The evaluation was carried out by two independent reviewers (Brandao and Pereira).

This instrument detailed analysis of key aspects, such as the clarity of the research questions, the comprehensiveness of the search strategy, the appropriateness of inclusion and exclusion criteria, and the transparency in the analysis of results. The checklist ensured that only high-quality reviews were considered, strengthening the conclusions of this umbrella review.¹¹

It is important to note that this assessment was descriptive and analytical in nature, and was not used as an exclusion criterion for studies, but rather to support the interpretation of the methodological robustness and reliability of the results presented. All eligible studies were included regardless of their methodological quality level.

The scientific documents were organised in Google Drive^® to facilitate access and collaboration among the authors. In addition, a Microsoft Excel^® spreadsheet was created to extract the following variables: year of publication, authors, number of studies included, parameters used for PDT application, outcomes evaluated, main results, methodological quality of the studies, and reported limitations. The data were presented in tables for a clear and structured view.

Data synthesis was performed narratively. A meta-analysis was not conducted due to the limited number of included systematic reviews, substantial heterogeneity across outcomes and effect measures, and the potential overlap of primary studies among reviews, in accordance with JBI recommendations for umbrella reviews.

The discussion of results considered the available scientific evidence, highlighting clinical implications and gaps identified in the literature. It was not the objective of this study to explore the specific parameters of PDT, such as dose, nanometers, type of light, and photosensitising agent, since these variables have already been addressed in a published scoping review.¹²

Results

The database search identified 201 studies. After 33 duplicates were excluded, 168 articles remained for screening. In the screening phase, titles and abstracts were examined, and several were excluded. The reasons for exclusion varied as follows: 127 articles presented a divergent topic; 18 focused on other therapies, such as laser therapy and ozone therapy; five corresponded to book chapters; two were letters to the editor; two were guidelines; one was a commentary; another referred to a review protocol; and one was an editorial.

After the screening, 11 articles were selected for full reading. During the reading stage seven articles were excluded for the following reasons: four articles addressed only laser therapy without the use of a photosensitising agent; one article dealt only with LED without the use of a photosensitising agent; another discussed the use of LASER or LED without the use of a photosensitising agent; and one study was retracted after the publication. A total of four systematic review studies met the inclusion criteria for this umbrella review. The flowchart presents the entire process for selecting and screening studies.

 

Flowchart 1. Illustrative flowchart of the selection process of studies included in the review sample

 

In the critical evaluation procedure, the quality of publications was methodologically assessed using the appropriate JBI checklist. Each publication met at least 50% of the evaluation criteria. The scores are illustrated in Table 2.

 

Table 2. Critical analysis of the methodological quality of the studies according to the JBI

 

Table 3 presents the characteristics of the four studies included in this umbrella review. The studies looked at the efficacy of PDT in treating infected ulcers, particularly in patients with DFU. The systematic reviews included between four and 15 randomised controlled trials (RCTs) each, with populations ranging from 76 to 458 patients.

To evaluate the impact of PDT on tissue repair and microbial control in DFU, studies that analysed these specific outcomes were reviewed. The main findings of the systematic reviews are presented below, highlighting the effects of PDT on healing and microbial control in DFU.

 

Table 3. Characterisation of the included systematic review studies included in the umbrella review

 

Tissue repair and wound area reduction

Hou and colleagues (2024)⁵ conducted a meta-analysis comparing the PDT-treated group with a control group. In the first analysis, they observed an average reduction in ulcer area of 2.73cm squared (95% CI -2.98-8.44; p>0.05), suggesting a trend of improvement, but not statistically significant. However, a second meta-analysis showed a difference in healing rate of 29.26% (95% CI 7.24–51.28; p=0.01), indicating that PDT is associated with a healing acceleration process. Therefore, they emphasised that most of the included studies had small samples, which may limit the detection of more robust effects. However, they support the inclusion of PDT in DFU treatment protocols to optimise healing.

In the systematic review by Brandão et al (2023)⁶ the effect of PDT on tissue repair was also significant. However, a high heterogeneity (I-squared=99%) was observed across the studies, possibly also due to different parameters applied. The authors observed a positive impact of PDT on DFU healing, favoring the experimental group with a significant difference (p=0.04) compared to conventional treatments. Boltes Cecatto and colleagues (2020)¹⁴ reported that PDT was highly effective in treating infected ulcers, corroborating the observations of other studies. Oliveira and colleagues (2022)¹³ showed in their meta-analysis that PDT significantly reduced the size of the ulcer compared to the control group (mean difference: 0.72cm squared; 95% CI 0.12-1.32; p=0.0187), indicating its positive effect on healing.

Overall, the evidence synthesised across the included systematic reviews suggests that PDT may contribute positively to tissue repair and wound healing in DFU. Although reductions in wound area were not consistently statistically significant across all analyses, improvements in healing rate and acceleration of the repair process were frequently reported. However, the strength of these findings is tempered by substantial heterogeneity, small sample sizes and variability in PDT parameters across studies. Taken together, the results indicate a promising role for PDT as an adjunctive therapy  to enhance tissue repair, while highlighting the need for more standardised and methodologically robust clinical trials to confirm these effects.

Microbial control

Evidence regarding the effects of PDT on microbial control in DFU is limited. Among the included systematic reviews, only one reported quantitative results for this outcome. Oliveira and colleagues¹³ observed a reduction in microbial viability in patients treated with PDT, with a 17% lower viability (OR=0.17; 95% CI 0.07–0.44; p=0.0003) compared to placebo or red light alone. Although these findings suggest a potential antimicrobial effect of PDT, the limited number of studies addressing this outcome precludes definitive conclusions. Therefore, the results should be interpreted with caution, highlighting the need for further high-quality studies specifically designed to assess microbial outcomes.

Discussion

The umbrella review result suggests that PDT may have a promising role as an adjuvant intervention for treating DFU, providing significant benefits, especially in tissue healing.⁶ Two studies included in this review demonstrated that PDT showed promise in terms of reducing the area of wounds.^5,13 This represents an essencial advance in the treatment of DFU, whose lesions often heal slowly due to compromised vascular conditions and neuropathy in people with DM.¹⁵

It is also essential to note that the high risk of infection in the wound bed occurs because of the imbalance between pro-inflammatory and anti-inflammatory effects of macrophages and neutrophils,¹⁵ Studies included in this review demonstrated that after the application of PDT sessions it was possible to observe a gradual and consistent reduction of the ulcerated area.^5,6

This process can be attributed to the fact that PDT creates a cellular environment that is less favorable for maintaining the chronic inflammation cycle common in chronic wounds, such as DFU, thereby promoting an earlier onset of tissue repair and facilitating lesion closure. Evidence shows that PDT can play an effective role in the statistically significant reduction of DFU’s area.^16,17

Another relevant finding refers to the increased healing rates of ulcers treated with PDT. Thus, in addition to decreasing the area, PDT seems to accelerate the tissue regeneration process, resulting in shorter recovery times compared to traditional methods of DFU treatment.¹² For better understanding, the area of the ulcer refers to the wound’s physical size at a given time. Montitoring the area provides evidence of reduction, indicating that the DFU is decreasing, a sign of progress towards closure. The healing rate, in turn, represents the speed at which the DFU closes over time, expressed as a percentage change or reduction in area over a specific period (such as a week or month). A high healing rate indicates a rapid decrease in the ulcer area, while a low rate suggests a slower closure.

Thereby, it is understood, from the findings presented, that the PDT helps to reduce the area of DFUs more quickly. This effect can be explained by PDT’s ability to induce an anti-inflammatory response and stimulate cell proliferation in injured tissues, promoting the reorganisation and regeneration of dermal and epidermal layers.¹⁸ Studies highlight this response is particularly beneficial in cases of DFU, where recovery tends to be slow due to circulatory problems and compromised immune responses.^15,19

Regarding microbial control, PDT demonstrated a microbicidal action, which contributed to bacterial load reduction in wounds, and prevention of secondary infections, or as a treatment of current infections. This microbial control is achieved through reactive oxygen species (ROS) generation, which are highly lethal to bacterial cells and other pathogens. The PDT action occurs when the photosensitising agent is activated by a specific light source, triggering the formation of these ROS at the application site.¹⁸

In addition, to its  direct impact on microbial control, PDT also appears to have a modulating effect on the inflammatory process, helping to interrupt the chronic inflammatory cycle associated with DFU. Studies suggest that the presence of bacteria and biofilms in wounds prolongs inflammation, preventing the formation of new tissue and delaying  healing.^20,21

Research conducted by Monami and colleagues²² demonstrated that the bacterial load decreased significantly after a single PDT treatment, and the benefit persisted for two weeks, reducing a colony-forming unit of infection-causing bacteria. With the significant reduction in the bacterial load promoted by PDT, a more suitable environment was created for the progression of the healing phases, enabling faster and more effective resolution of wounds. It is important to highlight evidence of lower microbial cell viability after using PDT. Microbial viability refers to the ability of microorganisms (such as bacteria, fungi, and viruses) to survive and remain active in each condition.²³ In the study by Oliveira and colleagues¹³ patients treated with PDT had a 17% lower viability.

Furthermore, another study by Mosti and colleagues²⁴ showed that PDT effectively reduced bacterial load in patients with infected vascular leg ulcers, enabling successful skin grafting in all patients involved in underscores PDT’s potential not only for bacterial reduction but also as an adjuvant treatment that facilitates other interventions in chronic, hard-to-heal wounds, such as DFU. Collectively, these findings suggest that PDT can play a valuable role in clinical protocols for managing wounds and reducing bacterial burden in a way that supports overall tissue repair.

Limitations of this study

Despite the promising and convergent results for PDT in DFU treatment presented here, it is important to consider the limitations in this review. Most meta-analyses presented had small sample sizes and included studies with ulcers of other etiologies, such as venous ulcers, which may restrict the generalisability of the results. In addition, heterogeneity in treatment protocols, such as differences in the dosages of photosensitisers and variations in the intensity of the light used may impact the observed efficacy. These limitations reinforce the need for further research with larger sample sizes and standardised protocols.

During the review of the studies included in the meta-analyses, we often had to refer to the complete theses and dissertations to understand the parameters and methods applied, due to the scarcity of details in the model-published articles. In many cases, the results were presented in summarised formats, without complete descriptions of the treatment protocols used, which did not make the reproducibility clear, or allow a more in-depth analysis of the findings. This methodological limitation may have contributed to the high variability in the parameters employed, increasing the heterogeneity of the meta-analyses.

In addition, some studies have restricted access. Thus, health professionals, especially those without institutional access, will have difficulty accessing the full versions or face the cost of articles that are not Open Access, limiting the dissemination of knowledge and the practical application of results in clinical settings.

Thus, it is worth emphasising the importance of funding for adjuvant therapy development in new treatments of DFU, such as PDT. This support can subsidise a broader team of researchers, providing necessary inputs and materials to conduct the research, favoring larger samples. The authors of this umbrella review reflect on the importance of studies, especially clinical studies, publishing their protocols separately or sending supplementary materials to journals that accept this format.

Implications to clinical practice

The evidence presented through this synthesis of four systematic reviews suggests that PDT is a promising adjuvant therapy to improve clinical outcomes, potentially reducing healing time and the incidence of infections in DFUs. This is especially relevant for people with diabetes, who often have ulcers that do not respond to conventional treatments due to the chronic inflammatory cycle. The relevance of PDT becomes even more evident considering the impact that foot ulcers have on the quality of life of people with diabetes.

Therefore, the implementation of PDT can offer a double benefit, promoting physical health and well-being. Finally, healthcare managers, clinical decision-makers and funding organisations will be able to use the results of this review to support the choice of PDT as a promising intervention to improve better outcomes in people with DFU, along with cost-saving.

Future research should focus on clinical trials with larger sample sizes and explore different therapeutic combinations (such as Hydrofera Blue + PDT + educational and nutritional programs), including detailed disclosure of study protocols. In addition, it is critical to evaluate the cost-effectiveness of PDT compared to conventional treatments to determine its feasibility in different clinical settings.

Conclusions

The findings of the systematic reviews indicate that PDT has a promising impact on both tissue repair and microbial control of DFU. Although there is heterogeneity in the studies reviewed, especially regarding the parameters of PDT application, there is a significant trend toward accelerated healing and reduced microbial load. The consistency of results across different reviews suggests that PDT can be considered an effective adjunctive therapy for the treatment of DFU. However, future studies with larger sample sizes and more standardised protocols are needed to strengthen the evidence and improve clinical recommendations about PDT in practice.

Conflict of interest

The authors declare no conflicts of interest.

Ethics statement

An ethics statement is not applicable.

Funding

The authors received no funding for this study.

Author(s)

Maria Girlane Sousa Albuquerque Brandão¹*, Mayra Gonçalves Menegueti², Marady Cristina Salviato Pereira³, Thiago Moura de Araújo¹, Soraia Assad Nasbine Rabeh², Idevania G Costa^4
1Institute of Health Sciences, University of International Integration of Afro-Brazilian Lusophony, Redenção, Ceará, Brazil
²Department of General and Specialized Nursing, Ribeirão Preto School of Nursing, University of São Paulo, Brazil
³Department of Wound, Ostomy and Continence Care, Cone Health, Greensboro, North Carolina, USA
⁴Department of Nursing, Lakehead University, Thunder Bay, Ontario, Canada

*Corresponding author email girlanealbuquerque@unilab.edu.br

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