Abstract
Objective: To observe the effect of autologous platelet-rich plasma combined with sodium hyaluronate on clinical efficacy and serum inflammatory factor levels in patients with knee osteoarthritis. Methods: A retrospective study was conducted on a total of 99 knee osteoarthritis patients who underwent arthroscopic surgery after failed conservative treatment in No. 215 Hospital of Shaanxi Nuclear Industry from January 2019 to January 2022. Among them, 45 patients treated with only sodium hyaluronate injection after arthroscopic debridement were grouped as the control group (CG), and 54 patients treated with platelet-rich plasma combined with intra-articular injection of sodium hyaluronate after arthroscopic debridement were the observation group (OG). Visual analogue scale/score (VAS) and Lysholm knee scale (LKS) were used to evaluate the clinical therapeutic effect before and 5 weeks after treatment, and ELISA was to detect the changes of matrix metalloproteinase-3 (MMP-3), interleukin-1β (IL-1β), high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α) levels in the serum of patients before and 5 weeks after treatment. Risk factors affecting patient outcomes were analyzed by logistic regression. Results: Compared to theCG, the improvement of clinical efficacy in the OG was higher (P < 0.05), as well as its LKS score, while the VAS score after treatment in OG was markedly lower (P < 0.05). After treatment, MMP-3, IL-1β, hs-CRP, and TNF-α in the OG were significantly lower than those in the CG (P < 0.05). There was nodifference in the incidence rate of adverse reactions between the two groups (P > 0.05). Logistic regression analysis showed that younger age and lower BMI were protective factors for efficacy in the patients, while higher LKS and TNF-α were risk factors affecting the efficacy in the patients. Conclusion: Intra-articular injection of platelet-rich plasma combined with sodium hyaluronate in the treatment of knee osteoarthritis can significantly reduce the symptoms of knee joint pain, improving knee joint function and in vivo inflammatory response.
Keywords: Autologous platelet-rich plasma, sodium hyaluronate, knee osteoarthritis, clinical efficacy, serum inflammatory factors
Introduction
Osteoarthritis is the most common joint disease, usually characterized by slow progression, involving articular cartilage, subchondral bone, ligaments, synovium, and adjacent muscles [1]. It has been found that osteoarthritis patients with large joints have a relatively poor prognosis, which can result in disability at a later stage, placing a heavy burden on society [2]. Knee osteoarthritis is a common osteoarthritis in orthopedics, which is a cartilage destruction of the articular surface of the knee joint caused by cartilage degeneration, necrosis and shedding [3]. Patients have excessive mechanical loads acting on normal articular cartilage, or normal mechanical loads acting on damaged articular cartilage, which leads to the development of osteoarthritis [4]. Knee osteoarthritis has a long disease course and cannot be cured completely. The expenditure of medical costs and patients’ inability to earn moneyor relatively reduced work intensity burdens both the family and patients financially [5]. In the United States, the incidence of knee osteoarthritis is second only to cardiovascular disease among people over 50, with an incidence of 30-50% in people over 65 years of age [6]. With the improvement of medicine, the life expectancy of people continues to grow, and the incidence rate is on a gradually increasing trend. In addition, due to the high population base, the aging of the population in China is becoming serious, resulting in a large number of patients with knee osteoarthritis, bringing a huge economic burden and nursing costs to each patient’s family and society [7].
There are currently many treatment options for knee osteoarthritis, which can be broadly divided into surgical and non-surgical treatments [8]. Both surgical and non-surgical treatment have achieved clinical results. However, there is still a lack of particularly simple, practical and effective treatment for the disease because the etiology and pathogenesis of knee osteoarthritis are not fully understood, and an ideal situation has not yet been achieved in terms of the effect or the process of treatment [9]. Sodium hyaluronate is the main component of synovial fluid, an ideal drug for the treatment of osteoarthritis, which can increase the lubrication function of joints and protect articular cartilage [10,11]. A growing number of studies have revealed that platelet-rich plasma (PRP) has a good effect in the treatment of inflammatory diseases [12]. PRP contains a variety of growth factors that facilitate the repair of knee cartilage, and PRP treatment of knee osteoarthritis by intra-articular injection repairs cartilage defects and restores knee joint motor function [13]. PRP is a high concentration of platelet concentrate obtained by centrifugation and separation of autologous whole blood, with a relatively normal platelet concentration of 200,000/ul, and the platelet count in PRP after centrifugation can exceed 2 million/µl [14]. Moreover, PRP contains a large number of growth factors, mainly platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), fibroblast growth factor (FGF) and insulin-like growth factor (IGF), which promote chondrocyte proliferation, inhibit osteoclast function, induce the synthesis of cartilage matrix, and promote the healing of cartilage and other tissues [15,16]. However, there is no systematic report on the therapeutic effect of combined treatment of autologous platelet-rich plasma and sodium hyaluronate in patients with knee osteoarthritis.
In this study, we aimed to analyze the effect of autologous platelet-rich plasma combined with sodium hyaluronate on the clinical efficacy and serum inflammatory factor levels in patients with knee osteoarthritis, to provide a reference for the feasibility of clinical treatment.
Materials and methods
Clinical information
A retrospective study was conducted on a total of 99 patients with knee osteoarthritis who underwent arthroscopic surgery after failure of conservative treatment in No. 215 Hospital of Shaanxi Nuclear Industry from January 2019 to January 2022. Among them, 45 patients treated with only sodium hyaluronate injection after arthroscopic debridement were grouped as the control group (CG), and 54 patients treated with platelet-rich plasma combined with intra-articular injection of sodium hyaluronate after arthroscopic debridement were set as the observation group (OG). This study was approved by the Medical Ethics Committee of No. 215 Hospital of Shaanxi Nuclear Industry.
Inclusion and exclusion criteria
Inclusion criteria: In line with the diagnostic criteria for knee osteoarthritis in the “Guidelines for the Diagnosis and Treatment of Osteoarthritis” [17]; Patients with failed conservative treatment; Patients diagnosed with Kellgren-Lawrence grades I-III; Patients with complete clinical data.
Exclusion criteria: Patients with knee joint tuberculosis, suppuration or intra-articular fracture; Patients with severe heart, lung, liver, kidney and other complications; Patients with psychosis, mental disorders and depression and unwilling or unable to cooperate with the experiment; Pregnant or breastfeeding patients; Intolerant to this treatment regimen.
Treatment regimen
The CG was treated with sodium hyaluronate (Shanghai Haohai Biotechnology Co., Ltd., GYZZ H20000326). Usage and dosage: sodium hyaluronate 2 mL/time after routine disinfection of the knee joint, once a week, was injected into the synovial fluid by withdrawing the lower edge of the patella and the lateral patellar ligament for 5 weeks.
The OG was treated with PRP on the basis of CG. The preparation method of PRP was as follows: 10 mL peripheral venous blood was collected and centrifuged in a high-speed rotary centrifuge at a rate of 1100 r/min for 8 min. A few red blood cells were collected from the supernatant and junction, and then centrifuged at 1100 r/min for 8 min. The upper anemic platelet plasma was removed to obtain PRP, which was then activated by adding 0.2 mL of 10% calcium chloride. After routine disinfection of the knee joint, PRP 2 mL/time, once a week, could be injected into the joint fluid by withdrawing the synovial fluid with the lower edge of the patella and the lateral patellar ligament as the puncture points for 5 weeks.
Serologic markers
Enzyme linked immunosorbent assay (ELISA) was used to detect changes in serum levels of matrix metalloproteinase-3 (MMP-3, ml026254), interleukin-1β (IL-1β, ml058034), high-sensitivity C-reactive protein (hs-CRP, ml092638) and tumor necrosis factor-α (TNF-α, ml077385) during treatment. The kit was purchased from Shanghai Enzyme Linked Immunology Co., Ltd.
Outcome measures
Main outcome measures: The clinical efficacy was compared between the two groups. Visual analogue scale/score (VAS) for pain [18] and Lysholm knee scale (LKS) [19] were used to evaluate the pain and knee ability function after treatment before and 5 weeks after treatment.
Secondary outcome measures: Clinical data of the two groups was compared. ELISA was used to detect the changes of matrix metalloproteinase-3 (MMP-3), interleukin-1β (IL-1β), high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α) levels in serum of patients before surgery and 5 weeks after treatment. The incidence of adverse reactions during treatment was compared between the two groups. Risk factors affecting patient outcomes were analyzed with logistics regression.
Criteria for response assessment
Significantly effective: the clinical symptoms basically disappeared, the knee joint function recovered with no joint effusion or swelling, and the Lysholm score difference before and after treatment was ≥ 30 points. Effective: clinical symptoms and knee joint function improved, there was a small amount of joint effusion or slight swelling, with Lysholm score difference before and after treatment of 6 to 29 points. Invalid: the above criteria were not met. Clinical response rate = (markedly effective + effective)/total number 100%.
Statistical analysis
Data collected were analyzed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA), and visualized using GraphPad Prism 8. Kolmogorov-Smirnov test was used to assess distribution normality. Data in this study conformed to a normal distribution, thus were presented as mean ± standard deviation, and were analyzed by t-test; specifically, Student t-test and Paired t-test were used for inter-group and intra-group comparison, respectively. Chi-square test was used to compare categorical variables, Logistics test was to analyze the risk factors affecting patients’ efficacy, and receiver operating curve was to analyze the value of risk factors in predicting the efficacy of patients. P < 0.05 indicated statistical significance.
Results
Clinical information
The two cohorts of patients were comparable with no significant differences in terms of sex, age, BMI, course of disease, history of diabetes and history of hypertension (P > 0.05) (Table 1).
Table 1.
Comparative analysis of baseline data
| Variable | Control Group (n=45) | Observation Group (n=54) | x2 Value | P Value |
|---|---|---|---|---|
| Gender | 0.312 | 0.576 | ||
| Male | 25 | 33 | ||
| Female | 20 | 21 | ||
| Age | 0.303 | 0.581 | ||
| ≥ 55 years | 25 | 27 | ||
| < 55 years | 20 | 27 | ||
| BMI | 0.325 | 0.568 | ||
| ≥ 23 kg/m2 | 14 | 14 | ||
| < 23 kg/m2 | 31 | 40 | ||
| Course of Disease | 0.001 | 0.968 | ||
| ≥ 5 years | 31 | 37 | ||
| < 5 years | 14 | 17 | ||
| History of Diabetes | 0.358 | 0.549 | ||
| Yes | 15 | 15 | ||
| No | 30 | 39 | ||
| History of Hypertension | 0.005 | 0.940 | ||
| Yes | 18 | 22 | ||
| No | 27 | 32 |
Note: Body Mass Index (BMI).
Comparison of efficacy evaluation
After treatment, the improvement of clinical efficacy in the OG was significantly better than that in the CG (P < 0.05, Table 2).
Table 2.
Comparison of efficacy evaluation between the two groups
| Grouping | Significantly effective | Effective | Invalid | Overall response rate |
|---|---|---|---|---|
| Control Group (n=45) | 17 (37.78%) | 15 (33.33%) | 13 (28.89%) | 32 (71.11%) |
| Observation Group (n=54) | 27 (50.00%) | 23 (42.59%) | 4 (7.41%) | 50 (92.59%) |
| x2 value | 7.964 | |||
| P value | 0.005 |
Changes in LKS and VAS scores before and after treatment
After treatment, LKS score was increased, while VAS score was decreased in both groups (both P < 0.05). Further comparison suggested that the OG held a higher LKS score than the CG after treatment, while its VAS score went markedly lower than that of the CG (both P < 0.05, Figure 1).
Figure 1.
Changes of LKS and VAS scores before and after treatment in patients. A. Comparison of LKS score changes before and after treatment. B. Comparison of VAS score changes before and after treatment. Note: Visual analogue scale/score (VAS), Lysholm knee scale (LKS), * indicates P < 0.001.
Changes of inflammatory factors before and after treatment
Comparing the changes of inflammatory factors before and after treatment between the two groups, it was found that MMP-3, IL-1β, hs-CRP and TNF-α in both groups decreased markedly compared with those before treatment (all P < 0.05). Further comparison showed that above indicators in the OG were much lower than those in the CG after treatment (all P < 0.05, Figure 2).
Figure 2.
Changes of inflammatory factors before and after treatment. A. Comparison of MMP-3 changes before and after treatment. B. Comparison of IL-1β changes before and after treatment. C. Comparison of hs-CRP changes before and after treatment. D. Comparison of TNF-α changes before and after treatment. Note: Matrix metalloproteinase-3 (MMP-3), interleukin-1 (IL-1β), high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α), P < 0.001.
Adverse reactions comparison
Comparison of adverse reactions between the two groups showed no statistical difference in the incidence rate of adverse reactions (P > 0.05, Table 3).
Table 3.
Comparison of Adverse Reactions between the two groups
| Grouping | Hemarthrosis | Knee infection | Fever | Deep vein thrombosis | Total Occurrence |
|---|---|---|---|---|---|
| Control Group (n=45) | 2 (4.44%) | 3 (6.67%) | 2 (4.44%) | 1 (2.22%) | 8 (17.77%) |
| Observation Group (n=54) | 1 (1.85%) | 2 (3.70%) | 1 (1.85%) | 1 (1.85%) | 5 (9.25%) |
| x2 value | 1.561 | ||||
| P value | 0.211 | ||||
Analysis of risk factors affecting the efficacy of patients
According to the clinical efficacy of the patients after treatment, there were 82 patients assigned into the effective group and 17 patients into the ineffective group. By univariate analysis, it was found that age, BMI, LKS score, IL-1β, and TNF-α were associated with patient treatment outcome (Table 4, P < 0.05). Subsequently, based on assigning values (Table 5), we conducted logistic regression analysis and found that younger age and lower BMI were protective factors for the efficacy of patients, while higher LKS and TNF-α were risk factors (Table 6, P < 0.05).
Table 4.
Univariate analysis of factors affecting the treatment efficacy
| Variable | Effective Group (n=82) | Invalid Group (n=17) | x2 value | P value |
|---|---|---|---|---|
| Gender | 0.316 | 0.573 | ||
| Male (n=58) | 47 | 11 | ||
| Female (n=41) | 35 | 6 | ||
| Age | 7.323 | 0.006 | ||
| ≥ 55 years old (n=52) | 38 | 14 | ||
| < 55 years old (n=47) | 44 | 3 | ||
| BMI | 13.420 | < 0.001 | ||
| ≥ 23 kg/m2 (n=28) | 17 | 11 | ||
| < 23 kg/m2 (n=71) | 65 | 6 | ||
| Course of Disease | 0.034 | 0.852 | ||
| ≥ 5 years (n=68) | 56 | 12 | ||
| < 5 years (n=31) | 26 | 5 | ||
| History of Diabetes | 1.149 | 0.283 | ||
| Yes (n=30) | 23 | 7 | ||
| No (n=69) | 59 | 10 | ||
| History of Hypertension | 2.892 | 0.089 | ||
| Yes (n=40) | 30 | 10 | ||
| No (n=59) | 52 | 7 | ||
| LKS Score | 56.17±5.52 | 60.00±4.58 | 2.669 | 0.008 |
| VAS Score | 7.46±1.21 | 7.52±1.50 | 0.194 | 0.845 |
| MMP-3 | 26.59±3.63 | 28.36±3.32 | 1.856 | 0.065 |
| IL-1β | 21.28±4.04 | 23.59±3.43 | 2.199 | 0.030 |
| hs-CRP | 8.42±1.33 | 9.10±1.26 | 1.926 | 0.057 |
| TNF-α | 43.53±6.46 | 47.30±5.99 | 2.234 | 0.027 |
Note: Body Mass Index (BMI), Visual analogue scale/score (VAS), Lysholm knee scale (LKS), Matrix metalloproteinase-3 (MMP-3), interleukin-1 (IL-1β), high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α).
Table 5.
Assignment
| Variable | Assignment |
|---|---|
| Age | ≥ 55 years old =1, < 55 years old =0 |
| BMI | ≥ 23 kg/m2 =1, < 23 kg/m2 =0 |
| LKS | Raw data used as continuous variables |
| IL-1β | Raw data used as continuous variables |
| TNF-α | Raw data used as continuous variables |
Note: Body Mass Index (BMI), Lysholm knee scale (LKS), interleukin-1 (IL-1β).
Table 6.
Multivariate analysis of factors affecting the treatment efficacy
| Variable | B | S.E. | Wals | Sig. | Exp (B) | 95% C.I. of EXP (B) | |
|---|---|---|---|---|---|---|---|
|
| |||||||
| Lower limit | Upper limit | ||||||
| Age | -2.388 | 0.863 | 7.663 | 0.006 | 0.092 | 0.017 | 0.498 |
| BMI | -1.480 | 0.696 | 4.524 | 0.033 | 0.228 | 0.058 | 0.890 |
| LKS | 0.161 | 0.078 | 4.256 | 0.039 | 1.174 | 1.008 | 1.368 |
| IL-1β | 0.158 | 0.082 | 3.667 | 0.055 | 1.171 | 0.996 | 1.377 |
| TNF-α | 0.136 | 0.060 | 5.058 | 0.025 | 1.145 | 1.018 | 1.289 |
Note: Body Mass Index (BMI), Lysholm knee scale (LKS), interleukin-1 (IL-1β).
Discussion
Osteoarthritis is a disease caused by degenerative changes in the bone and joint, such as the hip, knee, shoulder, and elbow, with an incidence of 3% [20]. Among these, knee osteoarthritis accounts for the highest incidence of 60.1% in people over 60 [4]. Severe cases of knee osteoarthritis will develop into limited mobility, which seriously affects patients’ life and health [6]. Therefore, how to take reasonable and effective treatment measures is of great significance to improve the life quality of knee osteoarthritis patients.
Sodium hyaluronate can improve the elasticity of knee joint fluid, make it difficult to damage, reduce the friction of articular cartilage, and protect the soft tissue in the knee joint [21]. Moreover, other studies [22] have found that intra-articular injection of sodium hyaluronate into the knee joint has a low and mild incidence of adverse reactions, which is suitable for non-steroidal anti-inflammatory drugs and analgesics when the effect is not significant, and has a better health and economic benefit for the early and mid-term treatment of knee osteoarthritis; so, intra-articular injection of sodium hyaluronate has also become a common means for the treatment of knee osteoarthritis. However, it can only relieve pain, and the duration of action is relatively short, so the therapeutic effect is often poor.
In recent years, many studies have reported that a variety of growth factors contained in platelet-rich plasma (PRP) are conducive to the repair of knee cartilage, and platelet-rich plasma (PRP) injection into the articular cavity is often chosen to repair cartilage defects and restore knee joint function of knee osteoarthritis patients [23]. However, in a study by Dório et al. [24], patients with knee osteoarthritis were found not to be superior to placebo in terms of pain and functional improvement after PRP treatment. Minor transient increases in pain were more frequent in the PRP group. Moreover, in a study by Di et al. [25], although both sodium hyaluronate and PRP alone were effective in improving knee functional status and clinical symptoms, PRP did not provide an overall better clinical improvement than sodium hyaluronate in terms of symptom function improvement or duration of effect at different follow-up points. These studies suggested that both agents were equally effective as monotherapy and that PRP monotherapy was inferior to sodium hyaluronate in terms of pain relief. However, it remains unclear whether the combination of the two can function more effectively. In this study, we found that the overall clinical response rate in the observation group, or OG washigher than that in the control group, or CG, and LKS and VAS scores of patients were improved after treatment, without increasing the occurrence of adverse reactions in the patients. This suggests that sodium hyaluronate combined with PRP can effectively improve the therapeutic effect of knee osteoarthritis. The reason is that sodium hyaluronate is a branched-chain polyanionic polymer, which can effectively protect a variety of soft tissues in the knee joint cavity, and at the same time, it can provide nutrition for its metabolic activities, thereby relieving clinical symptoms such as knee joint swelling and morning stiffness and improving knee joint function [26]. PRP is platelet plasma rich in a variety of growth factors obtained from the patient’s own venous blood after centrifugation, which can effectively improve cartilage matrix production function and promote chondrocyte production [27]. The combined use of the two promotes the recovery of a variety of soft tissues in the joint cavity, improves the knee stability, and plays a role in improving knee joint function and relieving pain.
At present, the new view stated that inflammation also plays an important role in the early stage of knee osteoarthritis lesions, and inflammatory cytokines affect the production of cytokines and enzymes through intracellular signal transduction pathways, thereby aggravating the progression of the disease [28]. MMP-3 is a cytokine involved in the pathogenesis of knee osteoarthritis and is closely related to cartilage matrix degradation in the knee joint, which can be reduced by inhibiting MMP-3 activity [29]. Many studies have revealed that the expression of TNF-α, IL-1, and hs-CRP in synovial fluid of OA patients is abnormally increased, resulting in cartilage progenitor cell disorder and chondrocyte death, accelerating joint aging and destruction. In addition, IL-1 can stimulate the production of reactive oxygen species, and the generated free radicals can directly damage articular cartilage [30]. In our study, the levels of MMP-3, IL-1β, hs-CRP, and TNF-α in OG were markedly lower than those in CG after treatment, which indicated that the combined treatment had better inhibitory effect on the occurrence of inflammatory reactions in patients. This is mainly due to the fact that platelets in PRP are also a source of modulators of inflammatory mediators, and PRP is precisely able to affect tissue regulation by increasing growth factors in platelet levels and regulating the release of inflammatory factors, thereby reducing pain associated with knee osteoarthritis [31].
At the end of the study, we analyzed the risk factors affecting the efficacy of patients. Younger age and lower BMI were protective factors for patient efficacy, while higher LKS and TNF-α were risk factors affecting patient efficacy. From the pathophysiology of osteoarthritis, it is revealed that it is a process of articular surface hyaline cartilage degeneration with exposed and sclerotic subchondral bone, while with the increase of age, the hyaline cartilage regeneration ability of patients is poor, and the autologous recovery ability is slower than that of young people. This leads to unsatisfactory therapeutic results in patients [32]. While articular cartilage in patients with larger BMI is under high pressure, increased limited proliferation and destruction of chondrocytes is high which is the main reason for unsatisfactory outcomes [33]. In addition, overweight patients have more rapid osteophyte hyperplasia at the cartilage margin which is more painful than in non-overweight individuals [34]. However, patients with lower LKS have more notable limitation of their own knee joint function, which is bound to increase the difficulty of treatment [35]. Inflammation has been shown to play an essential role in the pathogenesis, and inflammatory cytokines secreted in patients who develop knee osteoarthritis are involved in the aggravation of inflammation, and patients with higher levels of inflammatory factors before treatment were found to be not conducive to treatment [36]. Therefore, providing targeted treatment according to the patient’s own condition before treatment is the key to improve therapeutic efficacy.
In this study, we determined that autologous platelet-rich plasma combined with sodium hyaluronate can improve the clinical efficacy of patients with knee osteoarthritis and inhibit the level of serum inflammatory factors in patients. However, there are still certain limitations in this study. First of all, we did not follow up the patients, so that their long-term efficacy remains unclear in this study. Second, as a single center study, quite limited samples were included. F’inally, since it is a retrospective study, the results of this study may be biased. Therefore, we hope to carry out follow-up in future studies and include more samples to refine our study conclusions.
In summary, the use of intra-articular injection of platelet-rich plasma combined with sodium hyaluronate in the treatment of knee osteoarthritis can significantly reduce knee pain and improve knee function and in vivo inflammatory response.
Disclosure of conflict of interest
None.
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