Experimental study of extracorporeal shock wave therapy for periprosthetic osteolysis induced by wear particles

Experimental study of extracorporeal shock wave therapy for periprosthetic osteolysis induced by wear particles | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Experimental study of extracorporeal shock wave therapy for periprosthetic osteolysis induced by wear particles Fengnian Zhao, Yufei Chen, Ao Dong, Keguan Song This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5342963/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Mar, 2025 Read the published version in Journal of Orthopaedic Surgery and Research → Version 1 posted 9 You are reading this latest preprint version Abstract Extracorporeal shock wave therapy (ESWT) is a conservative orthopedic treatment that has been shown to be effective in a variety of orthopedic diseases; however, its effectiveness in addressing sterile prosthesis loosening remains uncertain. This study aimed to establish a model of periprosthetic osteolysis and to assess the impact of ESWT on osteolysis induced by wear particles. The findings indicated that the group receiving ESWT exhibited an increase in bone mineral density, alongside a reduction in the extent of osteolysis, the quantity of osteoclasts, and serum levels of IL-1β. Consequently, we conclude that ESWT significantly diminishes inflammatory factor levels, inhibits the development of periprosthetic osteoclasts, and effectively slows the progression of osteolysis, thereby presenting substantial clinical relevance. extracorporeal shock wave therapy wear particles osteolysis osteoclasts inflammatory factors Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Total joint replacement (TJA) is a well-established intervention that effectively alleviates pain and restores motor function in patients suffering from end-stage bone and joint diseases. However, research indicates that the rate of prosthetic revision can reach 10–15% within a decade following TJA [1–2] . Post-implantation, joint prostheses are subject to wear, resulting in the release of micron-sized wear particles that incite chronic inflammatory responses. This process can lead to aseptic loosening of the prosthesis due to osteolysis, which is a significant contributor to the failure of total joint replacements [3–5] . The disruption of the delicate equilibrium between osteogenesis and the osteoblastic process is critical in the pathogenesis of wear particle-induced osteolysis. Wear particles have been shown to stimulate the release of pro-inflammatory cytokines from immune cells, such as IL-1β and TNF-α, while concurrently diminishing the expression of osteoprotegerin (OPG) in osteoblasts. This cascade of events promotes the expression of receptor activator of nuclear factor κB ligand (RANKL) and nuclear factor κB (NF-κB), which, through the activation of nuclear factor of activated T cells (NFAT), enhances the expression of osteoclast-related genes. This ultimately triggers the recruitment and maturation of osteoclast precursors, thereby regulating osteoclast differentiation and proliferation, which culminates in osteolysis [6–12] . Currently, there are no effective preventative treatments available, with the only recourse being revision surgery in the advanced stages of the condition. However, revision surgery is often complex, invasive, costly, and associated with significant postoperative risks and suboptimal long-term outcomes. Consequently, there remains a pressing clinical need to investigate novel, cost-effective diagnostic and therapeutic strategies aimed at preventing prosthetic aseptic loosening. Extracorporeal shock wave therapy (ESWT), initially developed for the treatment of urinary calculi, has been repurposed as a non-invasive modality for addressing musculoskeletal disorders [13] . Evidence suggests that ESWT is notably effective in treating various bone and soft tissue conditions, including tendinitis, lateral epicondylitis, complications related to fracture healing, bone defects, and osteonecrosis of the femoral head [14–15] . ESWT has the capacity to activate bone marrow stem cells (BMSCs) and facilitate their differentiation into osteoblasts, while also promoting neoangiogenesis, enhancing callus formation, and accelerating fracture healing [16] . Nevertheless, to date, no studies have definitively established whether ESWT can mitigate periprosthetic osteolysis induced by wear particles or reduce the risk of prosthesis loosening following arthroplasty. In this investigation, we developed a model of wear particle-induced osteolysis to examine the effects of ESWT on inflammatory factor levels, periprosthetic osteolysis, and the activity and function of bone cells in a rat model. This study aims to elucidate the inhibitory effects and potential mechanisms of ESWT on periprosthetic osteolysis, thereby providing a theoretical and experimental foundation for its clinical application. Methods Experimental Animals A total of thirty healthy male Sprague-Dawley (SD) rats, each weighing approximately 200 ± 20 g, were utilized for this study. All animal experiments received approval from the Laboratory Animal Ethics Committee of the First Affiliated Hospital of Harbin Medical University. The care and treatment of the experimental animals adhered strictly to the Regulations on the Management of Experimental Animals established by Harbin Medical University. Experimental equipment Name of experimental instruments and consumables manufacturer The extracorporeal shock-wave therapy apparatus Xiangyu Medical,China automatic tissue dehydration apparatus Junjie,China Paraffin embedding machine Junjie,China Biological tissue stall chip baking machine Junjie,China Paraffin slicing machine Leica Biosystems,China Electric heating constant temperature blast drying box Leibo Terry,China microscope Nikon,Japan Microscope camera system Nikon,Japan Small animal live imaging system KUBTEC,USA superclean bench Thermofisher Scientific, USA refrigerated centrifuge Thermofisher Scientific, USA enzyme-labeled instrument Bio-Rad,China Ultra fine titanium particles Jinchun Metal,China 0.9% saline SJZ No.4 Pharmaceutical,China pentobarbital sodium Sanjing Pharmaceutical,China carprofen Aladdin,China Dimethylsulfoxide (DMSO) Solaibao,China polyethylene glycol 300(PEG300) Solaibao,China Tween 80 Solaibao,China Sodium penicillin for injection North China Pharmaceutical,China phosphate buffer Solaibao,China absolute ethyl alcohol Xilong Scientific,China dimethylbenzene Xilong Scientific,China 4% paraformaldehyde Solaibao,China EDTA decalcifying Fluid Solaibao,China Hematoxylin Solaibao,China Eosin Y water soluble Xiya Reagent,China The TRAP staining kit Sevierbio,China Rat IL -1β ELISA Kit Lianke Biotech,China Model Construction and Experimental Grouping for Femoral Wear Particle-Induced Osteolysis The thirty SD rats were randomly assigned to three groups: a blank control group, a model group, and an extracorporeal shock wave therapy (ESWT) treatment group. Prior to the procedures, the rats were weighed and anesthetized with an injection of 2.5% pentobarbital sodium administered via the tail vein at a dosage of 1 ml/kg. A distal femoral periprosthetic osteolysis model was constructed following established methodologies. The right knee joints of the rats were prepared and disinfected, and the surgical field was exposed. The patella was gently displaced to locate the medial space of the patellofemoral joint. The knee joint was flexed appropriately, and an incision of suitable length was made to separate the joint capsule, surrounding tissue, and skin, thereby accessing the joint cavity. The patella was dislocated to expose the intercondylar fossa of the distal femur. A needle was inserted into the femoral intercondylar socket, positioned 5 mm from the dorsal aspect of the femur. Following proper positioning, a bone tunnel was drilled using an electric drill to ensure alignment with the long axis of the femur. After achieving hemostasis, 50 µL of titanium particle suspension was injected, and pure titanium rods were placed to seal the bone tunnel, followed by hemostasis, reduction, and suturing. Postoperatively, 2 mg/kg of carprofen and 6000 U/kg of penicillin were administered for three consecutive days to mitigate the risk of infection. On postoperative days 4, 8, and 12, 0.1 ml of titanium particle suspension was injected into the knee cavity of all rats, with the exception of those in the control group, which received 0.1 ml of isotonic saline. Four weeks post-intervention, blood samples were collected from the main abdominal artery, and bone tissue was harvested from the distal femur for subsequent analyses. Extracorporeal Shock Wave Therapy Two weeks following the successful establishment of the osteolysis model, the rats were secured in a specialized frame to extend the right hind limb, thereby exposing the knee joint and surrounding tissues. Extracorporeal shock wave therapy was administered as a form of intervention. The treatment utilized a D15 probe (deep, with a diameter of 15 mm, tolerance ± 15%, energy density of 0.2 mJ/mm², tolerance ± 20%, penetration depth of 7 mm, tolerance ± 20%, and pulse width of 200 µs, tolerance ± 10%). The treatment pressure for the extracorporeal shock wave was set at 1.0 × 10² kPa, with a frequency of 5 Hz and a total of 1000 pulses per treatment session. The treatment site was alternated after every 250 shocks to prevent the occurrence of local hematomas or skin damage.During treatment, attention should be given to avoid important nerves and blood vessels around the knee joint. The rats were treated once a day, and the entire treatment lasted 10–12 minutes with intervention for 4 weeks. High-Resolution Computed Tomography (CT) Analysis Following the fixation of femoral tissue from each rat in 4% paraformaldehyde for a duration of 48 hours, high-resolution CT imaging was conducted under the parameters of 120 kV voltage, 128 mA current, and a slice thickness of 0.7 mm. The spatial distribution of femoral cancellous bone and osteolytic changes were examined, and a region of interest (ROI) was delineated for subsequent evaluation of bone mineral density, which was analyzed using Image-Pro Plus 5.0 software. Hematoxylin and Eosin (HE) Staining The femurs from each experimental group were similarly fixed in 4% paraformaldehyde for 48 hours, followed by decalcification using EDTA, which allowed for easy penetration into the bone tissue over approximately eight weeks. The samples underwent dehydration, paraffin embedding, and sectioning at a thickness of 4 µm, after which they were subjected to HE staining. Osteolytic areas were assessed in four to five fields, and the extent of osteolysis was quantified using Image-Pro Plus 5.0 software. Tartrate-Resistant Acid Phosphatase (TRAP) Staining The femurs from each group were fixed in 4% paraformaldehyde for 48 hours, followed by EDTA decalcification, which facilitated easy puncture into the bone tissue over a period of approximately eight weeks. The samples were then dehydrated, embedded in paraffin, sectioned to a thickness of 4 µm, and stained for TRAP. Osteolysis was evaluated in four to five fields, and the area of osteolysis was analyzed and quantified using Image-Pro Plus 5.0 software. Enzyme-Linked Immunosorbent Assay (ELISA) Urine samples were collected to quantify the concentration of interleukin-1 beta (IL-1β) using a Rat IL-1β ELISA Kit, following the manufacturer's instructions. The optical density (OD) was measured at 450 nm, and a fitted curve was generated from standard concentrations to calculate the concentration of the test samples based on the established formula. Statistical Analysis Statistical analyses were conducted using GraphPad Prism 6.0 software. Results are presented as mean ± standard deviation (x ± s). Comparisons among three groups were performed using one-way ANOVA, while pairwise comparisons were executed using t-tests, with a significance threshold set at P < 0.05 (*, P < 0.05; **, P < 0.01; ***, P < 0.001). Results Effects of ESWT on Bone Cortical Thickness and Mineral Density Following a 4-week treatment period, imaging data were obtained around the distal femur prosthesis using high-resolution computed tomography (CT) (Fig. 2 ). The findings indicated that the bone surrounding the distal femur remained continuous and intact, exhibiting no significant inflammatory responses or signs of osteolysis. In comparison to the blank control group, the model group demonstrated reduced bone density in areas of disrupted bone continuity and osteolysis (P < 0.01), suggesting a detrimental effect of titanium (Ti) particles on the bone adjacent to the implanted prosthesis. Conversely, the ESWT-treated group exhibited continuous and intact periprosthetic bone, along with a notable thickening of the bone cortex; the bone mineral density (BMD) in this group significantly increased (P < 0.001), with no evidence of osteolysis. IL-1β expression can be suppressed by ESWT Compared with that in the blank control group, the level of IL-1β in the serum was significantly greater (P < 0.001), and compared with that in the model group, the level of IL-1β in the ESWT group was significantly lower (P < 0.001, Fig. 3 ). Inhibition of Osteolysis and Osteoclastogenesis by ESWT In the model group, there was partial continuity of direct contact between the prosthesis and bone, with visible black titanium particles in the surrounding bone. This area exhibited extensive osteolytic cavities that were populated by numerous inflammatory macrophages and osteoclasts (P < 0.001), leading to a significant increase in the osteolysis area (P < 0.001). In contrast, the ESWT-treated group displayed complete and continuous direct contact between the prosthesis and bone, with only minor osteolytic cavities surrounding the titanium particles. This group also showed a reduced presence of inflammatory cells and a significant decrease in the number of osteoclasts (P < 0.001), as well as a reduction in osteolysis (P < 0.05) (Figs. 4 , 5 ). Discussion Joint arthroplasty is a key approach for joint injury and reconstruction, and despite the increasing popularity of its clinical use, postoperative complications such as infections, aseptic loosening and peripheral fractures still need to be focused on [17] . A retrospective study revealed that in 23269 patients who underwent hip revision, more than 50% of the secondary surgeries involved aseptic loosening [18] . The bioactive particles released by micromovement and wear between artificial joint components can promote osteoclast maturation and differentiation, lead to osteolysis, and affect the metabolism of osteoclasts and osteoblasts by triggering an inflammatory response. For example, bone metabolism is affected by the ability of macrophages, fibroblasts, osteoblasts and osteoclasts to synthesize and release chemokines and cytokines, including IL-1β blasts and TNF-α [19–20] . Bone metabolic homeostasis is dependent on the balance between osteoclasts and osteoblasts. After joint prosthesis replacement, wear particles disrupt this balance, leading to increased bone resorption and decreased bone formation, the main cause of aseptic loosening of the prosthesis [21] . Reducing osteocast formation and activity in periprosthetic bone tissue through treatment and maintaining local bone metabolic balance are key strategies for preventing artificial joint loosening. In previous studies, we reported that inhibiting TNF-α and enhancing OPG could effectively inhibit the periprosthetic osteolysis induced by Ti particles [22–24] . In addition, in the presence of Ti particles, the expression of NFATc1 in periprosthetic tissue increased significantly, and inhibiting RANKL could effectively inhibit the expression of NFATc1 and the proliferation and differentiation of osteoclasts [25] , indicating that the regulation of the RANKL/RANK/OPG/NFATc1 pathway can effectively prevent wear particle-induced osteolysis and further prove the importance of regulating bone metabolic homeostasis for the prevention of aseptic loosening of the prosthesis. As the preferred drug for the treatment of osteoporosis and femoral head necrosis, bisphosphonates can inhibit osteoclast activity, reduce bone resorption, increase bone density, reduce osteoblast apoptosis and promote bone formation, with the potential to prevent or reduce osteolysis [26] . However, some studies have reported that the long-term efficacy of bisphosphonate drugs is generally[27]and that there is a risk of increased atrial fibrillation and bone fragility [28] . When combined with anti-inflammatory drugs, a high blood concentration is needed to maintain the local effective concentration, causing serious side effects and delaying its application in clinical practice. Gene therapy has also made some advances in periprosthetic osteolysis therapy, but it is still in its early stage and cannot be used clinically in the short term [29] . Therefore, finding safe and economical nonsurgical nondrug treatments to intervene in and treat periprosthetic osteolysis remains an urgent clinical problem. With the increasing application of ESWT in the medical field, researchers have explored the site of action and treatment principles, and increasing evidence has revealed the positive influence of ESWT on the balance between osteobogenesis and osteolysis of bone tissue. ESWT can promote the differentiation of BMSCs into osteoblasts through the MAPK signaling pathway and can inhibit the proliferation of osteoclasts and reduce bone resorption [30–32] . Moreover, the expression of ERK and P38 was significantly increased in some bone defect areas, and an obvious osteogenesis process occurred, which promoted bone formation [33] . Studies have shown that high-energy extracorporeal shock wave therapy (ESWT) can be used at the interface between muscle and bone. Due to differential acoustic impedance, energy pulses act on bone tissue, stimulate the biosynthetic response of cancellous bone and cortical bone, activate mesenchymal stem cells, enable them to transform into osteoblasts, and accelerate the growth of bone tissue [34] . On the other hand, appropriate-strength ESWT (0.08 mJ/mm 2 , 500 times) inhibited the transcriptional activity of NFATc1 and the differentiation of mature osteoclasts and bone resorption through the regulation of c-fos gene expression [35] . The present study first confirmed via high-resolution CT analysis that ESWT could inhibit the occurrence of titanium particle-induced periprosthetic osteolysis around the distal femur in rats. Moreover, ESWT also increased the periprosthetic BMD in the osteolysis model, which is consistent with the conclusion of Shi et al. [36] , who reported that high-energy ESWT (0.28 mJ/mm2, 4 Hz, 4000 times) was better at improving the local BMD, demonstrating the potential of ESWT in treating periprosthetic osteolysis. ESWT helps reduce the serum IL-1β levels caused by wear particles and suppresses systemic inflammation. As observed by staining, ESWT reduced the number of osteoclasts and macrophages within the area of osteolysis, probably because it reduced the level of inflammation and inhibited the differentiation of osteoclasts, thereby inhibiting osteolysis. ESWT may also act directly on bone marrow-derived macrophages to prevent their differentiation into osteoclasts. However, this study has several limitations: only titanium particles were studied without involving other wear particles; the therapeutic effect of ESWT on titanium particle-induced osteolysis was preliminarily explored, but the osteogenic effect was not verified at the protein level, and the ability of ESWT to inhibit the osteoclastic differentiation of BMSCs was not evaluated. Although the inhibitory effect and underlying molecular mechanism of ESWT on osteolysis at the in vivo level have been defined, the influence and regulatory mechanism of ESWT on BMSCs, BMMs and osteoclasts at the cellular level still need further investigation. Conclusion ESWT can significantly suppress the levels of inflammatory factors, the generation of osteoclasts around the prosthesis, and effectively delay the progression of osteolysis. It can serve as a treatment for periprosthetic osteolysis induced by wear particles and has high clinical application value. Declarations Ethics approval and consent to participate All the animal experiments were approved by the Laboratory Animal Ethics Committee of the First Affiliated Hospital of Harbin Medical University. All experimental animals were treated and cared for in strict accordance with the Regulations on the Management of Experimental Animals of Harbin Medical University. Consent for publication Not applicable. Availability of data and materials All data generated or analysed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding The authors reported there is no funding associated with the work featured in this article. Authors’ contributions Fengnian Zhao put forward the research conception, designed the experimental scheme, investigated and collected the experimental data, carried out data analysis, and accomplished the writing of the manuscript. 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Supplementary Files Experimentalequipment.xlsx Cite Share Download PDF Status: Published Journal Publication published 14 Mar, 2025 Read the published version in Journal of Orthopaedic Surgery and Research → Version 1 posted Editorial decision: Revision requested 31 Dec, 2024 Reviews received at journal 30 Dec, 2024 Reviewers agreed at journal 26 Dec, 2024 Reviews received at journal 19 Nov, 2024 Reviewers agreed at journal 13 Nov, 2024 Reviewers invited by journal 13 Nov, 2024 Editor assigned by journal 04 Nov, 2024 Submission checks completed at journal 03 Nov, 2024 First submitted to journal 27 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5342963","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":378099582,"identity":"e752c992-23fa-49a3-b844-0c70c8851a7c","order_by":0,"name":"Fengnian Zhao","email":"","orcid":"","institution":"Aviation General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fengnian","middleName":"","lastName":"Zhao","suffix":""},{"id":378099583,"identity":"75320d85-81f5-450e-be8d-42ebcb68f831","order_by":1,"name":"Yufei Chen","email":"","orcid":"","institution":"First Affiliated Hospital of Harbin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yufei","middleName":"","lastName":"Chen","suffix":""},{"id":378099586,"identity":"3982bbb5-f814-4365-8976-5a632fb8d5a2","order_by":2,"name":"Ao Dong","email":"","orcid":"","institution":"First Affiliated Hospital of Harbin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ao","middleName":"","lastName":"Dong","suffix":""},{"id":378099587,"identity":"ff91613a-267d-4a0c-b9d0-3b4f05d9015b","order_by":3,"name":"Keguan Song","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYJACxgYI1fjg4x8bBjYStDA3G85sSCNJC3ubNGfDYcLK5dt7D7+cUVGb2D+7sU2accd5ez7p5gcMPyq24dRicOZcmuWGM8cTZ9w52GxdeOZ2YpvMMQPGnjO3cWuRyDEzfNh2LLHhRmLj7RlstxPYJBIMmBnbcGuRnwHS8u9Y4vwbiQ3SPGzn7Nkk0j/g1cJwI8f44caGmsQNNxKbpHnbDjC2SeTgt8XgzBkzxhnHDhhvvJHYbDjjTHIiUEvBQXx+kW/vMf7YU1MnO+9G+sMHHyrs7OVnpG988KMCj8MYGNgkGBjQouMAPvVAwPyBgaGOgJpRMApGwSgY0QAAGOdjrW9IYQgAAAAASUVORK5CYII=","orcid":"","institution":"First Affiliated Hospital of Harbin Medical University","correspondingAuthor":true,"prefix":"","firstName":"Keguan","middleName":"","lastName":"Song","suffix":""}],"badges":[],"createdAt":"2024-10-27 22:38:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5342963/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5342963/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13018-025-05661-y","type":"published","date":"2025-03-14T15:58:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69073248,"identity":"9a7dded7-d1b8-4bdf-b1b9-1e7d730154c4","added_by":"auto","created_at":"2024-11-15 10:26:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":91381,"visible":true,"origin":"","legend":"\u003cp\u003eA: Photo of titanium rod implantation before the osteolytic rat model was constructed; B: Shock wave treatment site; C: Shock wave treatment position.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5342963/v1/c9256f41386eeb8cb605eaaf.png"},{"id":69073249,"identity":"7ce82321-f11e-463d-b49f-e92c2f71863c","added_by":"auto","created_at":"2024-11-15 10:26:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97796,"visible":true,"origin":"","legend":"\u003cp\u003eHigh-resolution CT analysis of the periprosthetic BMD in each rat group.\u003c/p\u003e\n\u003cp\u003eA: blank control group; B: model group; C: ESWT treatment group; D: Bone mineral density in each group per unit area (** ，P\u0026lt;0.01；*** ，P\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5342963/v1/2a497fce1c4d6c76c908f4ab.jpg"},{"id":69073455,"identity":"d7e79c88-5eeb-45a3-a083-4fab9d116927","added_by":"auto","created_at":"2024-11-15 10:34:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":91284,"visible":true,"origin":"","legend":"\u003cp\u003eIL-1β levels in the serum of rats determined via ELISA (* * *, P \u0026lt;0.001)\u003c/p\u003e","description":"","filename":"Figure3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5342963/v1/2e9d404a79ad4fb27bf44a5d.jpg"},{"id":69073252,"identity":"0928175a-d0ad-4c5c-9ccb-8143647295e9","added_by":"auto","created_at":"2024-11-15 10:26:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1814500,"visible":true,"origin":"","legend":"\u003cp\u003eThe area of periprosthetic osteolysis in each rat group was analyzed via HE staining.\u003c/p\u003e\n\u003cp\u003eA: blank control group; B: model group; C: ESWT treatment group; D: osteolysis area of each group per unit area (*P\u0026lt;0.05; **P\u0026lt;0.01; ***P\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5342963/v1/65320b52c49cea21e96ab50a.png"},{"id":69073253,"identity":"83f1756c-f46e-4efa-a75b-f4e9477cc0d5","added_by":"auto","created_at":"2024-11-15 10:26:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1431923,"visible":true,"origin":"","legend":"\u003cp\u003eTRAP staining analysis.\u003c/p\u003e\n\u003cp\u003eA: blank control group; B: model group; C: ESWT treatment group; D: number of osteoclasts per unit area in each group per unit area (*P\u0026lt;0.05; **P\u0026lt;0.01; ***P\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5342963/v1/a754459209ebb4f3e267fc30.png"},{"id":78689871,"identity":"43f2ce54-a141-4f29-8760-8065d7a2365d","added_by":"auto","created_at":"2025-03-17 16:13:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4139240,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5342963/v1/aed99e85-9769-4261-a23a-7e3ee3e94656.pdf"},{"id":69073250,"identity":"b29138dc-f59f-4994-bd7b-256ac5283905","added_by":"auto","created_at":"2024-11-15 10:26:05","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":11006,"visible":true,"origin":"","legend":"","description":"","filename":"Experimentalequipment.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5342963/v1/4809126efd03f2e2559df7f3.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Experimental study of extracorporeal shock wave therapy for periprosthetic osteolysis induced by wear particles","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTotal joint replacement (TJA) is a well-established intervention that effectively alleviates pain and restores motor function in patients suffering from end-stage bone and joint diseases. However, research indicates that the rate of prosthetic revision can reach 10–15% within a decade following TJA\u003csup\u003e[1–2]\u003c/sup\u003e. Post-implantation, joint prostheses are subject to wear, resulting in the release of micron-sized wear particles that incite chronic inflammatory responses. This process can lead to aseptic loosening of the prosthesis due to osteolysis, which is a significant contributor to the failure of total joint replacements\u003csup\u003e[3–5]\u003c/sup\u003e. The disruption of the delicate equilibrium between osteogenesis and the osteoblastic process is critical in the pathogenesis of wear particle-induced osteolysis. Wear particles have been shown to stimulate the release of pro-inflammatory cytokines from immune cells, such as IL-1β and TNF-α, while concurrently diminishing the expression of osteoprotegerin (OPG) in osteoblasts. This cascade of events promotes the expression of receptor activator of nuclear factor κB ligand (RANKL) and nuclear factor κB (NF-κB), which, through the activation of nuclear factor of activated T cells (NFAT), enhances the expression of osteoclast-related genes. This ultimately triggers the recruitment and maturation of osteoclast precursors, thereby regulating osteoclast differentiation and proliferation, which culminates in osteolysis\u003csup\u003e[6–12]\u003c/sup\u003e. Currently, there are no effective preventative treatments available, with the only recourse being revision surgery in the advanced stages of the condition. However, revision surgery is often complex, invasive, costly, and associated with significant postoperative risks and suboptimal long-term outcomes. Consequently, there remains a pressing clinical need to investigate novel, cost-effective diagnostic and therapeutic strategies aimed at preventing prosthetic aseptic loosening.\u003c/p\u003e \u003cp\u003eExtracorporeal shock wave therapy (ESWT), initially developed for the treatment of urinary calculi, has been repurposed as a non-invasive modality for addressing musculoskeletal disorders\u003csup\u003e[13]\u003c/sup\u003e. Evidence suggests that ESWT is notably effective in treating various bone and soft tissue conditions, including tendinitis, lateral epicondylitis, complications related to fracture healing, bone defects, and osteonecrosis of the femoral head\u003csup\u003e[14–15]\u003c/sup\u003e. ESWT has the capacity to activate bone marrow stem cells (BMSCs) and facilitate their differentiation into osteoblasts, while also promoting neoangiogenesis, enhancing callus formation, and accelerating fracture healing \u003csup\u003e[16]\u003c/sup\u003e. Nevertheless, to date, no studies have definitively established whether ESWT can mitigate periprosthetic osteolysis induced by wear particles or reduce the risk of prosthesis loosening following arthroplasty. In this investigation, we developed a model of wear particle-induced osteolysis to examine the effects of ESWT on inflammatory factor levels, periprosthetic osteolysis, and the activity and function of bone cells in a rat model. This study aims to elucidate the inhibitory effects and potential mechanisms of ESWT on periprosthetic osteolysis, thereby providing a theoretical and experimental foundation for its clinical application.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eExperimental Animals\u003c/p\u003e\u003cp\u003eA total of thirty healthy male Sprague-Dawley (SD) rats, each weighing approximately 200 ± 20 g, were utilized for this study. All animal experiments received approval from the Laboratory Animal Ethics Committee of the First Affiliated Hospital of Harbin Medical University. The care and treatment of the experimental animals adhered strictly to the Regulations on the Management of Experimental Animals established by Harbin Medical University.\u003c/p\u003e\u003cp\u003eExperimental equipment\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eName of experimental instruments and consumables\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003emanufacturer\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe extracorporeal shock-wave therapy apparatus\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eXiangyu Medical,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eautomatic tissue dehydration apparatus\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJunjie,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaffin embedding machine\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJunjie,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiological tissue stall chip baking machine\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJunjie,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaffin slicing machine\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeica Biosystems,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElectric heating constant temperature blast drying box\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeibo Terry,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emicroscope\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNikon,Japan\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicroscope camera system\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNikon,Japan\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmall animal live imaging system\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKUBTEC,USA\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esuperclean bench\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThermofisher Scientific, USA\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erefrigerated centrifuge\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThermofisher Scientific, USA\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eenzyme-labeled instrument\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBio-Rad,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUltra fine titanium particles\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJinchun Metal,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0.9% saline\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSJZ No.4 Pharmaceutical,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epentobarbital sodium\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSanjing Pharmaceutical,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecarprofen\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAladdin,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDimethylsulfoxide (DMSO)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolaibao,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epolyethylene glycol 300(PEG300)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolaibao,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTween 80\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolaibao,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium penicillin for injection\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNorth China Pharmaceutical,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ephosphate buffer\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolaibao,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eabsolute ethyl alcohol\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eXilong Scientific,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edimethylbenzene\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eXilong Scientific,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4% paraformaldehyde\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolaibao,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEDTA decalcifying Fluid\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolaibao,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematoxylin\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolaibao,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosin Y water soluble\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eXiya Reagent,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe TRAP staining kit\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevierbio,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRat IL -1β ELISA Kit\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLianke Biotech,China\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eModel Construction and Experimental Grouping for Femoral Wear Particle-Induced Osteolysis\u003c/p\u003e\u003cp\u003eThe thirty SD rats were randomly assigned to three groups: a blank control group, a model group, and an extracorporeal shock wave therapy (ESWT) treatment group. Prior to the procedures, the rats were weighed and anesthetized with an injection of 2.5% pentobarbital sodium administered via the tail vein at a dosage of 1 ml/kg. A distal femoral periprosthetic osteolysis model was constructed following established methodologies. The right knee joints of the rats were prepared and disinfected, and the surgical field was exposed. The patella was gently displaced to locate the medial space of the patellofemoral joint. The knee joint was flexed appropriately, and an incision of suitable length was made to separate the joint capsule, surrounding tissue, and skin, thereby accessing the joint cavity. The patella was dislocated to expose the intercondylar fossa of the distal femur. A needle was inserted into the femoral intercondylar socket, positioned 5 mm from the dorsal aspect of the femur. Following proper positioning, a bone tunnel was drilled using an electric drill to ensure alignment with the long axis of the femur. After achieving hemostasis, 50 µL of titanium particle suspension was injected, and pure titanium rods were placed to seal the bone tunnel, followed by hemostasis, reduction, and suturing. Postoperatively, 2 mg/kg of carprofen and 6000 U/kg of penicillin were administered for three consecutive days to mitigate the risk of infection. On postoperative days 4, 8, and 12, 0.1 ml of titanium particle suspension was injected into the knee cavity of all rats, with the exception of those in the control group, which received 0.1 ml of isotonic saline. Four weeks post-intervention, blood samples were collected from the main abdominal artery, and bone tissue was harvested from the distal femur for subsequent analyses.\u003c/p\u003e\u003cp\u003eExtracorporeal Shock Wave Therapy\u003c/p\u003e\u003cp\u003eTwo weeks following the successful establishment of the osteolysis model, the rats were secured in a specialized frame to extend the right hind limb, thereby exposing the knee joint and surrounding tissues. Extracorporeal shock wave therapy was administered as a form of intervention. The treatment utilized a D15 probe (deep, with a diameter of 15 mm, tolerance ± 15%, energy density of 0.2 mJ/mm², tolerance ± 20%, penetration depth of 7 mm, tolerance ± 20%, and pulse width of 200 µs, tolerance ± 10%). The treatment pressure for the extracorporeal shock wave was set at 1.0 × 10² kPa, with a frequency of 5 Hz and a total of 1000 pulses per treatment session. The treatment site was alternated after every 250 shocks to prevent the occurrence of local hematomas or skin damage.During treatment, attention should be given to avoid important nerves and blood vessels around the knee joint. The rats were treated once a day, and the entire treatment lasted 10–12 minutes with intervention for 4 weeks.\u003c/p\u003e\u003cp\u003eHigh-Resolution Computed Tomography (CT) Analysis\u003c/p\u003e\u003cp\u003eFollowing the fixation of femoral tissue from each rat in 4% paraformaldehyde for a duration of 48 hours, high-resolution CT imaging was conducted under the parameters of 120 kV voltage, 128 mA current, and a slice thickness of 0.7 mm. The spatial distribution of femoral cancellous bone and osteolytic changes were examined, and a region of interest (ROI) was delineated for subsequent evaluation of bone mineral density, which was analyzed using Image-Pro Plus 5.0 software.\u003c/p\u003e\u003cp\u003eHematoxylin and Eosin (HE) Staining\u003c/p\u003e\u003cp\u003eThe femurs from each experimental group were similarly fixed in 4% paraformaldehyde for 48 hours, followed by decalcification using EDTA, which allowed for easy penetration into the bone tissue over approximately eight weeks. The samples underwent dehydration, paraffin embedding, and sectioning at a thickness of 4 µm, after which they were subjected to HE staining. Osteolytic areas were assessed in four to five fields, and the extent of osteolysis was quantified using Image-Pro Plus 5.0 software.\u003c/p\u003e\u003cp\u003eTartrate-Resistant Acid Phosphatase (TRAP) Staining\u003c/p\u003e\u003cp\u003eThe femurs from each group were fixed in 4% paraformaldehyde for 48 hours, followed by EDTA decalcification, which facilitated easy puncture into the bone tissue over a period of approximately eight weeks. The samples were then dehydrated, embedded in paraffin, sectioned to a thickness of 4 µm, and stained for TRAP. Osteolysis was evaluated in four to five fields, and the area of osteolysis was analyzed and quantified using Image-Pro Plus 5.0 software.\u003c/p\u003e\u003cp\u003eEnzyme-Linked Immunosorbent Assay (ELISA)\u003c/p\u003e\u003cp\u003eUrine samples were collected to quantify the concentration of interleukin-1 beta (IL-1β) using a Rat IL-1β ELISA Kit, following the manufacturer's instructions. The optical density (OD) was measured at 450 nm, and a fitted curve was generated from standard concentrations to calculate the concentration of the test samples based on the established formula.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were conducted using GraphPad Prism 6.0 software. Results are presented as mean ± standard deviation (x ± s). Comparisons among three groups were performed using one-way ANOVA, while pairwise comparisons were executed using t-tests, with a significance threshold set at P \u0026lt; 0.05 (*, P \u0026lt; 0.05; **, P \u0026lt; 0.01; ***, P \u0026lt; 0.001).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eEffects of ESWT on Bone Cortical Thickness and Mineral Density\u003c/p\u003e \u003cp\u003eFollowing a 4-week treatment period, imaging data were obtained around the distal femur prosthesis using high-resolution computed tomography (CT) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The findings indicated that the bone surrounding the distal femur remained continuous and intact, exhibiting no significant inflammatory responses or signs of osteolysis. In comparison to the blank control group, the model group demonstrated reduced bone density in areas of disrupted bone continuity and osteolysis (P \u0026lt; 0.01), suggesting a detrimental effect of titanium (Ti) particles on the bone adjacent to the implanted prosthesis. Conversely, the ESWT-treated group exhibited continuous and intact periprosthetic bone, along with a notable thickening of the bone cortex; the bone mineral density (BMD) in this group significantly increased (P \u0026lt; 0.001), with no evidence of osteolysis.\u003c/p\u003e \u003cp\u003eIL-1β expression can be suppressed by ESWT\u003c/p\u003e \u003cp\u003eCompared with that in the blank control group, the level of IL-1β in the serum was significantly greater (P \u0026lt; 0.001), and compared with that in the model group, the level of IL-1β in the ESWT group was significantly lower (P \u0026lt; 0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInhibition of Osteolysis and Osteoclastogenesis by ESWT\u003c/p\u003e \u003cp\u003eIn the model group, there was partial continuity of direct contact between the prosthesis and bone, with visible black titanium particles in the surrounding bone. This area exhibited extensive osteolytic cavities that were populated by numerous inflammatory macrophages and osteoclasts (P \u0026lt; 0.001), leading to a significant increase in the osteolysis area (P \u0026lt; 0.001). In contrast, the ESWT-treated group displayed complete and continuous direct contact between the prosthesis and bone, with only minor osteolytic cavities surrounding the titanium particles. This group also showed a reduced presence of inflammatory cells and a significant decrease in the number of osteoclasts (P \u0026lt; 0.001), as well as a reduction in osteolysis (P \u0026lt; 0.05) (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eJoint arthroplasty is a key approach for joint injury and reconstruction, and despite the increasing popularity of its clinical use, postoperative complications such as infections, aseptic loosening and peripheral fractures still need to be focused on \u003csup\u003e[17]\u003c/sup\u003e. A retrospective study revealed that in 23269 patients who underwent hip revision, more than 50% of the secondary surgeries involved aseptic loosening \u003csup\u003e[18]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe bioactive particles released by micromovement and wear between artificial joint components can promote osteoclast maturation and differentiation, lead to osteolysis, and affect the metabolism of osteoclasts and osteoblasts by triggering an inflammatory response. For example, bone metabolism is affected by the ability of macrophages, fibroblasts, osteoblasts and osteoclasts to synthesize and release chemokines and cytokines, including IL-1β blasts and TNF-α\u003csup\u003e[19–20]\u003c/sup\u003e. Bone metabolic homeostasis is dependent on the balance between osteoclasts and osteoblasts. After joint prosthesis replacement, wear particles disrupt this balance, leading to increased bone resorption and decreased bone formation, the main cause of aseptic loosening of the prosthesis \u003csup\u003e[21]\u003c/sup\u003e. Reducing osteocast formation and activity in periprosthetic bone tissue through treatment and maintaining local bone metabolic balance are key strategies for preventing artificial joint loosening. In previous studies, we reported that inhibiting TNF-α and enhancing OPG could effectively inhibit the periprosthetic osteolysis induced by Ti particles\u003csup\u003e[22–24]\u003c/sup\u003e. In addition, in the presence of Ti particles, the expression of NFATc1 in periprosthetic tissue increased significantly, and inhibiting RANKL could effectively inhibit the expression of NFATc1 and the proliferation and differentiation of osteoclasts\u003csup\u003e[25]\u003c/sup\u003e, indicating that the regulation of the RANKL/RANK/OPG/NFATc1 pathway can effectively prevent wear particle-induced osteolysis and further prove the importance of regulating bone metabolic homeostasis for the prevention of aseptic loosening of the prosthesis.\u003c/p\u003e\u003cp\u003eAs the preferred drug for the treatment of osteoporosis and femoral head necrosis, bisphosphonates can inhibit osteoclast activity, reduce bone resorption, increase bone density, reduce osteoblast apoptosis and promote bone formation, with the potential to prevent or reduce osteolysis \u003csup\u003e[26]\u003c/sup\u003e. However, some studies have reported that the long-term efficacy of bisphosphonate drugs is generally[27]and that there is a risk of increased atrial fibrillation and bone fragility \u003csup\u003e[28]\u003c/sup\u003e. When combined with anti-inflammatory drugs, a high blood concentration is needed to maintain the local effective concentration, causing serious side effects and delaying its application in clinical practice. Gene therapy has also made some advances in periprosthetic osteolysis therapy, but it is still in its early stage and cannot be used clinically in the short term\u003csup\u003e[29]\u003c/sup\u003e. Therefore, finding safe and economical nonsurgical nondrug treatments to intervene in and treat periprosthetic osteolysis remains an urgent clinical problem.\u003c/p\u003e\u003cp\u003eWith the increasing application of ESWT in the medical field, researchers have explored the site of action and treatment principles, and increasing evidence has revealed the positive influence of ESWT on the balance between osteobogenesis and osteolysis of bone tissue. ESWT can promote the differentiation of BMSCs into osteoblasts through the MAPK signaling pathway and can inhibit the proliferation of osteoclasts and reduce bone resorption\u003csup\u003e[30–32]\u003c/sup\u003e. Moreover, the expression of ERK and P38 was significantly increased in some bone defect areas, and an obvious osteogenesis process occurred, which promoted bone formation \u003csup\u003e[33]\u003c/sup\u003e. Studies have shown that high-energy extracorporeal shock wave therapy (ESWT) can be used at the interface between muscle and bone. Due to differential acoustic impedance, energy pulses act on bone tissue, stimulate the biosynthetic response of cancellous bone and cortical bone, activate mesenchymal stem cells, enable them to transform into osteoblasts, and accelerate the growth of bone tissue\u003csup\u003e[34]\u003c/sup\u003e. On the other hand, appropriate-strength ESWT (0.08 mJ/mm\u003csup\u003e2\u003c/sup\u003e, 500 times) inhibited the transcriptional activity of NFATc1 and the differentiation of mature osteoclasts and bone resorption through the regulation of c-fos gene expression \u003csup\u003e[35]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe present study first confirmed via high-resolution CT analysis that ESWT could inhibit the occurrence of titanium particle-induced periprosthetic osteolysis around the distal femur in rats. Moreover, ESWT also increased the periprosthetic BMD in the osteolysis model, which is consistent with the conclusion of Shi et al. \u003csup\u003e[36]\u003c/sup\u003e, who reported that high-energy ESWT (0.28 mJ/mm2, 4 Hz, 4000 times) was better at improving the local BMD, demonstrating the potential of ESWT in treating periprosthetic osteolysis. ESWT helps reduce the serum IL-1β levels caused by wear particles and suppresses systemic inflammation. As observed by staining, ESWT reduced the number of osteoclasts and macrophages within the area of osteolysis, probably because it reduced the level of inflammation and inhibited the differentiation of osteoclasts, thereby inhibiting osteolysis. ESWT may also act directly on bone marrow-derived macrophages to prevent their differentiation into osteoclasts. However, this study has several limitations: only titanium particles were studied without involving other wear particles; the therapeutic effect of ESWT on titanium particle-induced osteolysis was preliminarily explored, but the osteogenic effect was not verified at the protein level, and the ability of ESWT to inhibit the osteoclastic differentiation of BMSCs was not evaluated. Although the inhibitory effect and underlying molecular mechanism of ESWT on osteolysis at the in vivo level have been defined, the influence and regulatory mechanism of ESWT on BMSCs, BMMs and osteoclasts at the cellular level still need further investigation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eESWT can significantly suppress the levels of inflammatory factors, the generation of osteoclasts around the prosthesis, and effectively delay the progression of osteolysis. It can serve as a treatment for periprosthetic osteolysis induced by wear particles and has high clinical application value.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eAll the animal experiments were approved by the Laboratory Animal Ethics Committee of the First Affiliated Hospital of Harbin Medical University. All experimental animals were treated and cared for in strict accordance with the Regulations on the Management of Experimental Animals of Harbin Medical University.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors reported there is no funding associated with the work featured in this article.\u003c/p\u003e\n\u003cp\u003eAuthors’\u0026nbsp;contributions\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFengnian Zhao\u0026nbsp;\u003c/strong\u003eput forward the research conception, designed the experimental scheme, investigated and collected the experimental data, carried out data analysis, and accomplished the writing of the manuscript.\u0026nbsp;\u003cstrong\u003eYufei Chen\u0026nbsp;\u003c/strong\u003ecollected\u0026nbsp;and analyzed\u0026nbsp;research data and\u0026nbsp;was involved in manuscript writing.\u003cstrong\u003eAo Dong\u0026nbsp;\u003c/strong\u003ecollects and analyzes research data and is involved in manuscript writing.\u0026nbsp;\u003cstrong\u003eKeguan Song\u0026nbsp;\u003c/strong\u003ereviewed, edited, and supervised manuscripts.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTsukamoto M, Ohnishi H, Mori T, Kawasaki M, Uchida S, Sakai A. 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Osteoporos Int. 2017;28(10):2945-2953.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-orthopaedic-surgery-and-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"josr","sideBox":"Learn more about [Journal of Orthopaedic Surgery and Research](http://josr-online.biomedcentral.com)","snPcode":"13018","submissionUrl":"https://submission.nature.com/new-submission/13018/3","title":"Journal of Orthopaedic Surgery and Research","twitterHandle":"@MSKmedBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"extracorporeal shock wave therapy, wear particles, osteolysis, osteoclasts, inflammatory factors","lastPublishedDoi":"10.21203/rs.3.rs-5342963/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5342963/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eExtracorporeal shock wave therapy (ESWT) is a conservative orthopedic treatment that has been shown to be effective in a variety of orthopedic diseases; however, its effectiveness in addressing sterile prosthesis loosening remains uncertain. This study aimed to establish a model of periprosthetic osteolysis and to assess the impact of ESWT on osteolysis induced by wear particles. The findings indicated that the group receiving ESWT exhibited an increase in bone mineral density, alongside a reduction in the extent of osteolysis, the quantity of osteoclasts, and serum levels of IL-1β. Consequently, we conclude that ESWT significantly diminishes inflammatory factor levels, inhibits the development of periprosthetic osteoclasts, and effectively slows the progression of osteolysis, thereby presenting substantial clinical relevance.\u003c/p\u003e","manuscriptTitle":"Experimental study of extracorporeal shock wave therapy for periprosthetic osteolysis induced by wear particles","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-15 10:26:01","doi":"10.21203/rs.3.rs-5342963/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-31T17:39:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-30T16:19:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"216549623713956855663828487841974011035","date":"2024-12-26T22:35:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-19T13:53:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79003958591854707817872132150985820625","date":"2024-11-13T17:20:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-13T12:03:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-04T05:43:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-04T04:34:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Orthopaedic Surgery and Research","date":"2024-10-27T22:22:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-orthopaedic-surgery-and-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"josr","sideBox":"Learn more about [Journal of Orthopaedic Surgery and Research](http://josr-online.biomedcentral.com)","snPcode":"13018","submissionUrl":"https://submission.nature.com/new-submission/13018/3","title":"Journal of Orthopaedic Surgery and Research","twitterHandle":"@MSKmedBMC","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fd63ec78-b877-48c7-bd8d-0fc2d67ee1e0","owner":[],"postedDate":"November 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-17T16:10:49+00:00","versionOfRecord":{"articleIdentity":"rs-5342963","link":"https://doi.org/10.1186/s13018-025-05661-y","journal":{"identity":"journal-of-orthopaedic-surgery-and-research","isVorOnly":false,"title":"Journal of Orthopaedic Surgery and Research"},"publishedOn":"2025-03-14 15:58:21","publishedOnDateReadable":"March 14th, 2025"},"versionCreatedAt":"2024-11-15 10:26:01","video":"","vorDoi":"10.1186/s13018-025-05661-y","vorDoiUrl":"https://doi.org/10.1186/s13018-025-05661-y","workflowStages":[]},"version":"v1","identity":"rs-5342963","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5342963","identity":"rs-5342963","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}