Skip to main content
Download PDF

Intra-articular injection of gold micro-particles with hyaluronic acid for painful knee osteoarthritis

BMC Musculoskeletal Disorders volume 25, Article number: 211 (2024) Cite this article

Abstract

Background

Recently, in an open pilot study, we found up to two years, a potential pain-relieving effect of intra-articular gold micro-particles using the patient’s synovial fluid for patients with knee osteoarthritis (KOA). During the study the excluded group of patients, due to multisite pain, co-morbidities, and other exclusion criteria., received intra-articular gold micro-particles using hyaluronic acid,. We aimed to identify if pre-treatment characteristics influence the global outcome two years after intra-articular treatment for painful KOA with gold microparticles using hyaluronic acid.

Methods

Using hyaluronic acid as the carrier, 136 patients with KOA received intraarticular injections with 20 mg gold microparticles (72.000 particles, 20–40 μm in diameter). In the analysis, we included the Global Rating of Change Scale, Pain Detect Questionnaire (PDQ), Body Mass Index (BMI), and Kellgren & Lawrence score at the inclusion, Western Ontario, and McMaster Universities Osteoarthritis Index (WOMAC) sub-scores for pain, stiffness, and function at inclusion and two years.

Results

On the Global Rating Change Scale, 69.1% of patients reported a positive effect, 28.7% no effect, and 2.2% worse. PDQ and the three WOMAC subscores all improved at two years of follow-up. PDQ ≥ 13 (P = 0.028), BMI (P = 0.022) and Kellgren & Lawrence grade 4 (P = 0.028) at inclusion reduced the effect with a minor odds ratio compared to the baseline effect of treatment (P = 0.025). WOMAC subscores at inclusion did not influence the outcome (P > 0.5).

Conclusions

Severe osteoarthritis, obesity, and neuropathic pain, reduced the effect of intra-articular gold microparticles for knee OA.

Trial registration

The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the North Denmark Region by 27/07/2016 (N-20,160,045). The regional data protection agency approved the project by 06/07/2016 (2008-58-0028, ID 2016 − 116) and registered in ClinicalTrial.Gov by 04/01/2018 (NCT03389906).

Peer Review reports

Introduction

Intra-articular treatment with steroids, hyaluronic acid, and platelet-rich fibrin provides in some cases temporary relief from pain and improvement of function in knee osteoarthritis (KOA) [1,2,3]. In an open pilot study, we recently found a longer-acting, up to two years, pain-relieving effect of intra-articular gold micro-particles for patients with knee osteoarthritis (KOA). The observed pain-reducing effect appears to be partly a result of immunosuppression and regenerative processes [4].

Patients with individual risk factors, including the preoperative degree of osteoarthritis, pain, function smoking, deprivation, obesity, and the use of opioids, achieve poor outcomes after knee replacement arthroplasty [5,6,7,8]. Several studies indicate an association between signs of pain sensitization as a predictor of chronic postoperative pain [9,10,11] and chronic residual pain after total joint replacement [12,13,14]. A recent review reports central neurophysiological changes in patients with KOA and recommends that more neuroplasticity studies are needed to prove this association [15]. The Pain Detect Questionnaire (PDQ) might be a surrogate assessment for pain sensitization [16] and preoperative PDQ is associated with chronic postoperative pain after total knee arthroplasty [17]. A cut-off at 13 points on PDQ indicate a possible neuropathic pain component [18, 19] and may determine a poorer outcome after intra-articular treatment with gold micro-particles. It is important to identify the patients at risk of poor patient-reported outcome and to evaluate the risks and benefits of intra-articular gold micro-particle injections.

During the inclusion of our open pilot study, we excluded a larger group of KOA patients due to multisite pain, co-morbidities, and other exclusion criteria [4]. This group received intra-articular gold micro-particles using hyaluronic acid, whereas the included group received the treatment using the patient’s synovial fluid. The question for this study is whether pre-treatment characteristics influence the global outcome two years after intra-articular treatment for painful KOA with gold microparticles using hyaluronic acid.

This study aims to identify if pre-treatment characteristics influence the global outcome two years after intra-articular treatment of painful knee OA patients with gold micro-particles.

Methods

Study flow

We evaluated pain and function at baseline, after eight weeks, and at a two-year follow in two groups of patients with painful KOA. The patients received intra-articular 20 mg gold micro-particles using hyaluronic acid (HA) as the carrier.

Participants

From January 2017 through March 2018, we enrolled 136 patients with radiographically confirmed KOA (Kellgren & Lawrence grade ≥ 1) [20], pain for more than three months, and maximal pain intensity VAS (Visual Analogue Scale, 0–10) ≥ 5 during the last week. We enrolled sligible patients at the specialized, public outpatient clinic at Aalborg University Hospital, Denmark. The exclusion criteria were (1) active adjuvant treatment for any malignancy, (2) active infection and antibiotic treatment, (3) active treatment with steroids or biological medication, (4) inability to comply with the protocol, and (5) inadequacy in written and spoken national language (Fig. 1).

Fig. 1
figure 1

Flowchart of 136 knee osteoarthritic patients who received intra-articular injection of 20 mg gold micro-particles using hyaluronic acid

Full size image

Study treatment

Pure gold particles, 20 mg sterile 99.99%, a total of 72.000 particles, 20–40 μm in diameter (BerlockMicroImplants (BMI), Berlock ApS) [21, 22] were injected intra-articular into the knee joint. Two ml HA (Suplasyn®, 20 mg/2 ml) was mixed with the sterile gold microparticles and injected into the patient’s knee.

Primary outcome measures

Using the Global Rating of Change Scale [23], we asked the question, concerning your knee, how will you describe yourself compared to immediately before the injection of gold into your knee, and evaluated the answer on an 11-point scale from very much worse (-5) to complete recovered (5) with a score of zero indicating no changes.

Secondary outcome measures

The PainDetect questionnaire (PDQ) [18] comprises three major components It is a gradation of pain, pain course pattern, and radiating pain. Seven questions evaluate the gradation of pain. The patient scored each question using a 0 to 5 score with 0 = never, 1 = hardly notice, 2 = slightly, 3 = moderately, 4 = strongly, and 5 = very strongly. There is one question evaluating pain course patterns. Patients select from one of four pictures indicating which best describes their course of pain. A unique score of 0, -1, or + 1 is associated with each picture). One question evaluates radiating pain with a yes (score of + 2) or no (score of 0) response option. PDQ is scored from 0 to 38, with total scores < 13 considered to represent nociceptive pain, 13–18 possible neuropathic pain, and > 18 representing neuropathic pain.

The Western Ontario and McMaster Universities Arthritis Index (WOMAC) sub-scores for pain, stiffness, and function [24], and contain 24 questions: 5 pain questions, 2 stiffness questions, and 17 physical function questions. Each question utilizes a 5-point scale, from 0 (none) to 4 (extreme).

Explanatory variables for the outcome

The explanatory variables analyzed for the outcome are PDQ, age, sex, body mass index (BMI), and Kellgren & Lawrence grade.

Statistical analysis

The Stata software, version 17.0 (StataCorp) was used when analyzing the clinical outcomes.

Ordinal logistic regression was used when analyzing the explanatory variables’ influence on the Global Rating of Change Scale, and the difference over time in WOMAC pain, stiffness, and function. The explanatory variables are PDQ, age, sex, body mass index (BMI), and Kellgren &Lawrence grade.

Wilcoxon test for trend was used for matched pairs test of before-after and Kruskal-Wallis test for between groups tests. The minimally clinically important difference for the Global Rating of Change Scale was defined as 2 [23], and for WOMAC pain, stiffness and function as, respectively, 4, 2 and 10 [25].

Data availability

The datasets generated during the current study are available from the corresponding author upon reasonable request.

Ethical approvals

The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the North Denmark Region by 27/07/2016 (N-20,160,045). The regional data protection agency approved the project by 06/07/2016 (2008-58-0028, ID 2016 − 116) and registered in ClinicalTrial.Gov by 04/01/2018 (NCT03389906).

We have followed the Consort guideline for reporting non-randomized pilot and feasibility studies [26]. The first author takes responsibility for the integrity and accuracy of the reported data and the credibility of the study to the protocol.

Consent

All participants consented to participation in the research via written forms and verbally.

Results

Enrollment and follow-up

After assessment for inclusion, total of 136 patients were assessed for inclusion, and 136 were enrolled and underwent treatment with an intra-articular injection of 20 mg gold microparticles using hyaluronic acid as the carrier (Fig. 1). Table 1 presents the baseline characteristics. No patients presented with symptomatic accumulation or effusion needed aspiration, why hyaluronic acid was the carrier. All 136 patients completed the follow-up. During follow-up, three patients with the Kellgren &Lawrence grade IV [20] received total knee arthroplasty, ten patients had an arthroscopic procedure, and nine received additional intraarticular injection with gold micro-particles. All 136 patients were included in the analysis until censored due to additional treatment. The 22 patients who received additional treatment were included in the predictor analysis with a Global Rating of Change Score. The follow-up time was a mean of 25.1 months.

Table 1 Baseline characteristics of the 136 knee osteoarthritic patients receiving gold using HA. Values are median and range; and mean and 95% CI. Scores on the Kellgren–Lawrence scale range from 0 to 4, with a score of 1, 2, 3, or 4 indicating definite osteoarthritis and higher scores indicating more severe disease
Full size table

Primary outcome measures

On the 11-point Global Rating of Change Scale [23], at 2-year follow-up 94 (69.1%) patients reported a positive effect, and 39 (28.7%) reported no effect and 3 (2.2%) were worse (median 2 (-3; 5)). There was no difference in Global Rating af Change Scale from 8 weeks to 2-year follow-up.

Secondary outcome measures

Compared to the baseline, the three WOMAC sub-scores [24] and PDQ [18] all improved at two years of follow-up (all P < 0.0001) (Fig. 2). WOMAC sub-scores at inclusion did not determine the effect (P > 0.5). There was no difference in WOMAC sub-scores from 8 weeks to 2-year follow-up.

Fig. 2
figure 2

Change in womac pain, stiffness and activity, and pain detect questionnaire, before and 2 years after intra-articular injection of 20 mg gold micro-particles in 136 knee osteoarthritic patients (P < 0.01)

Full size image

Explanatory variables for outcome

The PDQ [18] scoring found that 1/3 of the patients had nociceptive pain with a score ≥ 13 (Table 1). In the ordinal logistic regression against the Global Rating of Change Score [23], PDQ ≥ 13, high BMI, and Kellgren &Lawrence grade 4 [20] at inclusion reduced the effect of intra-articular gold microparticles (Table 2). The odds ratio for a positive effect was lowest for Kellgren & Lawrence grade 4, followed by PDQ ≥ 13 and high BMI, with BMI being the most significant. Between-group analysis for these three explanatory variables confirmed the findings (Figs. 3 and 4, and 5). Figures 3 and 4 indicate a non-linear association of BMI and Kellgren & Lawrence grade at inclusion to the 2-year effect. Three was no difference in radiographic changes in patients with a PDQ < 13 compared to patients with a PDQ ≥ 13 (P = 0.28) or > 18 (P = 0.19) (Table 3). We found a negative odds ratio for improvement of stiffness in patients with a high BMI (P = 0.021).

Table 2 Logistic interval regression analysis of confounders at inclusion for outcome 2 years after intra-articular injection of 20 mg gold micro-particles in 136 knee osteoarthritic patients
Full size table
Fig. 3
figure 3

The association between Kellgren-Lawrence grade at inclusion and 2-year results after intra-articular injection of 20 mg gold micro-particles in 136 knee osteoarthritic patients (KL2, P = 0.04)

Full size image
Fig. 4
figure 4

The association between BMI class at inclusion and 2-year results after intra-articular injection of 20 mg gold micro-particles in 136 knee osteoarthritic patients

Full size image
Fig. 5
figure 5

The association between Pain Detect Questionnaire at inclusion and 2-year results after intra-articular injection of 20 mg gold micro-particles in 136 knee osteoarthritic patients (P = 0.041)

Full size image
Table 3 At inclusion distribution of the degree of neuropathic pain measured by Pain Detect Questionnaire (PDQ) about Kellgren-Lawrence degree of radiographic changes
Full size table

Discussion

This, non-placebo controlled, explorative study obtained individual patient data from included patients who received intra-articular gold microparticles for KOA using hyaluronic acid. Overall, the pattern of observed improvements was equal at the 2-year follow-up. We found a change in pain, stiffness, and activity, better than reported minimally clinically important differences [25].There was a significant improvement in pain and joint function in more than 2/3 of the patients. A neuropathic pain component (PDQ ≥ 13), obesity, and severe osteoarthritis reduce the effect of intra-articular gold microparticles for KOA.

Pain in osteoarthritis (OA) has few relations to specific radiological changes. There is generally a poor association between Kellgren &Lawrence and clinical pain intensity [13, 20] and individuals with osteoarthritic changes may not at all have pain [13, 20]. Gold ions may reduce pain, joint swelling, and inflammation [27,28,29], and the current study found that intra-articular gold microparticles improved pain and function, indicating that inflammation and many other factors [30], may be a cause of pain and disability. In addition, a molecular pathway that includes pro-inflammatory mediators may mediate pain [4, 31,32,33].

Chronic OA pain manifests with reduced pain threshold and general hyperalgesia due to sensitization processes [12, 14, 15]. We found PDQ [18] ≥ 13 in 33% of the patients, resembling sensitization and neuropathic pain. We found PDQ ≥ 13 associated with a poorer outcome of treatment. These results may indicate that patients with KOA demonstrate symptoms of neuropathic pain and sensitization. In a randomized study of intra-articular Botox for KOA-only patients with nociceptive pain, PDQ < 13, did benefit from the treatment [19]. A recent investigation of KOA patients with PDQ > 18 had fewer radiographic changes representing a specific phenotype of KOA [34], and the current study did not find a difference but a minimal tendency in radiographic changes concerning neuropathic pain, which indicates that more research is needed to identify the role for the PDQ in OA research.

The distribution of gold particles in the body varies depending on their size and route of administration [35]. Gold nanoparticles are used as contrast agents for X-ray and computed tomography scans, drug delivery and cancer therapy, and as carriers for therapeutic agents or as radiation enhancers. It is general knowledge that gold nanoparticles will enter an unknown multitude of cells, which might make long-term treatment problematic. Preclinical studies suggest that macrophages phagocytose gold nanoparticles intracellularly that oxidize in the lysosomes [35]. The macrophages remove the gold nanoparticles from the tissue as these cells move away over time.

Gold microparticles larger than 20 microns are too big for the macrophages to engulf or remove [35]. Therefore, the gold microparticles dissolve slowly by macrophages through dissolucytosis. The macrophages secrete cyanide compounds and dissolve the gold into cyanide-gold complexes such as Au (CN)2− [21]. The gold microparticles stay put and continuously expose the matrix and the new cells to gold ions and influence the production of a new intercellular matrix. The fact that only cells close to the gold microparticles become loaded with gold implies that no gold ions are spread to gold-sensitive organs and exclude any toxic effects. Gold ions released from gold microparticles are a purely local process that slowly, andcontinuously produces local pharmaceutical levels of active gold ions into the intercellular space [4]. The use of gold microparticles, therefore, is considered a safe technique [35].

Limitations

This exploratory study did not include a control or a placebo group and may overestimate the effect of intra-articular gold treatment. The patient’s expectations, the intention to treat the patient, and the puncture may influence the results. In addition, the relatively small number of patients may influence the results.

The use of WOMAC has limitations. As a composite score, it uses several questions integrated into a total score, not evaluating each question by itself. WOMAC and other composite scores may over- or underestimate the effect of treatment and intervention [36]. Studies indicate that WOMAC is more sensitive to changes in knee osteoarthritis symptoms and function than other scores, mainly due to a lower number of questions [37,38,39]. We used the WOMAC score as it has been validated in the context of knee osteoarthritis and is considered a valid outcome measure by the Osteoarthritis Research Society International (OARSI) Standing Committee for Clinical Trials Response Criteria Initiative and the Outcome Measures in Rheumatology (OMERACT) committee [40].

No patients were lost to follow-up. In addition, the intervention was carefully standardized and administered by the same physician (SR), the pain evaluation before and after eight weeks was done by the same research nurse (TJ), and the 2-year follow-up was performed by two medical students (ES and NKJ). We recorded no adverse effects related to the treatments. Any additional treatment events, TKA, arthroscopy, and injection were performed in 16% of cases during the two-year follow-up. In randomized studies on arthroscopy for degenerative changes, up to 36% in the control group received arthroscopy during follow-up [41]. In our study, 7% underwent knee arthroscopy. In randomized studies on TKA and non-surgical treatment of KOA, 14–32% underwent TKA replacement [42]. In our study, 2% underwent TKA. Regarding additional treatment after HA injection, such as reinjection, one study reports 50% reinjection within 12 weeks [43]. We found no placebo-controlled randomized studies on HA reporting additional arthroscopy or TKA. A review in 2016 [44] showed a lack of synthesis standardization leads to the opposite conclusion about the balance and benefits.

Conclusions

A significant proportion of patients with knee osteoarthritis report a positive long-term effect of intra-articular injection of gold microparticles using hyaluronic acid. A neuropathic pain component (Pain Detect Questionnaire ≥ 13), obesity, and severe osteoarthritis hamper the effect. Compared to the results of our previous study [4], this study indicates that a part of the exclusion criteria used in our previous study may not be necessary for future studies. In addition, the current study found that 16% of patients needed additional treatment during follow-up. Future randomized, double-blinded studies need to identify the potential clinical use of intra-articular injection of gold microparticles for of knee osteoarthritis.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;10:CD005328.

    Google Scholar 

  2. Bhandari M, Bannuru RR, Babins EM, Martel-Pelletier J, Khan M, Raynauld JP, et al. Intra-articular hyaluronic acid in the treatment of knee osteoarthritis: a Canadian evidence-based perspective. Therapeutic Adv Musculoskelet Disease. 2017;9:231–46.

    Article  CAS  Google Scholar 

  3. Henrotin Y, Bannuru R, Malaise M, Ea HK, Confavreux C, Bentin J et al. Hyaluronan derivative HYMOVIS® increases cartilage volume and type ii collagen turnover in osteoarhritic knee: data from MOKHA study. BMC Musculoskelet Disord. 2019;20.

  4. Rasmussen S, Kjær Petersen K, Kristiansen MK, Skallerup J, Aboo C, Thomsen ME, et al. Gold micro-particles for knee osteoarthritis. Eur J Pain (United Kingdom). 2022;26:811–24.

    CAS  Google Scholar 

  5. Mohammad HR, Gooberman-Hill R, Delmestri A, Broomfield J, Patel R, Huber J, et al. Risk factors associated with poor pain outcomes following primary knee replacement surgery: analysis of data from the clinical practice research datalink, hospital episode statistics and patient reported outcomes as part of the STAR research programme. PLoS ONE. 2021;16(12 December):1–16.

    Google Scholar 

  6. Simic M, Harmer AR, Agaliotis M, Nairn L, Bridgett L, March L, et al. Clinical risk factors associated with radiographic osteoarthritis progression among people with knee pain: a longitudinal study. Arthritis Res Ther. 2021;23:1–10.

    Article  Google Scholar 

  7. Arden N, Altman D, Beard D, Carr A, Clarke N, Collins G, Cooper C, Culliford D, Delmestri A, Garden S, Griffin T, Javaid K, Judge A, Latham J, Mullee M, Murray D, Ogundimu E, Pinedo-Villanueva R, Price A, Prieto-Alhambra DRJ. Lower limb arthroplasty: can we produce a tool to predict outcome and failure, and is it cost-effective? An epidemiological study. Southampt NIHR Journals Libr. 2017; Jun.

  8. Rayahin JE, Chmiel JS, Hayes KW, Almagor O, Belisle L, Chang AH, Moisio K, Zhang YSL. Factors associated with pain experience outcome in knee osteoarthritis. Arthritis Care Res (Hoboken). 2014;66:1828–35.

    Article  PubMed  Google Scholar 

  9. Petersen KK, Arendt-Nielsen L, Simonsen O, Wilder-Smith O, Laursen MB. Presurgical assessment of temporal summation of pain predicts the development of chronic postoperative pain 12 months after total knee replacement. Pain. 2015;156:55–61.

    Article  PubMed  Google Scholar 

  10. Petersen KK, Siebuhr AS, Graven-Nielsen T, Simonsen O, Boesen M, Gudbergsen H, et al. Sensitization and serological biomarkers in knee osteoarthritis patients with different degrees of synovitis. Clin J Pain. 2016;32:841–8.

    Article  PubMed  Google Scholar 

  11. Petersen KK, Vaegter HB, Stubhaug A, Wolff A, Scammell BE, Arendt-Nielsen L, et al. The predictive value of quantitative sensory testing: a systematic review on chronic postoperative pain and the analgesic effect of pharmacological therapies in patients with chronic pain. Pain. 2021;162:31–44.

    Article  PubMed  Google Scholar 

  12. Arendt-Nielsen L. Pain sensitisation in osteoarthritis. Clin Exp Rheumatol. 2017;35:68–74.

    PubMed  Google Scholar 

  13. Neogi T. Structural correlates of pain in osteoarthritis. Clin Exp Rheumatol. 2017;35:75–8.

    PubMed  Google Scholar 

  14. Skou ST, Graven-Nielsen T, Rasmussen S, Simonsen OH, Laursen MB, Arendt-Nielsen L. Facilitation of pain sensitization in knee osteoarthritis and persistent post-operative pain: a cross-sectional study. Eur J Pain (United Kingdom). 2014;18:1024–31.

    CAS  Google Scholar 

  15. Iuamoto LR, Ito FLK, Tomé TA, Hsing WT, Meyer A, Imamura M et al. Effects of neuroplasticity in people with knee osteoarthritis a systematic review of the literature. Med (United States). 2022;101.

  16. Moss P, Benson HAE, Will R, Wright A. Patients with knee Osteoarthritis who score highly on the PainDETECT Questionnaire Present with Multimodality Hyperalgesia, increased Pain, and impaired physical function. Clin J Pain. 2018;34:15–21.

    Article  PubMed  Google Scholar 

  17. Kurien T, Arendt-Nielsen L, Petersen KK, Graven-Nielsen T, Scammell BE. Preoperative Neuropathic Pain-like symptoms and Central Pain mechanisms in knee osteoarthritis predicts poor outcome 6 months after total knee replacement surgery. J Pain. 2018;19:1329–41.

    Article  PubMed  Google Scholar 

  18. Freynhagen R, Baron R, Gockel U, Tölle TR, painDETECT. A new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22:1911–20.

    Article  PubMed  Google Scholar 

  19. Arendt-Nielsen L, Jiang GL, DeGryse R, Turkel CC. Intra-articular onabotulinumtoxinA in osteoarthritis knee pain: effect on human mechanistic pain biomarkers and clinical pain. Scand J Rheumatol. 2017;46:303–16.

    Article  CAS  PubMed  Google Scholar 

  20. Kellgren JH, Lawrence JS. RADIOLOGICAL ASSESSMENT OF OSTEO-ARTHROSIS llY. 1957.

  21. Danscher G, Larsen A. Effects of dissolucytotic gold ions on recovering brain lesions. Histochem Cell Biol. 2010;133:367–73.

    Article  CAS  PubMed  Google Scholar 

  22. Märki N, Witte S, Kuchen S, Reichenbach S, Ramseyer A, Gerber V, et al. Safety of Intra-articular Gold microimplants in Horses–A Randomized, Blinded, controlled experimental study. J Equine Vet Sci. 2018;60:59–66e2.

    Article  Google Scholar 

  23. Kamper SJ, Maher CG, Mackay G. Global rating of change scales: a review of strengths and weaknesses and considerations for design. J Man Manipulative Therapy. 2009;17:163–70.

    Article  Google Scholar 

  24. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833–40.

    CAS  PubMed  Google Scholar 

  25. Kim MS, Koh IJ, Choi KY, Sung YG, Park DC, Lee HJ, et al. The minimal clinically important difference (MCID) for the WOMAC and factors related to achievement of the MCID after Medial opening Wedge high tibial osteotomy for knee osteoarthritis. Am J Sports Med. 2021;49:2406–15.

    Article  PubMed  Google Scholar 

  26. Lancaster GA, Thabane L. Guidelines for reporting non-randomised pilot and feasibility studies. Pilot Feasibility Stud. 2019;5.

  27. Berners-Price SJ, Filipovska A. Gold compounds as therapeutic agents for human diseases. Metallomics. 2011;3:863–73.

    Article  CAS  PubMed  Google Scholar 

  28. Clark P, Tugwell P, Bennet K, Bombardier C, Shea B. Wells G S-AM. Injectable gold for rheumatoid arthritis (review). Cochrane Database Syst Rev 1997. 2010;:Art. No.: CD000520.

  29. Lehman AJ, Esdaile JM, Klinkhoff AV, Grant E, Fitzgerald A, Canvin J. A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study. Arthritis Rheum. 2005;52:1360–70.

    Article  CAS  PubMed  Google Scholar 

  30. Collins JE, Katz JN, Dervan EELE. Trajectories and risk profiles of pain in persons with radiographic, symptomatic knee osteoarthritis: data from the osteoarthritis initiative. Osteoarthr Cartil. 2014;22:622–30.

    Article  CAS  Google Scholar 

  31. Ren G, Lutz I, Railton P, Wiley JP, McAllister J, Powell J, et al. Serum and synovial fluid cytokine profiling in hip osteoarthritis: distinct from knee osteoarthritis and correlated with pain. BMC Musculoskelet Disord. 2018;19:1–11.

    Article  Google Scholar 

  32. Zhang RX, Ren KDR. Osteoarthritis pain mechanisms: basic studies in animal models. Osteoarthr Cartil. 2013;21:1308–15.

    Article  Google Scholar 

  33. Sofat N, Ejindu V, Kiely P. What makes osteoarthritis painful? The evidence for local and central pain processing. Rheumatology. 2011;50:2157–65.

    Article  PubMed  Google Scholar 

  34. Van Helvoort EM, Welsing PMJ, Jansen MP, Gielis WP, Loef M, Kloppenburg M, et al. Neuropathic pain in the IMI-APPROACH knee osteoarthritis cohort: prevalence and phenotyping. RMD Open. 2021;7:1–9.

    Google Scholar 

  35. Danscher G, Rasmussen S. nanoGold and µGold inhibit autoimmune inflammation: a review. Histochem Cell Biol. 2023;159:225–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Roos EMLL. The knee injury and osteoarthritis outcome score (KOOS): from joint injury to osteoarthritis. Heal Qual Life Outcomes. 2003;1:64.

    Article  Google Scholar 

  37. Rolfson O, Bohm E, Franklin P, Lyman S, Denissen G, Dawson J, et al. Patient-reported outcome measures in arthroplasty registries: report of the Patient-Reported Outcome Measures Working Group of the International Society of Arthroplasty RegistriesPart II. Recommendations for selection, administration, and analysis. Acta Orthop. 2016;87:9–23.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Parkes MJ, Callaghan MJ, O’Neill TW, Forsythe LM, Lunt M, Felson DT. Sensitivity to change of patient-preference measures for Pain in patients with knee osteoarthritis: data from two trials. Arthritis Care Res. 2016;68:1224–31.

    Article  CAS  Google Scholar 

  39. Escobar A, Quintana JM, Bilbao A, Aróstegui I, Lafuente I, Vidaurreta I. Responsiveness and clinically important differences for the WOMAC and SF-36 after total knee replacement. Osteoarthr Cartil. 2007;15:273–80.

    Article  CAS  Google Scholar 

  40. Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, et al. OMERACT-OARSI initiative: Osteoarthritis research society international set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthr Cartil. 2004;12:389–99.

    Article  CAS  Google Scholar 

  41. Katz JN, Wright J, Spindler KP, Mandl LA, Safran-Norton CE, Reinke EK, et al. Predictors and outcomes of crossover to surgery from physical therapy for meniscal tear and osteoarthritis a randomized trial comparing physical therapy and surgery. J Bone Jt Surg - Am Vol. 2016;98:1890–6.

    Article  Google Scholar 

  42. Skou ST, Roos EM, Laursen MB, Rathleff MS, Arendt-Nielsen L, Rasmussen S, et al. Total knee replacement and non-surgical treatment of knee osteoarthritis: 2-year outcome from two parallel randomized controlled trials. Osteoarthr Cartil. 2018;26:1170–80.

    Article  CAS  Google Scholar 

  43. Park YG, Ha CW, Yoo JH, Lee WS, Lee HJ, In Y, et al. Intra-articular injection of a Novel DVS cross-linked Hyaluronic Acid manufactured by Biological Fermentation (YYD302) in patients with knee osteoarthritis: a Double-Blind, randomized, Multicenter, Noninferiority Study. Clin Ther. 2021;43:1843–60.

    Article  CAS  PubMed  Google Scholar 

  44. O’Hanlon CE, Newberry SJ, Booth M, Grant S, Motala A, Maglione MA, et al. Hyaluronic acid injection therapy for osteoarthritis of the knee: concordant efficacy and conflicting serious adverse events in two systematic reviews. Syst Rev. 2016;5:1–11.

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Gregers Gregersen, DVM, Professor Gorm Danscher, DVM, DMSc., and Tina Jensen, research nurse, for their assistance during the project.

Funding

Department of Clinical Medicine provided funding for this study. Center for Neuroplasticity and Pain (CNAP) (Lars Arendt-Nielsen) provided funding for this study. CNAP is supported by the Danish National Research Foundation (DNRF121) and the Danish Rheumatism Association (R204-A7645). The Danish National Mass Spectrometry Platform for Functional Proteomics (PRO-MS; grant no. 5072-00007B); The Obelske family foundation, the Svend Andersen Foundation, and the SparNord foundation are acknowledged for grants to the analytical platform, enabling parts of this study.

Author information

Authors and Affiliations

  1. Department of Clinical Medicine, Aalborg University, 249 Selma Lagerløfs Vej, Gistrup, 9260, Denmark

    Sten Rasmussen, Emilie Skjoldemose, Nia Kristine Jørgensen & Allan Stensballe

  2. Department of Orthopedic Surgery, Sport and Arthroscopy, Aalborg University Hospital, Aalborg, Denmark

    Sten Rasmussen

  3. Department of Health Science and Technology, Aalborg University, Aalborg, Denmark

    Kristian Kjaer Petersen, Christopher Aboo, Jacob Skallerup Andersen, Allan Stensballe & Lars Arendt-Nielsen

  4. Center for Neuroplasticity and Pain, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark

    Kristian Kjaer Petersen & Lars Arendt-Nielsen

  5. Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark

    Allan Stensballe

  6. Department of Gastroenterology & Hepatology, Mech-Sense, Aalborg University Hospital, Aalborg, Denmark

    Lars Arendt-Nielsen

  7. Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark

    Lars Arendt-Nielsen

Authors
  1. Sten Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristian Kjaer Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher Aboo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacob Skallerup Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emilie Skjoldemose
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nia Kristine Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Allan Stensballe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lars Arendt-Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SR was the principal investigator in the study and participated in data collection, analysis, and interpretation. All authors assisted in collecting, analyzing, and interpreting the data and contributed to writing the manuscript. All authors read and approved the final manuscript. SR takes responsibility for the integrity of the work, from inception to the finished article.

Corresponding author

Correspondence to Sten Rasmussen.

Ethics declarations

Ethics approval and consent to participate

The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the North Denmark Region by 27/07/2016 (N-20160045). The regional data protection agency approved the project by 06/07/2016 (2008-58-0028, ID 2016 − 116) and registered in ClinicalTrial.Gov by 04/01/2018 (NCT03389906). All participants consented to participation in the research via a written and verbally informed consent.

Consent for publication

Not applicable.

Competing interests

The authors have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rasmussen, S., Petersen, K.K., Aboo, C. et al. Intra-articular injection of gold micro-particles with hyaluronic acid for painful knee osteoarthritis. BMC Musculoskelet Disord 25, 211 (2024). https://doi.org/10.1186/s12891-024-07321-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12891-024-07321-4

Keywords

BMC Musculoskeletal Disorders

ISSN: 1471-2474

Contact us