Low-Intensity Pulsed Ultrasound (LIPUS) In Periodontology: A Systematic Review and Meta-Analysis

Abstract
Low-intensity pulsed ultrasound (LIPUS) has gained attention for its potential role in periodontal regeneration and healing. This systematic review and meta-analysis aim to assess the efficacy of LIPUS in periodontal therapy by evaluating clinical and preclinical studies. The findings suggest that LIPUS enhances periodontal tissue regeneration by stimulating angiogenesis, reducing inflammatory cytokines and promoting osteoblast differentiation. Additionally, LIPUS facilitates extracellular matrix production and accelerates bone remodeling, making it a promising adjunct in periodontal treatment. Meta-analysis data indicate a significant improvement in clinical attachment level (CAL), probing depth (PD) reduction and alveolar bone regeneration with LIPUS application. However, variability in study protocols, sample sizes and treatment parameters calls for further well-designed trials to confirm its clinical benefits and establish standardized treatment guidelines. This review provides a comprehensive evaluation of the current literature, identifies gaps and suggests future research directions for integrating LIPUS into routine periodontal care.

Keywords: Low-intensity pulsed ultrasound; LIPUS; Periodontology; Periodontal regeneration; Alveolar bone; Meta-analysis

Introduction
Periodontal diseases, characterized by the progressive destruction of the supporting structures of the teeth, remain a significant challenge in dental practice. These conditions lead to the deterioration of the periodontal ligament, alveolar bone and gingival tissues, ultimately resulting in tooth loss if left untreated¹. The primary etiological factor for periodontal diseases is bacterial plaque, which triggers an inflammatory response that further exacerbates tissue destruction². Despite advancements in periodontal therapy, achieving complete regeneration of lost periodontal structures remains a clinical challenge³.

Conventional treatment modalities, including scaling and root planning, surgical interventions and regenerative procedures such as guided tissue regeneration (GTR) and bone grafting, aim to halt disease progression and promote tissue repair⁴. However, these approaches often have limitations, such as patient morbidity, variable clinical outcomes and limited regenerative potential⁵. As a result, adjunctive therapies have been explored to enhance periodontal regeneration and improve treatment efficacy.

One such promising adjunct is low-intensity pulsed ultrasound (LIPUS), a non-invasive biophysical modality that has been widely used in orthopedic and musculoskeletal healing⁶. LIPUS operates through the transmission of low-intensity sound waves that create mechanical stimulation at the cellular level, promoting tissue repair and regeneration⁷. Studies in orthopedics have demonstrated that LIPUS accelerates fracture healing, enhances angiogenesis and modulates inflammatory responses⁸. Given these beneficial effects, researchers have turned their attention to exploring LIPUS as a potential therapy for periodontal regeneration⁹.

Emerging evidence suggests that LIPUS may have a positive impact on periodontal healing by stimulating osteoblastic differentiation, promoting extracellular matrix synthesis and reducing inflammatory cytokine levels¹⁰. Additionally, LIPUS has been reported to enhance alveolar bone remodeling, facilitate periodontal ligament cell proliferation and support the regeneration of cementum and connective tissues¹¹. These effects position LIPUS as a potential non-invasive alternative to conventional regenerative therapies¹². 

This systematic review and meta-analysis aim to evaluate the effects of LIPUS in periodontal therapy by assessing available clinical and preclinical data. The review will provide a detailed examination of the biological mechanisms underlying LIPUS-induced periodontal regeneration, its clinical efficacy and the future implications of its use in routine dental care¹³. By consolidating current evidence and identifying research gaps, this study seeks to contribute to the development of standardized treatment protocols and enhance the clinical application of LIPUS in periodontology¹⁴.

Materials and Methods

Search strategy and Eligibility criteria
A comprehensive search was conducted in PubMed, Scopus, Web of Science and Cochrane Library databases for studies published between January 2000 and February 2025. The keywords used included "Low-intensity pulsed ultrasound," "LIPUS," "periodontology," "periodontal regeneration," and "alveolar bone healing"^15-17.

Inclusion criteria
Studies were included in the review if they met the following criteria:
·                  Randomized controlled trials (RCTs) evaluating the effect of LIPUS on periodontal regeneration^18-20.
·                  Animal studies investigating the histological and radiographic effects of LIPUS on alveolar bone healing^21-23.
·                  In vitro studies assessing the biological mechanisms of LIPUS, including cell proliferation, osteoblastic differentiation and extracellular matrix production^24,25.
·                  Studies with clearly defined intervention and control groups, specifying LIPUS treatment parameters (frequency, intensity, duration)²⁶.
·                  Studies reporting at least one quantitative periodontal outcome, such as clinical attachment level (CAL), probing depth (PD) reduction, bone density or bone volume^27,28.
·                  Articles published in peer-reviewed journals in English between January 2000 and February 2025.

Exclusion criteria
Studies were excluded if they met any of the following conditions:
·                  Case reports, narrative reviews, opinion pieces, editorials and conference abstracts without original data^16-17.
·                  Non-English language publications due to translation constraints and potential inconsistencies in methodology¹⁹.
·                  Studies lacking a control group or failing to report quantitative periodontal outcome measures^21-23.
·                  Animal studies not focusing on periodontal structures or those investigating LIPUS effects in non-dental applications^22-24.
·                  In vitro studies without validated outcome measures related to periodontal regeneration^25,26.
·                  Studies with incomplete or ambiguous reporting of LIPUS parameters, making replication and comparison difficult^27-28.
·                  Articles with small sample sizes (<10 subjects for animal studies, <20 patients for clinical studies) that could introduce bias and limit statistical power²⁹. 

Data extraction and quality assessment
Two independent reviewers extracted data on study design, sample size, intervention parameters, follow-up duration and clinical outcomes. The Cochrane Risk of Bias tool was used for RCTs, while the SYRCLE risk of bias tool was applied for animal studies^20-22. Discrepancies in data extraction were resolved through discussion or consultation with a third reviewer²³.

Study selection process
A total of 1,345 articles were identified through database searches. After removing duplicates, 956 articles remained for title and abstract screening. Two reviewers independently assessed the relevance of each study and 47 full-text articles were retrieved for detailed review (Table 1). Among these, 15 studies met the inclusion criteria and were included in the final analysis^15-29.

Table 1: Study Selection and Methodological Characteristics

This table summarizes the methodological characteristics of studies included in this systematic review, highlighting differences in study design across clinical, animal and in vitro research models.

Statistical analysis
Meta-analysis was performed using Review Manager (RevMan) 5.4 software. Heterogeneity was assessed using the I² statistic and a random-effects model was applied in case of significant heterogeneity (I² > 50%). The primary outcome measures included clinical attachment level (CAL) gain, probing depth (PD) reduction and alveolar bone regeneration. Secondary outcomes included bone density and histological markers of regeneration. The standard mean difference (SMD) was used to assess continuous variables, with statistical significance set at p < 0.05.

Standard Mean Difference (SMD) The Standard Mean Difference (SMD) is used to standardize effect sizes across studies with different measurement scales. The formula is:

 





Heterogeneity Assessment (I² Statistic)
To assess heterogeneity among the included studies, the I² statistic is used:

Interpretation of I² values

·                  25% = Low heterogeneity

·                  50% = Moderate heterogeneity

·                  75% = High heterogeneity

Random-effects model for meta-analysis

·                  Given the variability in LIPUS treatment parameters, a random-effects model was employed to estimate the overall effect size: 

Results
A total of 1,345 articles were identified through database searches. After title and abstract screening, 47 full-text articles were reviewed and 15 studies met the inclusion criteria. The included studies comprised five clinical trials, six animal studies and four in vitro studies (Table 2).

Table 2: Effect of LIPUS on Periodontal Regeneration

 
Quantitative meta-analysis results
The meta-analysis revealed that LIPUS application resulted in: • A mean CAL gain of 1.2 mm (95% CI: 0.8-1.6 mm, p < 0.05) • A mean PD reduction of 1.5 mm (95% CI: 1.0-2.0 mm, p < 0.05) • A 20% increase in alveolar bone volume as observed in animal studies • Enhanced osteoblast differentiation and extracellular matrix formation in vitro (Table 3).

Table 3: Summary of Meta-Analysis Results

Heterogeneity and sensitivity analysis
The I² statistic indicated moderate heterogeneity (I² = 45%) among clinical studies, suggesting variability in LIPUS treatment duration, intensity and sample populations (Table 4). Sensitivity analysis was performed by excluding studies with a high risk of bias, which did not significantly alter the overall effect size.

Table 4: Heterogeneity and Sensitivity Analysis

 
Subgroup analysis
Subgroup analysis was conducted based on LIPUS intensity and duration of application. Studies using an intensity of 30 mW/cm² consistently reported significant improvements in periodontal parameters (Table 5), while those using higher intensities (50 mW/cm²) showed greater bone volume enhancements in animal models. The duration of LIPUS treatment also influenced outcomes, with studies applying LIPUS for at least 8 weeks showing the most pronounced effects. 

Table 5: Subgroup Analysis by LIPUS Intensity and Duration

These detailed analyses provide strong evidence supporting the role of LIPUS in periodontal regeneration and highlight the need for standardized treatment protocols to maximize clinical benefits.

Discussion
The findings of this systematic review and meta-analysis indicate that LIPUS has a significant impact on periodontal regeneration. The statistical analysis provides robust evidence supporting its clinical benefits³⁰.

LIPUS promotes periodontal tissue healing by stimulating osteoblastic activity, enhancing angiogenesis and modulating inflammatory responses³¹. Several studies have demonstrated its ability to accelerate bone healing by increasing the expression of growth factors such as vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs)³². A study by El-Bialy, et al, showed that LIPUS application led to a 35% increase in VEGF expression in periodontal tissues, promoting neovascularization and improved bone healing³³. Similarly, Wang, et al, reported that LIPUS enhances BMP-2 expression, a crucial factor in osteogenic differentiation and periodontal regeneration³⁴.

Furthermore, LIPUS has been shown to reduce inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which are known to contribute to periodontal tissue destruction³⁵. A randomized controlled trial by Kim et al. (2020) demonstrated a significant reduction in TNF-α levels in patients treated with LIPUS compared to conventional therapy alone, indicating its anti-inflammatory properties³⁶.

The meta-analysis revealed that LIPUS significantly improves CAL, PD reduction and alveolar bone regeneration³⁷. The overall effect size indicated a mean CAL gain of 1.2 mm (p < 0.05) and PD reduction of 1.5 mm (p < 0.05), suggesting that LIPUS enhances periodontal healing beyond conventional therapies alone³⁸. In a systematic review by Zhang, et al, pooled data from six clinical trials confirmed that LIPUS-treated groups showed significantly higher CAL gain compared to non-LIPUS-treated controls, supporting its role in periodontal regeneration³⁹.

The heterogeneity assessment indicated moderate variability among studies (I² = 45%), likely due to differences in LIPUS treatment duration, frequency and intensity settings⁴⁰. A study by Chen, et al, highlighted that variations in LIPUS parameters could influence treatment outcomes, with optimal results observed at an intensity of 30 mW/cm² and a frequency of 1.5 MHz applied for 20 minutes daily over eight weeks⁴¹. These findings suggest that standardization of LIPUS treatment protocols is essential to maximize its clinical benefits⁴².

Overall, the evidence from both clinical and preclinical studies strongly supports the role of LIPUS in enhancing periodontal healing. However, further well-designed randomized controlled trials (RCTs) with standardized treatment parameters and long-term follow-up are needed to confirm its efficacy and integration into routine periodontal therapy⁴³.

Clinical implications
These findings suggest that LIPUS could serve as a valuable adjunct to conventional periodontal therapy, particularly in cases requiring enhanced bone regeneration and healing⁴⁴. Given its non-invasive nature, LIPUS may be beneficial for patients who are contraindicated for surgical periodontal interventions⁴⁵. The ability of LIPUS to stimulate osteoblastic activity, reduce inflammation and promote extracellular matrix production suggests that it may enhance clinical outcomes when combined with traditional therapies such as scaling and root planning, guided tissue regeneration (GTR) and bone grafting⁴⁶.

Moreover, LIPUS has the potential to accelerate postoperative healing and improve periodontal regeneration in cases of advanced periodontitis or peri-implantitis, where conventional approaches may be less effective⁴⁷. Additionally, LIPUS can be integrated into non-surgical management protocols for maintaining periodontal health in high-risk patients, such as those with diabetes or immunosuppressive conditions⁴⁸. However, standardizing treatment protocols, including optimal duration, frequency and intensity settings, is essential to maximize its clinical benefits and ensure reproducibility in diverse patient populations⁴⁹.

Limitations and Future Directions
Despite the promising results of LIPUS in periodontal regeneration, several limitations exist in the current body of literature⁵⁰. The lack of standardized treatment parameters results in variations in outcomes, making it difficult to establish clinical guidelines⁵¹. Studies have reported a range of frequencies, intensities and application durations, leading to inconsistent findings regarding the efficacy of LIPUS in periodontal regeneration⁵². A major limitation of existing clinical trials is their relatively small sample sizes and short follow-up durations, which limit the generalizability of findings and prevent definitive conclusions on long-term benefits⁵³.

Additionally, while preclinical studies provide valuable mechanistic insights, the translation of these findings into human clinical practice requires further validation through large-scale, multicenter randomized controlled trials (RCTs)⁵⁴. Few studies have examined the long-term stability of LIPUS-induced periodontal regeneration, leaving uncertainty regarding its sustained benefits beyond the initial treatment period⁵⁵. Cost-effectiveness analyses are also lacking, making it difficult to determine the financial feasibility of incorporating LIPUS into routine periodontal care⁵⁶.

Future research should focus on optimizing treatment protocols through well-designed RCTs with standardized LIPUS application parameters⁵⁷. Long-term studies with extended follow-up periods are necessary to assess the durability of regenerative outcomes⁵⁸. Additionally, studies should investigate the synergistic effects of LIPUS with biomaterials, growth factors and stem cell-based therapies to further enhance periodontal regeneration⁵⁹. Exploring the molecular mechanisms underlying LIPUS-induced tissue repair using advanced imaging and molecular biology techniques will help refine its clinical application⁶⁰.

Conclusion
This systematic review and meta-analysis provide evidence supporting the efficacy of LIPUS in periodontal regeneration. The findings indicate that LIPUS significantly improves CAL, PD reduction and alveolar bone healing. Mechanistically, LIPUS enhances angiogenesis, promotes osteoblastic activity and modulates inflammatory responses, creating a favorable environment for periodontal regeneration. Despite its promising results, the lack of standardized protocols and long-term clinical data necessitates further high-quality research to validate its clinical utility.

Given its non-invasive nature and regenerative potential, LIPUS represents a valuable adjunct in periodontal therapy. However, future studies must focus on optimizing treatment parameters, assessing long-term stability and determining cost-effectiveness to integrate LIPUS into routine periodontal care successfully. If further validated through rigorous clinical trials, LIPUS has the potential to revolutionize periodontal treatment, offering a non-invasive, efficient and patient-friendly approach to enhancing tissue regeneration and improving periodontal health outcomes.

Declarations
Conflict of Interest: The author declares none.

Funding: No funds were received for this study.

Ethical issues: Not required

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