Efficacy and safety of arthroscopic surgery combined with hyaluronic acid for meniscal injuries: A systematic review and meta-analysis of randomized controlled studies

Abstract

Objective

The efficacy and safety of arthroscopic surgery combined with hyaluronic acid in the treatment of meniscal injuries were evaluated by Meta-analysis to provide an evidence-based basis for the selection of clinical treatment options.

Methods

PubMed, Cochrane Library, EMBASE, Scopus, Web of Science English databases, and Chinese databases of China National Knowledge Infrastructure, WAN FANG, VIP, and China SinoMed had been searched up to June 2021. Quality evaluation was performed concerning the Cochrane Systematic Evaluation Tool. The obtained data were analyzed using the statistical software Review Manager 5.3.

Results

Eleven randomized controlled trials with a total of 955 patients were eventually included, 473 in the arthroscopic combined with hyaluronic acid group (combined treatment group) and 482 in the arthroscopy alone group (surgery group). The results of the study revealed that the excellent treatment [OR = 3.44, 95% CI (2.10, 5.65), p < .00,001], the VAS score [MD = −0.99, 95% CI (−1.50, −0.48), p = .0002], the Lysholm score [MD = 9.70, 95% CI (6.41, 12.99), p < .00,001] and the joint mobility [MD = 6.31, 95% CI (0.84, 11.78), p = .02] of the combined treatment group were significantly better than the surgery group, the difference was statistically significant. The complications rate was comparable in both groups [OR = 0.86, 95% CI (0.29, 2.53), p = .78], with no statistically significant difference.

Conclusion

Arthroscopic surgery combined with hyaluronic acid for meniscal injury can improve the efficiency of treatment compared with arthroscopic surgery alone, as well as the efficacy in relieving joint pain and improving joint function and mobility, without increasing the incidence of complications. Arthroscopic surgery combined with hyaluronic acid administration has good effectiveness and safety profile. Therefore, hyaluronic acid supplementation is recommended after arthroscopic surgery when treating meniscal injuries.

Keywords

meniscus hyaluronic acid arthroscopy excellent rate meta-analysis

Introduction

The meniscus is a fibrocartilaginous disc structure in the knee joint, covering approximately 1/2 to 2/3 of the tibial plateau. The intact meniscus structure has the functions of joint stabilization, load distribution, shock absorption, lubrication and nutrition.¹ Meniscal injury is one of the most prevalent knee injuries, and it causes joint instability and weakened impact resistance, which contributes to the occurrence of degenerative osteoarthritis.² At this stage, arthroscopic surgery is the preferred treatment, although the treatment effect is still acceptable, there are still problems such as postoperative complications, postoperative pain, and limited joint function.³ Therefore, it is a major challenge for clinicians to increase the regenerative and self-healing capacity of the meniscus after injury and to enhance the postoperative healing rate as well as the quality of life of patients.^4,5 Hyaluronic acid is an important part of extracellular matrix and synovial fluid, which has the functions of lubricating, nourishing, protecting intra-articular tissues, and stabilizing the knee joint.⁶ Previous studies have reported that intra-articular supplementation with exogenous HA is effective in reducing joint friction, relieving pain, and increasing joint mobility, while directing the secretion of endogenous HA and helping to re-establish the dynamic balance of the joint.^7,8 In recent years, hyaluronic acid has been widely used in the treatment of soft tissue injuries such as muscles and ligaments as well as osteoarthritis, especially in the treatment of cartilage injuries with satisfactory repair results.⁸ For meniscal fibrocartilage, which is also mainly composed of chondrocytes and extracellular matrix, whether hyaluronic acid can increase its regeneration and repair ability after injury and then promote injury healing has attracted extensive attention of researchers.¹

With the development of clinical applications, studies related to arthroscopic surgery combined with hyaluronic acid in the treatment of meniscal injury have been published at home and abroad, but there are problems such as large differences in grade, small samples, and inconsistent conclusions among the studies, making the scientific consequences of hyaluronic acid controversial. To address the current lack of evidence-based evidence, this study was conducted to obtain high-quality evidence-based medical evidence for arthroscopic surgery combined with hyaluronic acid in the treatment of meniscal injuries by Meta-analysis of relevant studies, to provide a reference for the selection of clinical treatment options.

Methods

This Meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement’s relevant standards. The protocol was registered in the PROSPERO database (CRD42021269001).

Search strategy

Two investigators searched PubMed, Cochrane Library, EMBASE, Scopus, Web of Science English databases, and Chinese databases of Chinese databases of China National Knowledge Infrastructure, WAN FANG, VIP, and China SinoMed for arthroscopic surgery combined with hyaluronic acid compared with arthroscopic surgery alone to screen eligible randomized controlled trials concerning inclusion criteria. All databases were searched from build to June 2021, while the references of the included literature were searched. Data reports were not available or original sources were lacking, the authors will be contacted by letter to obtain the literature that meets the requirements as completely as possible. In PubMed, for example, the English search terms included “Meniscus”, “Menisci” and “hyaluronic acid”. The search strategy diagram is shown in Figure 1.

Figure 1.

Search strategy diagram.

Inclusion and exclusion criteria

Inclusion criteria: (1) meniscal injury diagnosed by MRI, with symptoms and signs related to meniscal injury (McMurray sign, knee pain, swelling and locking, etc.); (2) prospective randomized controlled trial; (3) interventions: experimental group with arthroscopic surgery combined with intra-articular injection of hyaluronic acid, and control group treated with arthroscopic surgery alone.

Exclusion criteria: (1) previous history of unrepaired or reconstructed cruciate ligament injury; (2) with gout, rheumatoid arthritis and severe articular cartilage damage or combined with severe osteoarthritis (K-L stage IV); (3) with other serious systemic diseases; (4) animal experiments, computer models, case reports, reviews, systematic reviews of literature, and literature for which the full-textual content was not available.

Literature screening and data extraction

Two investigators independently screened the literature in the search results by first disposing of duplicates through Endnote X9 software combined with the manual review, followed by reading the titles and abstracts of the literature for initial screening, excluding studies that were not relevant to the topic, obtaining and browsing the full-textual content for re-screening when necessary, and finally finalizing the included literature primarily based on inclusion and exclusion criteria. Data extraction included first author, year of publication, sample size, age, gender, interventions, outcome indicators, and other relevant content. The primary outcome indicators included excellent rate, pain visual analog score (VAS), and Lysholm score. Secondary outcome indicators were joint mobility and complication rate.

Literature quality assessment

Each included literature was assessed for potential risk by two investigators. All studies were assessed for the risk of bias by referring to the Cochrane Handbook for Systematic Reviews of Interventions for the following domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. Overall quality was graded as low (low risk of bias), high (high risk of bias), or unclear risk of bias for each domain entry. If two investigators disagree, a third author participates in the discussion until the consensus is reached.

Statistical analysis

Data analysis was performed using Review Manager statistical software [RevMan (Computer program). Version 5.3]. The difference in dichotomous variables was expressed as odds ratio (OR) with 95% confidence interval (CI) and the difference in continuous variables was expressed as mean difference (MD) and 95% confidence interval (CI). A p-value of less than 0.05 was considered statistically significant. The Higgins I² statistic was used to assess heterogeneity, I²< 50% was defined as no significant heterogeneity among studies, and the fixed effects model was used to calculate pooled effect estimates. Otherwise, the random effects model or descriptive evaluation were used, and sensitivity analysis or subgroup analysis were carried out to investigate the source of heterogeneity.

Results

Literature search results and basic characteristics of the study

According to the search strategy, 1616 relevant studies were initially retrieved, including 163 from Pubmed, 362 from Embase, 46 from Cochrane Library, 330 from Scopus, 151 from Web of Science, 206 from China National Knowledge Infrastructure, 176 from WAN FANG, 69 from VIP, and 113 from China SinoMed. 868 studies remained after using Endnote X9 software and manual recheck, and then 48 articles were selected by reading the titles and abstracts. The full text was reviewed again, and a total of 11 randomized controlled trials, including 6 in English and 5 in Chinese, were included in strict accordance with the inclusion criteria. Literature screening process and results is shown in Figure 2. A total of 955 patients were included, with 473 in the combined treatment group and 482 in the surgery group. The basic information of each study is shown in Table 1. Baseline data such as patient age and sample size were comparable, with all p > 0.05.

Figure 2.

Flowchart for the selection of included studies.

Risk of bias assessment

A total of eleven randomized controlled trials^9–19 were included in this study. Random sequence generation was recorded adequately in seven studies,^{9,10,12,14–17} of which six^{9,10,12,14–16} were random number table and one¹⁷ was dedicated software. The other studies^11,13,18,19 did not explain the specific method. Allocation concealment was recorded adequately in two studies,^17,18 unclear in eight,^{9–11,13–16,19} and high in one.¹² The performance bias was recorded adequately in four studies,^15–18 unclear in three,^9,10,12 and high in four.^11,13,14,19 The detection bias was recorded adequately in five studies^15–19 and unclear in six.^9–14 The attrition bias was recorded adequately in all studies.^9–19 The reporting bias and other bias were mainly low risk. The risk of bias assessment and risk of bias summary are shown in Figures 3 and 4.

Figure 3.

Risk of bias assessment.

Figure 4.

Risk of bias summary.

Meta-analysis results

Excellent rate

Six studies^9–14 were conducted to compare excellent rate, and a total of 662 patients were included, including 331 in the combined treatment group and 331 in the surgery alone group. There was no significant heterogeneity among the studies (I² = 0%), so the fixed effects model was used to calculate the effect sizes. The results showed that the overall clinical excellent rate of arthroscopic surgery combined with hyaluronic acid in the treatment of meniscus injuries was higher than that of patients with arthroscopic surgery alone [OR = 3.44, 95% CI (2.10, 5.65), p < .001] (Figure 5).

Figure 5.

Comparison of the excellent rate between the combined treatment group and the surgery alone group.

Pain visual analog score (VAS)

Eight studies^{9,10,12,14–18} were conducted to compare VAS score, and a total of 657 patients were included, including 324 in the combined treatment group and 333 in the surgery alone group. Heterogeneity was significant (I² = 98%). The heterogeneity among the studies did not change significantly after sensitivity analysis by excluding the literature one by one, and the heterogeneity was still significant after subgroup analysis. The investigators analyzed that the possible reason for the high heterogeneity might be since VAS score are more influenced by patients' subjective factors, so the random effects model was finally used to calculate the effect size. The results showed that the VAS score of arthroscopic surgery combined with hyaluronic acid in the treatment of meniscus injuries was lower than that of arthroscopic surgery alone, which means it has a better effect in relieving joint pain [MD = −0.99, 95% CI (−1.50, −0.48), p = .0002] (Figure 6).

Figure 6.

Comparison of pain visual analog score between the combined treatment group and the surgery alone group.

Lysholm score

Four studies^9,10,13,19 were conducted to compare Lysholm score, and a total of 446 patients were included, including 243 in the combined treatment group and 203 in the surgery alone group. Heterogeneity was significant (I² = 85%). There was no significant change in heterogeneity after performing sensitivity analysis as well as subgroup analysis, so the random effects model is used to calculate the effect size. The results showed that the Lysholm score of arthroscopic surgery combined with hyaluronic acid in the treatment of meniscus injuries was higher than that of arthroscopic surgery alone, which means it has a better effect in improving joint function [MD = 9.70, 95% CI (6.41,12.99), p < .00,001] (Figure 7).

Figure 7.

Comparison of Lysholm score between the combined treatment group and the surgery alone group.

Joint mobility

Five studies^{13,14,16–18} were conducted to compare Joint mobility, and a total of 269 patients were included, including 180 in the combined treatment group and 189 in the surgery alone group. Heterogeneity was significant (I² = 93%). Again, there was no change in heterogeneity after performing sensitivity analysis and subgroup analysis, so the random effects model is used to calculate the effect size. The results show that arthroscopic surgery combined with hyaluronic acid in the treatment of meniscus injury patients has better joint mobility than arthroscopic surgery alone, which means improvement of joint mobility is more obvious [MD = 6.31, 95% CI (0.84, 11.78), p = .02] (Figure 8).

Figure 8.

Comparison of joint mobility between the combined treatment group and the surgery alone group.

Complication rate

Five studies^12,14–17 were conducted to compare complication rate, and a total of 306 patients were included, including 153 in the combined treatment group and 153 in the surgery alone group. Heterogeneity was slightly significant (I² = 63%). In sensitivity analyses, I² was reduced to 0% after excluding one study, so the fixed effects model was selected to calculate the effect size after excluding this study. The results showed that there was no significant difference in the complication rate of arthroscopic surgery combined with hyaluronic acid and arthroscopic surgery for meniscal injuries. [OR = 0.86, 95% CI (0.29, 2.53), p = .78] (Figure 9).

Figure 9.

Comparison of complication rate between the combined treatment group and the surgery alone group.

Discussion

Currently, arthroscopic surgery is the gold standard for treating meniscus injuries. After accurate assessment of the location and extent of the meniscus injury through the microscope, precise resection or repair is performed to preserve the maximum amount of meniscus tissue.^5,20 At the same time, it can repair the joint’s other structural injury, effectively cleaning the osteophytes, synovium, and other loose tissues in the joint cavity, and eliminating as much as possible the factors that cause pain and other symptoms in the joint.^21,22 However, studies have reported that some patients still have obvious pain symptoms after arthroscopy, and the reoperation and nonunion rate after arthroscopy both approach 10%–30%.^23,24 Hyaluronic acid has nutritional and protective effects on joint tissues, and can effectively inhibit the release of synovial pain transmitters to reduce pain, which has been widely used in the treatment of human joint diseases.^6,18,25 In animal experiments, regular intra-articular hyaluronic acid supplementation was given after removal of the rabbit meniscus, and significant meniscal regeneration and formation of new translucent tissue were detected after 6 months, with significantly higher intra-articular glycosaminoglycan content and collagen remodeling than in the control group.²⁶ Lin et al.⁹ reported that in the treatment of human meniscus injury, the combination of hyaluronic acid after arthroscopy can effectively reduce inflammatory factors such as IL-1 and IL-6 in patients’ synovial fluid, thereby inhibiting the inflammatory response. Although there are several clinical reports on arthroscopic surgery combined with hyaluronic acid for the treatment of meniscal injuries, there is still a lack of multicenter, large sample randomized controlled trials. There is also a lack of reliable evidence-based evidence on the advantages of supplementing hyaluronic acid after arthroscopic meniscus surgery. In this study, we conducted a Meta-analysis of studies related to arthroscopic surgery combined with hyaluronic acid for meniscal injuries to comprehensively evaluate the efficacy and safety of arthroscopic surgery combined with hyaluronic acid for meniscal injuries. The results confirmed that the combination of hyaluronic acid improved the treatment efficiency compared with arthroscopic surgery alone, and also had more advantages in relieving joint pain and improving joint function and mobility without increasing the incidence of complications.

This Meta-analysis confirmed that the excellent rate of arthroscopic surgery combined with hyaluronic acid for meniscal injury was significantly higher than that of arthroscopic surgery alone. Lin et al.⁹ reported a statistically significant treatment efficiency of 90.74% versus 75.93% in the combined treatment group versus the surgery alone group, which is similar to the present study. Previous studies have confirmed that hyaluronic acid can inhibit prostaglandin E2-induced meniscal cell apoptosis through CD44 receptors, and activate PI3K and MAPK pathways to enhance the proliferation and migration of meniscal cells and increase the expression of type II collagen, ultimately promoting the repair and healing of the injured meniscus, which may be the molecular mechanism for the better efficiency of the combined treatment group.^27,28 The Lysholm score was selected for the improvement of the postoperative joint function of patients. This study was highly heterogeneous, and the source of heterogeneity may be due to the fact that the results are subjective scores with large individual differences. In addition, the duration of treatment and the time points of measurement scores were not entirely consistent across studies, which may have contributed to the large heterogeneity. To reduce the possible bias introduced by subjective scores on the assessment of joint function, further comparative analysis of joint mobility was performed in this study. The results showed that the combination of hyaluronic acid was more effective in improving the patient’s joint mobility compared to arthroscopic surgery alone. In contrast, the study by Başar, et al.¹⁸ reported that postoperative joint mobility was (93.2 ± 6.1) versus (92.0 ± 7.5) in patients in the combined treatment group versus the surgery alone group, respectively, which was not statistically significant and differed from the findings of this study. We analyzed this discrepancy due to its inclusion criteria of degenerative meniscal injury combined with osteoarthritis and the average age of the included patients, which resulted in a non-significant improvement in the postoperative joint mobility of the patients.

This study confirmed that arthroscopy combined with hyaluronic acid treatment can effectively reduce joint pain in patients. However, in the study by Filardo et al.,¹⁷ joint pain symptoms improved in both the combined treatment group and the surgery alone group compared to the preoperative period, but there was no difference between the two groups. Further analysis revealed that the authors chose a highly viscoelastic, long-durable hyaluronic acid product for a single injection in order to avoid multiple injections of the drug and the corresponding risk of infection caused. However, due to the limited single injection dose (only 3 mL), it is difficult to ensure an effective therapeutic dose and affect the therapeutic effect.

Finally, to determine the safety of combination of hyaluronic acid, our study also conducted a Meta-analysis of complication rates, which revealed that combined use of hyaluronic acid did not increase the incidence of complications. The heterogeneity of this result was large, and after excluding the included studies one by one, it was found that I² decreased to 0 after excluding the study of Westrich et al.,¹⁶ while the result did not change. On the one hand, it confirms the robustness of the result, and on the other hand, it shows that the study by Westrich et al. is the main source of the heterogeneity of this indicator. The heterogeneity was found to stem from the inconsistent baseline condition of the patients in this study, with more patients in the surgery alone group had symptoms such as preoperative joint swelling. Postoperative complications reported in previous clinical studies were pain or swelling of the joint associated with drug injections, which resolved spontaneously without specific treatment. There have been no reports of serious adverse events associated with the combination of hyaluronic acid. In addition, hyaluronic acid has been shown to have an excellent safety profile as a commonly used drug in the treatment of cartilage injury and osteoarthritis.^6,7,25. Therefore, it is clear that the combined use of hyaluronic acid in the postoperative period has a good safety profile.

This study has the following limitations: (1) The specific site, type, and grading of meniscal injuries were not specified in this article, and most of the studies are based on imaging examination (mainly MRI) and clinical symptoms as the diagnostic criteria, which could potentially bias the assessment of treatment outcome. (2) Surgical procedures were not uniform for each study, but the treatment principle of preserving as much meniscal tissue as possible and the increased sample size was helpful in improving the stability of the results. (3) There is variation in the dose and frequency of hyaluronic acid treatment, with three of the investigators, including Filardo et al.^15,17,18 giving patients only a single injection of hyaluronic acid, which would lead to greater study heterogeneity and possible bias. (4) The studies are mostly short-term to medium-term follow-up, and more large-sample, multicenter RCT studies are needed to verify long-term clinical efficacy and safety.

In conclusion, arthroscopic surgery combined with hyaluronic acid for meniscal injury can improve the efficiency of treatment compared with arthroscopic surgery alone, as well as the efficacy in relieving joint pain and improving joint function and mobility, without increasing the incidence of complications. Arthroscopic surgery combined with hyaluronic acid administration has good effectiveness and safety profile. Therefore, hyaluronic acid supplementation is recommended after arthroscopic surgery when treating meniscal injuries.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by grants from the National Natural Science Foundation of China (No. 81572098, No. 81772415 and No. 8217091742) and the Natural Science Foundation of Shanxi Province (No. 20210302123285 and No. 20210302123283).

ORCID iD

Zhiqiang Dong

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