Rapid pain relief after intra-articular injection of adipose-derived stromal vascular fraction in patients with knee osteoarthritis: a retrospective cohort study

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However, the timing of pain relief and the influence of SVF cell dose on early clinical outcomes remain incompletely defined. Methods This retrospective study included 146 patients (217 knees) with Kellgren–Lawrence (K–L) grade II–IV knee OA who underwent intra-articular injection of autologous SVF and completed a minimum follow-up of 1 year. Pain was assessed using the visual analog scale (VAS), and patients reported the time to perceived pain improvement after treatment. Radiographic severity was evaluated using the K–L grading system. Correlation analyses were performed to assess associations between pain-related outcomes, SVF cell number, and radiographic severity. Results VAS scores improved significantly from baseline to the final follow-up (P < 0.01). Patients reported perceived pain improvement at a mean of 18.9 ± 14.5 days after SVF injection. The mean injected dose was 7.4 × 10⁷ total SVF cells per knee, including approximately 7.0 × 10⁶ stromal cells. Higher SVF cell numbers were significantly associated with greater pain improvement and lower VAS scores at final follow-up (P < 0.001 for both). Radiographic severity was not significantly correlated with pain outcomes. No clinically relevant adverse events were observed. Conclusions Intra-articular injection of high-dose autologous SVF was associated with rapid and clinically meaningful pain relief, with symptom improvement occurring within approximately 3 weeks after treatment. The dose-dependent association and the lack of correlation with radiographic severity suggest that early pain relief is primarily mediated by the anti-inflammatory and paracrine effects of SVF rather than immediate structural cartilage regeneration. Knee osteoarthritis Stromal vascular fraction Intra-articular injection Pain relief Dose–response relationship INTRODUCTION Knee osteoarthritis (OA) is one of the most prevalent degenerative joint diseases and a leading cause of chronic pain, disability, and reduced quality of life worldwide, with its prevalence steadily increasing due to population aging and rising obesity rates. [ 1 – 3 ] Knee OA is now recognized as a whole-joint disorder involving not only articular cartilage degeneration but also synovial inflammation, subchondral bone remodeling, and osteophyte formation, all of which contribute to persistent pain and progressive functional decline. [ 1 , 2 , 4 ] Conventional nonoperative treatments for knee OA, including non-steroidal anti-inflammatory drugs, physical therapy, and intra-articular injections of corticosteroids or hyaluronic acid, primarily provide symptomatic relief and fail to modify the underlying disease process. [ 2 , 3 ] Although total knee arthroplasty remains an effective treatment for end-stage OA, it is invasive, associated with perioperative risks, and unsuitable for many patients due to age, comorbidities, or personal preference. [ 3 ] These limitations have driven increasing interest in minimally invasive regenerative therapies capable of alleviating pain while potentially modulating the intra-articular disease environment in patients with knee OA. [ 2 , 3 ] Among emerging regenerative approaches, adipose tissue–derived cell therapies have attracted growing attention owing to the abundance, accessibility, and high cellular yield of adipose tissue compared with other mesenchymal stem cell (MSC) sources. [ 3 , 5 ] Stromal vascular fraction (SVF) is a heterogeneous, non-cultured cell population derived from adipose tissue and composed of adipose-derived stromal cells, endothelial progenitor cells, pericytes, fibroblasts, macrophages, lymphocytes, and various growth factors and cytokines. [ 1 , 6 , 7 ] Unlike cultured adipose-derived stromal cells, SVF can be harvested and administered in a single procedure without cell expansion, reducing processing time, cost, and regulatory complexity and making it particularly suitable for real-world clinical practice. [ 8 , 9 ] Preclinical and translational studies suggest that the therapeutic effects of SVF are mediated predominantly through paracrine and immunomodulatory mechanisms rather than direct cell engraftment or differentiation, including suppression of pro-inflammatory cytokines, enhancement of anabolic signaling, and polarization of macrophages toward an anti-inflammatory M2 phenotype. [ 6 , 7 ] Clinically, multiple prospective studies, randomized controlled trials, and systematic reviews have demonstrated that intra-articular SVF injection is generally safe and associated with significant improvements in pain and functional outcomes, as assessed by the visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), and Lysholm score. [ 1 , 3 , 10 ] Importantly, several comparative and observational studies indicate that SVF may provide relatively rapid pain relief after intra-articular injection, with early reductions in VAS scores observed during the initial post-treatment period. [ 8 , 11 , 12 ] This early analgesic effect is thought to reflect the heterogeneous cellular composition of SVF and its immediate paracrine anti-inflammatory activity within the joint environment. [ 6 , 7 ] Despite these encouraging findings, existing studies are limited by small sample sizes, heterogeneous treatment protocols, and inconsistent evaluation of early pain trajectories, leaving the rapid analgesic effects of SVF incompletely characterized, particularly in large real-world clinical cohorts. [ 3 , 13 ] Therefore, further investigation using larger real-world populations is warranted to better define the magnitude and timing of pain relief following intra-articular SVF injection in patients with knee osteoarthritis. [ 2 , 3 ] Accordingly, the purpose of the present study was to evaluate the clinical effectiveness of intra-articular injection of autologous adipose-derived SVF in patients with knee osteoarthritis, with particular emphasis on the rapid relief of pain following treatment. MATERIALS AND METHODS Study Design and Participants This study was reviewed and approved by the Institutional Review Board of our hospital, and written informed consent was obtained from all participants. We retrospectively reviewed the medical records of 151 consecutive patients with knee OA who were treated with intra-articular injections of SVF at our clinic and had completed 1 year of follow-up between July 2024 and November 2024. The inclusion criteria were knee OA with Kellgren-Lawrence (K-L) grade [ 14 ] II, III or IV confirmed by clinical evaluation, radiography, and magnetic resonance imaging (MRI); and symptoms of unilateral knee joint pain and/or functional limitations despite a minimum of 3 months treatment with oral non-steroidal anti-inflammatory drugs. The exclusion criteria were a previous history of steroid injection within 1 year; comorbidities in hip or ankle joints; or hematological or cardiovascular disease(s), systemic infection(s), or immunosuppressive disorder(s). Patients who had knee instability, varus or valgus malalignment of the knee joint of ≥ 5°, metabolic arthritis, joint infections, or large meniscal tears were also excluded. Of the 151 qualified patients, 3 dropped out and 2 were lost during the follow-up. Therefore, a total of 146 patients (217 knees) were included, comprising 50 men and 96 women, with a mean age of 64.3 years (range, 43–86 years). The mean preoperative body mass index was 26.4 kg/m 2 (range, 22.8–28.9), and the distribution of radiographic severity according to the Kellgren–Lawrence grading system is summarized in Table 1 . Table 1 Baseline characteristics Age, y 64.3 ± 7.2 (43–86) Sex, male/female, n 50/96 Side of involvement, right/left, n 107/110 Body mass index, kg/m 2 26.4 ± 1.6 (22.8–28.9) Kellgren-Lawrence grade, n (%) II 94 (43.3) III 86 (39.6) IV 37 (17.1) Data are presented as means ± standard deviation (range) unless otherwise indicated Isolation of SVF From Subcutaneous Adipose Tissue Subcutaneous adipose tissue samples were obtained through tumescent liposuction from the gluteal regions of patients 1 day before SVF injection. We collected 140 mL of adipose tissue, and this was sus pended in phosphate-buffered saline solution, placed in a sterile box, and transported to the laboratory. A 120 mL aliquot of the tissue was used for injection. Mature adipocytes and connective tissues were separated from the SVF by centrifugation (Hanil Scientific Inc., Gyeonggi-do, South Korea). [ 15 ] Before injection, bacteriologic tests including mycoplasma (iNtRON, Gyeonggi-do, South Korea), endotoxin (Associates of Cape Cod, MA), and gram stain kit (BD Biociences, Franklin Lakes, NJ) were performed to ensure that the samples were not contaminated, and cell viability was assessed using the methylene blue dye exclusion test (NanoEntek, Seoul, South Korea). The remaining 20 mL of adipose tissue was processed similarly and used for laboratory analysis to examine the plastic-adherent cells that form colony-forming unit fibroblasts (CFU-Fs) and to confirm the multilineage differentiation of adipose-derived stem cells. Confirmation of MSC Characteristics When plated at low densities, MSCs adhere to tissue culture plastic and generate colonies. [ 16 , 17 ] The CFU-F assay was used to confirm the generation of mesenchymal progenitors of adipose-derived stem cells. The cells were cultured in T25 flasks (16 cells/cm 2 ) to evaluate the frequency of mesenchymal-like pro genitors. Colonies of 50-cell aggregates were scored under an optical microscope to assess their colony forming ability. Cells regularly seeded at 50 cells/cm 2 were allowed to multiply and their flow cytometric immunophenotype was examined using fluorescence activated cell sorting (FACS). MSC marker phenotyping was performed using CD14, CD34, CD90, and CD105 antibodies according to an established protocol. [ 18 , 19 ] FACS-based analysis of the flow cytometric immunophenotype requires 2 × 10 6 cells per CD marker. Therefore, we obtained 8 × 10 6 of cells for 4 CD markers through culture expansion. To confirm the multilineage differentiation of MSCs, adipose-derived stem cells were plated at 5 × 10 3 cells/cm 2 in Dulbecco’s modified Eagle’s medium (HyClone, Logan, UT) supplemented with 10% fetal bovine serum (HyClone), and allowed to adhere for 24 hours. The culture medium was then replaced with specific inductive media to determine the adipogenic, osteogenic, and chondrogenic differentiation potential. [ 20 ] We used CFU-F to evaluate the capacity of human subcutaneous adipose tissue to generate mesenchymal progenitors. Adipose-derived stem cells comprised 9.6% of the SVF cells. The SVF cells contained an average of 7.0 × 10 6 stem cells, and an average of 7.3 × 10 7 SVF cells (range 6.5–8.4 × 10 6 cells), were used for implantation. FACS analysis indicated positive ex pressions of CD90 (99.14%) and CD105 (93.73%) and negative expressions of CD34 (5.17%) and CD14 (2.46%). The treated stem cells exhibited adipogenic, osteogenic, and chondrogenic differentiation potential, as revealed by staining assays. SVF Injection All injections were performed using the same technique by an experienced senior orthopedic surgeon. Patients lay down on the table in a supine position with their knees extended during intra-articular injection. An arthrocentesis was performed to eliminate a knee effusion, before SVF was administered by transversely inserting a needle between the articular surface and patellofemoral joint in the midpoint of the patella, after pushing the patella upwards and shifting it to the lateral side. [ 21 ] The patients were advised against additional treatments including physical therapy, acupuncture, steroid injection, and opioid or strong analgesics until 1 year after the injection. They were also told to avoid weight-bearing motions that impose an excessive burden on the affected knee, such as standing for prolonged periods, jogging, and lifting heavy objects, for the first 3 days. Outcome Assessment All patients were evaluated clinically and radiologically before injection and during follow-up(s). For clinical evaluation, the visual analog scale (VAS) for pain was collected and all patients were asked how soon after receiving injection treatment they began to feel improvement in pain. Adverse events were recorded for safety evaluation. Radiological evaluations included a weight-bearing anterior-posterior (AP) view, true lateral view at 30° of knee flexion, and hip-to-ankle standing AP radiograph on a long cassette. To avoid potential bias, an independent observer, who was a musculoskeletal-trained radiologist not involved in the care of patients and blinded to the intention of this study, performed the radiological evaluation. The K-L grading system [ 14 ] was used to assess the AP radiographs Statistical Analysis The principal dependent variable was the VAS scores during the follow-up visits. Descriptive statistics were calculated as means ± standard deviations unless otherwise indicated. The Wilcoxon signed-rank test was used to evaluate differences between the preoperative and final follow-up values. The Spearman’s rank-order correlation test was used to evaluate potential bivariate associations between different factors to identify significant correlations. Statistical analyses were performed using SPSS, Version 13.0 (IBM Corp., Armonk, NY, USA), and a P -value of < 0.05 was considered statistically significant. RESULTS Pain Scores and Radiological Outcomes The mean VAS score significantly improved from 37.7 ± 6.3 at baseline to 67.3 ± 9.5 at the final follow-up ( P < 0.01). Patients reported a mean time to perceived pain improvement of 18.9 ± 14.5 days following SVF injection. No clinically significant adverse events were observed during the 12-month follow-up period. Although mild knee stiffness accompanied by swelling was reported in 9 patients, these symptoms resolved spontaneously without the need for additional intervention. Radiographic evaluation using the Kellgren–Lawrence (K–L) grading system demonstrated that, prior to treatment, most knees were classified as grade II (94 knees, 43.3%), grade III (86 knees, 39.6%), or grade IV (37 knees, 17.1%) (Table 1 ). At the 1-year follow-up, the distribution of K–L grades remained largely unchanged, with grade II observed in 91 knees (41.9%), grade III in 87 knees (40.1%), and grade IV in 39 knees (18.0%), and no statistically significant difference was identified compared with baseline ( P = 0.096). Outcome Associations Correlation analyses were performed to evaluate the associations between pain-related outcomes and SVF cell number, as well as radiographic disease severity assessed by the Kellgren–Lawrence (K–L) grading system (Tables 2 and 3 ). No significant correlation was observed between SVF cell number and baseline VAS score (Spearman’s ρ = 0.088, P = 0.195). In contrast, SVF cell number demonstrated a significant negative correlation with VAS score at the final follow-up (ρ = −0.262, P < 0.001), indicating that a higher SVF cell number was associated with lower pain levels at 1 year after injection. Additionally, the magnitude of pain improvement, defined as the difference between baseline and final follow-up VAS scores, showed a moderate positive correlation with SVF cell number (ρ = 0.370, P < 0.001). A significant positive correlation was also identified between SVF cell number and the duration until symptom improvement (ρ = 0.219, P = 0.001), suggesting that patients receiving higher numbers of SVF cells tended to report symptom improvement over a longer time period (Table 2 ). Associations between K–L grade and pain-related outcomes were generally weak (Table 3 ). Baseline K–L grade demonstrated a weak but statistically significant positive correlation with baseline VAS score (ρ = 0.151, P = 0.026), indicating higher baseline pain levels in patients with more advanced radiographic osteoarthritis. Similarly, final follow-up K–L grade was weakly correlated with baseline VAS score (ρ = 0.166, P = 0.014). However, neither baseline nor final follow-up K–L grade showed significant correlations with final follow-up VAS score, the degree of pain improvement, or the duration until symptom improvement (all P > 0.05), suggesting that radiographic severity was not strongly associated with post-treatment pain outcomes following SVF injection. Table 2 Correlations between Pain Outcomes and SVF Number a SVF Number S rho P value Initial VAS 0.088 0.195 Final follow-up VAS -0.262 < 0.001 Difference between initial and final follow-up VAS 0.370 < 0.001 Duration until symptom improvement, days 0.219 0.001 a Calculated using the Spearman rank-order test. VAS, visual analogue scale; S, Spearman; SVF, stromal vascular fraction. Table 3 Correlations between Pain Outcomes and K-L Grade at Baseline and at the Final Follow-up a K-L Grade Baseline Final Follow-up S rho P value S rho P value Initial VAS 0.151 0.026 0.166 0.014 Final follow-up VAS 0.125 0.067 0.120 0.078 Difference between initial and final follow-up VAS -0.010 0.885 0.001 0.990 Duration until symptom improvement, days -0.057 0.406 -0.056 0.414 a Calculated using the Spearman rank-order test. VAS, visual analogue scale; S, Spearman; K-L, Kellgren-Lawrence. DISCUSSION The most notable finding of the present study is the rapid improvement in pain following intra-articular injection of autologous stromal vascular fraction (SVF), with patients reporting symptomatic relief at a mean of approximately 3 weeks after treatment. This early clinical response distinguishes our results from many previously published SVF studies and may be attributable, at least in part, to the relatively high SVF cell number administered in our cohort. Previous clinical studies and systematic reviews have consistently demonstrated that intra-articular SVF injection is safe and effective for reducing pain and improving function in patients with knee osteoarthritis; however, the onset of symptom relief has typically been reported at follow-up intervals of 1 to 3 months rather than within the first few weeks. [ 1 , 22 ] Several trials and reviews have described meaningful improvements in pain scores beginning at 4–12 weeks after injection, highlighting substantial variability in the timing of clinical response across studies. [ 22 ] In a double-blind randomized self-controlled trial, Hong et al. [ 2 ] reported that patients with Kellgren–Lawrence (K–L) grade II–III knee osteoarthritis experienced significant improvements in VAS and WOMAC scores beginning at 1 month after SVF injection, with continued improvement at subsequent follow-up visits. Notably, the SVF preparations used in that study generally yielded approximately 1–3 × 10 7 total SVF cells per knee, which is substantially lower than the SVF cell number administered in the present study. Similarly, Lapuente et al. [ 23 ] demonstrated significant clinical improvement at 1-year follow-up, with pain relief occurring progressively over the first several postoperative months rather than within weeks after injection. These findings suggest that, in most prior studies, early pain improvement within the first few weeks was not a predominant feature of SVF therapy. Systematic reviews further support these observations. Shanmugasundaram et al. [ 22 ] analyzed 11 clinical studies of SVF therapy and reported that the earliest consistent improvements in pain were observed between 4 and 12 weeks after treatment, with most studies administering SVF cell numbers in the range of 10 6 to low 10 7 cells. Likewise, Goncharov et al. [ 1 ] highlighted the substantial heterogeneity in SVF preparation protocols and cell yields, noting that few studies directly examined the relationship between injected SVF cell number and the timing of pain relief, with most clinical improvements reported at 1–3 months after injection. A comparison of SVF cell dose and the timing of pain improvement across previously published studies and the present cohort is summarized in Table 4 . Table 4 Comparison of SVF Cell Number and Time to Pain Improvement Across Studies a Study Study design / OA grade Reported SVF cell number (per knee) Reported time to pain improvement Key notes Hong et al., 2019 Double-blind randomized self-controlled trial / K–L II–III ≈ 1–3 × 10 7 total SVF cells From 1 month VAS and WOMAC improvement reported at 1, 3, 6, and 12 months Lapuente et al., 2020 Retrospective cohort / moderate–severe OA Lower SVF yield; exact number not standardized Several months; primary endpoint at 1 year Focus on immunomodulatory and long-term effects Shanmugasundaram et al., 2021 (Systematic review) 11 clinical studies / mixed OA grades Typically 10 6 to low 10 7 cells 4–12 weeks Marked heterogeneity in SVF preparation Goncharov et al., 2023 (Systematic review) 22 studies / knee OA Mostly within 10 6 –10 7 cells 1–3 months Dose–response relationship rarely analyzed Yokota et al., 2022 Parallel single-arm trials / K–L II–IV SVF dose lower than cultured ASC protocols Earlier than ASCs, but not within weeks ASC superior for long-term outcomes Present study Retrospective cohort / K–L II–IV 7.4 × 10 7 total SVF cells (≈ 7.0 × 10 6 stromal cells) 18.9 ± 14.5 days (≈ 3 weeks) Shortest time to pain improvement among compared studies a SVF, stromal vascular fraction; ASC, adipose-derived stromal cell; OA, osteoarthritis; K–L, Kellgren–Lawrence; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index In contrast to these prior reports, the present study employed a higher mean SVF cell dose of approximately 7.4 × 10 7 total SVF cells, including approximately 7.0 × 10 6 stromal cells, administered per knee, and demonstrated a significantly shorter time to perceived pain improvement, with patients reporting symptom relief at a mean of 18.9 ± 14.5 days (approximately 3 weeks) after treatment. Correlation analysis further revealed that higher SVF cell numbers were significantly associated with greater reductions in VAS scores, supporting a potential dose-dependent relationship between SVF cell number and pain relief. Importantly, radiographic disease severity assessed using the K–L grading system was not significantly associated with pain outcomes, including pain at final follow-up, the magnitude of pain improvement, or the time to perceived symptom relief (Table 3 ). This finding suggests that the observed pain reduction following SVF injection may occur independently of structural disease severity, as reflected by radiographic grading. Several previous studies have similarly reported a discordance between radiographic severity and clinical pain outcomes following SVF therapy, indicating that pain relief may precede or occur independently of structural cartilage repair. [ 2 , 22 ] From a mechanistic perspective, accumulating evidence indicates that the primary early therapeutic effects of SVF are mediated through anti-inflammatory and paracrine mechanisms rather than direct structural regeneration of cartilage. SVF is a heterogeneous cell population comprising adipose-derived stromal cells, endothelial progenitor cells, pericytes, macrophages, and various immune cells. Experimental and translational studies have shown that SVF, particularly through its enrichment of M2-polarized macrophages, rapidly enhances the secretion of anti-inflammatory cytokines such as interleukin-10, interleukin-1 receptor antagonist, and transforming growth factor–β, while suppressing pro-inflammatory mediators including interleukin-1β and tumor necrosis factor–α. [ 22 , 23 ] Lapuente et al. [ 23 ] further provided clinical and biochemical evidence supporting this mechanism by demonstrating significant reductions in pro-inflammatory cytokines and matrix metalloproteinases within the synovial fluid following SVF injection, accompanied by increases in anabolic and anti-inflammatory mediators. Importantly, these molecular changes occurred in parallel with clinical pain improvement, reinforcing the concept that symptom relief is driven primarily by immunomodulation rather than immediate cartilage regeneration. Clinical comparative studies further corroborate the predominance of paracrine effects in SVF therapy. Yokota et al. [ 9 ] reported that although both SVF and cultured adipose-derived stromal cell injections significantly improved pain and function, SVF-treated knees exhibited earlier symptomatic improvement, whereas stromal cell therapy demonstrated more sustained long-term structural and functional benefits. Similarly, a recent systematic review focusing on K–L grade II–III osteoarthritis concluded that SVF therapy is characterized by rapid paracrine-driven pain reduction, while cartilage regeneration, when present, likely contributes to longer-term outcomes rather than early symptom improvement. [ 3 ] From a clinical standpoint, the ability to achieve early pain relief is highly relevant. Rapid symptom improvement may enhance patient satisfaction, reduce reliance on analgesic medications, and facilitate earlier engagement in rehabilitation and daily activities. The early analgesic effect observed across a range of K–L grades in the present study suggests that SVF therapy with an adequate cell dose may be broadly applicable in patients with knee osteoarthritis. This study has several limitations. First, its retrospective design and the absence of a control group limit the ability to draw definitive causal conclusions regarding the observed clinical improvements. Second, although a significant association between SVF cell number and pain reduction was identified, the optimal SVF cell dose required to maximize both early and long-term clinical benefits remains undefined. Third, radiographic outcomes were assessed using conventional grading systems, which may not fully capture subtle structural changes or biological remodeling within the joint. Finally, heterogeneity in patient characteristics and SVF preparation techniques may have influenced treatment response. Future prospective, randomized, dose-comparison studies with standardized SVF processing protocols and longer follow-up are warranted to address these limitations. CONCLUSION In conclusion, intra-articular injection of autologous SVF resulted in rapid and clinically meaningful pain relief, with symptom improvement occurring within approximately 3 weeks after treatment. The lack of association between radiographic disease severity and pain outcomes, together with evidence from prior clinical and experimental studies, suggests that this early analgesic effect is predominantly mediated by the anti-inflammatory and paracrine actions of SVF, rather than by immediate structural cartilage regeneration. These findings highlight the potential of high-dose SVF therapy as an effective, biologically active, and broadly applicable treatment option for patients with knee osteoarthritis, particularly for achieving early symptomatic benefit. Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Yonsei Sarang Hospital (YSSR IRB 2025-12-001). Written informed consent was obtained from all participants prior to enrollment. Consent to participate Written informed consent was obtained from all participants. Consent for publication Not applicable. Clinical trial number Not applicable. Competing interests The authors declare no competing interests. Funding No external funding. Author Contribution Y.S.K. and Y.G.K. conceptualized the study. D.S.S. and Y.B.K. performed methodology. Y.B.K. conducted analysis. J.H.C. collected data. Y.S.K. drafted the manuscript. Y.B.K. and Y.G.K. revised it. All authors had given final approval of the version to be submitted and agreed on the journal to be published. Acknowledgements None. Data Availability Available from the corresponding author upon reasonable request. References Goncharov EN, Koval OA, Nikolaevich Bezuglov E, Encarnacion Ramirez MJ, Engelgard M, Igorevich EI, Saporiti A, Valentinovich Kotenko K, Montemurro N. Stromal Vascular Fraction Therapy for Knee Osteoarthritis: A Systematic Review. Med (Kaunas). 2023;59(12). https://doi.org/10.3390/medicina59122090 . Hong Z, Chen J, Zhang S, Zhao C, Bi M, Chen X, Bi Q. 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Repair of osteochondral defects in the minipig model by OPF hydrogel loaded with adipose-derived mesenchymal stem cells. Regen Med. 2015;10(2):135–51. https://doi.org/10.2217/rme.14.77 . Marchal JA, Picón M, Perán M, Bueno C, Jiménez-Navarro M, Carrillo E, Boulaiz H, Rodríguez N, Álvarez P, Menendez P, et al. Purification and long-term expansion of multipotent endothelial-like cells with potential cardiovascular regeneration. Stem Cells Dev. 2012;21(4):562–74. https://doi.org/10.1089/scd.2011.0072 . Telikicherla M, Kamath SU. Accuracy of Needle Placement into the Intra-Articular Space of the Knee in Osteoarthritis Patients for Viscosupplementation. J Clin Diagn Res. 2016;10(2):Rc15–7. https://doi.org/10.7860/jcdr/2016/17127.7275 . Shanmugasundaram S, Vaish A, Chavada V, Murrell WD, Vaishya R. Assessment of safety and efficacy of intra-articular injection of stromal vascular fraction for the treatment of knee osteoarthritis-a systematic review. Int Orthop. 2021;45(3):615–25. https://doi.org/10.1007/s00264-020-04926-x . Lapuente JP, Dos-Anjos S, Blázquez-Martínez A. Intra-articular infiltration of adipose-derived stromal vascular fraction cells slows the clinical progression of moderate-severe knee osteoarthritis: hypothesis on the regulatory role of intra-articular adipose tissue. J Orthop Surg Res. 2020;15(1):137. https://doi.org/10.1186/s13018-020-01664-z . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. 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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-8572223","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":575285951,"identity":"21b5fd0e-3833-40bf-b924-1f05c641b25c","order_by":0,"name":"Yong Sang Kim","email":"","orcid":"","institution":"Yonsei Sarang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"Sang","lastName":"Kim","suffix":""},{"id":575285952,"identity":"db4592b3-9e12-4ba7-a162-fb8a6185c380","order_by":1,"name":"Dong Suk Suh","email":"","orcid":"","institution":"Yonsei Sarang 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Koh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYBADAwYJ5gNAWkKGFC1sCSAtPKRo4TEAMQhrMTjee/jll4o7xvzSPZ9f3aix4GFgP3x0A14tZ86lWcuceWYmOefsNuucY0CH8aSl3cCr5UaOmbFk22Ebgxu524xz2IBaJHjMiNWS88w45x9xWowffmw7bAZkMD/ObSNCi+SZM2bMDGcOG0vOSDNjzu2T4GEj5Be+4z3GH39UHDbsl0h+/DnnW50cP/vhY3i1KBxgYJOGxgWbBJjEpxwE5BsYmD/+gLCZPxBSPQpGwSgYBSMTAADKHkthjEicTwAAAABJRU5ErkJggg==","orcid":"","institution":"Yonsei Sarang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yong","middleName":"Gon","lastName":"Koh","suffix":""}],"badges":[],"createdAt":"2026-01-11 08:08:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8572223/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8572223/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100512568,"identity":"118facbe-13b7-4bdf-a156-48eb2831202f","added_by":"auto","created_at":"2026-01-18 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08:22:21","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97730,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8572223/v1/93181744c72be4ff1072003b.html"},{"id":101666097,"identity":"64f8d98b-1267-4a48-85a9-4e2cd6a1b6d3","added_by":"auto","created_at":"2026-02-02 11:43:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":734772,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8572223/v1/dc0c6603-830b-49d0-b9f6-1239d3d50ef6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rapid pain relief after intra-articular injection of adipose-derived stromal vascular fraction in patients with knee osteoarthritis: a retrospective cohort study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eKnee osteoarthritis (OA) is one of the most prevalent degenerative joint diseases and a leading cause of chronic pain, disability, and reduced quality of life worldwide, with its prevalence steadily increasing due to population aging and rising obesity rates. [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Knee OA is now recognized as a whole-joint disorder involving not only articular cartilage degeneration but also synovial inflammation, subchondral bone remodeling, and osteophyte formation, all of which contribute to persistent pain and progressive functional decline. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eConventional nonoperative treatments for knee OA, including non-steroidal anti-inflammatory drugs, physical therapy, and intra-articular injections of corticosteroids or hyaluronic acid, primarily provide symptomatic relief and fail to modify the underlying disease process. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Although total knee arthroplasty remains an effective treatment for end-stage OA, it is invasive, associated with perioperative risks, and unsuitable for many patients due to age, comorbidities, or personal preference. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] These limitations have driven increasing interest in minimally invasive regenerative therapies capable of alleviating pain while potentially modulating the intra-articular disease environment in patients with knee OA. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAmong emerging regenerative approaches, adipose tissue\u0026ndash;derived cell therapies have attracted growing attention owing to the abundance, accessibility, and high cellular yield of adipose tissue compared with other mesenchymal stem cell (MSC) sources. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Stromal vascular fraction (SVF) is a heterogeneous, non-cultured cell population derived from adipose tissue and composed of adipose-derived stromal cells, endothelial progenitor cells, pericytes, fibroblasts, macrophages, lymphocytes, and various growth factors and cytokines. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Unlike cultured adipose-derived stromal cells, SVF can be harvested and administered in a single procedure without cell expansion, reducing processing time, cost, and regulatory complexity and making it particularly suitable for real-world clinical practice. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Preclinical and translational studies suggest that the therapeutic effects of SVF are mediated predominantly through paracrine and immunomodulatory mechanisms rather than direct cell engraftment or differentiation, including suppression of pro-inflammatory cytokines, enhancement of anabolic signaling, and polarization of macrophages toward an anti-inflammatory M2 phenotype. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e Clinically, multiple prospective studies, randomized controlled trials, and systematic reviews have demonstrated that intra-articular SVF injection is generally safe and associated with significant improvements in pain and functional outcomes, as assessed by the visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), and Lysholm score. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Importantly, several comparative and observational studies indicate that SVF may provide relatively rapid pain relief after intra-articular injection, with early reductions in VAS scores observed during the initial post-treatment period. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThis early analgesic effect is thought to reflect the heterogeneous cellular composition of SVF and its immediate paracrine anti-inflammatory activity within the joint environment. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eDespite these encouraging findings, existing studies are limited by small sample sizes, heterogeneous treatment protocols, and inconsistent evaluation of early pain trajectories, leaving the rapid analgesic effects of SVF incompletely characterized, particularly in large real-world clinical cohorts. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Therefore, further investigation using larger real-world populations is warranted to better define the magnitude and timing of pain relief following intra-articular SVF injection in patients with knee osteoarthritis. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAccordingly, the purpose of the present study was to evaluate the clinical effectiveness of intra-articular injection of autologous adipose-derived SVF in patients with knee osteoarthritis, with particular emphasis on the rapid relief of pain following treatment.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003e This study was reviewed and approved by the Institutional Review Board of our hospital, and written informed consent was obtained from all participants. We retrospectively reviewed the medical records of 151 consecutive patients with knee OA who were treated with intra-articular injections of SVF at our clinic and had completed 1 year of follow-up between July 2024 and November 2024. The inclusion criteria were knee OA with Kellgren-Lawrence (K-L) grade [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] II, III or IV confirmed by clinical evaluation, radiography, and magnetic resonance imaging (MRI); and symptoms of unilateral knee joint pain and/or functional limitations despite a minimum of 3 months treatment with oral non-steroidal anti-inflammatory drugs. The exclusion criteria were a previous history of steroid injection within 1 year; comorbidities in hip or ankle joints; or hematological or cardiovascular disease(s), systemic infection(s), or immunosuppressive disorder(s). Patients who had knee instability, varus or valgus malalignment of the knee joint of \u0026ge;\u0026thinsp;5\u0026deg;, metabolic arthritis, joint infections, or large meniscal tears were also excluded. Of the 151 qualified patients, 3 dropped out and 2 were lost during the follow-up. Therefore, a total of 146 patients (217 knees) were included, comprising 50 men and 96 women, with a mean age of 64.3 years (range, 43\u0026ndash;86 years). The mean preoperative body mass index was 26.4 kg/m\u003csup\u003e2\u003c/sup\u003e (range, 22.8\u0026ndash;28.9), and the distribution of radiographic severity according to the Kellgren\u0026ndash;Lawrence grading system is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 (43\u0026ndash;86)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, male/female, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50/96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSide of involvement, right/left, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107/110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 (22.8\u0026ndash;28.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKellgren-Lawrence grade, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94 (43.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86 (39.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (17.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (range) unless otherwise indicated\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIsolation of SVF From Subcutaneous Adipose Tissue\u003c/h3\u003e\n\u003cp\u003eSubcutaneous adipose tissue samples were obtained through tumescent liposuction from the gluteal regions of patients 1 day before SVF injection. We collected 140 mL of adipose tissue, and this was sus pended in phosphate-buffered saline solution, placed in a sterile box, and transported to the laboratory. A 120 mL aliquot of the tissue was used for injection. Mature adipocytes and connective tissues were separated from the SVF by centrifugation (Hanil Scientific Inc., Gyeonggi-do, South Korea). [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Before injection, bacteriologic tests including mycoplasma (iNtRON, Gyeonggi-do, South Korea), endotoxin (Associates of Cape Cod, MA), and gram stain kit (BD Biociences, Franklin Lakes, NJ) were performed to ensure that the samples were not contaminated, and cell viability was assessed using the methylene blue dye exclusion test (NanoEntek, Seoul, South Korea). The remaining 20 mL of adipose tissue was processed similarly and used for laboratory analysis to examine the plastic-adherent cells that form colony-forming unit fibroblasts (CFU-Fs) and to confirm the multilineage differentiation of adipose-derived stem cells.\u003c/p\u003e\n\u003ch3\u003eConfirmation of MSC Characteristics\u003c/h3\u003e\n\u003cp\u003eWhen plated at low densities, MSCs adhere to tissue culture plastic and generate colonies. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] The CFU-F assay was used to confirm the generation of mesenchymal progenitors of adipose-derived stem cells. The cells were cultured in T25 flasks (16 cells/cm\u003csup\u003e2\u003c/sup\u003e) to evaluate the frequency of mesenchymal-like pro genitors. Colonies of 50-cell aggregates were scored under an optical microscope to assess their colony forming ability. Cells regularly seeded at 50 cells/cm\u003csup\u003e2\u003c/sup\u003e were allowed to multiply and their flow cytometric immunophenotype was examined using fluorescence activated cell sorting (FACS). MSC marker phenotyping was performed using CD14, CD34, CD90, and CD105 antibodies according to an established protocol. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] FACS-based analysis of the flow cytometric immunophenotype requires 2 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e cells per CD marker. Therefore, we obtained 8 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e of cells for 4 CD markers through culture expansion. To confirm the multilineage differentiation of MSCs, adipose-derived stem cells were plated at 5 \u0026times; 10\u003csup\u003e3\u003c/sup\u003e cells/cm\u003csup\u003e2\u003c/sup\u003e in Dulbecco\u0026rsquo;s modified Eagle\u0026rsquo;s medium (HyClone, Logan, UT) supplemented with 10% fetal bovine serum (HyClone), and allowed to adhere for 24 hours. The culture medium was then replaced with specific inductive media to determine the adipogenic, osteogenic, and chondrogenic differentiation potential. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] We used CFU-F to evaluate the capacity of human subcutaneous adipose tissue to generate mesenchymal progenitors. Adipose-derived stem cells comprised 9.6% of the SVF cells. The SVF cells contained an average of 7.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e stem cells, and an average of 7.3 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e SVF cells (range 6.5\u0026ndash;8.4 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e cells), were used for implantation. FACS analysis indicated positive ex pressions of CD90 (99.14%) and CD105 (93.73%) and negative expressions of CD34 (5.17%) and CD14 (2.46%). The treated stem cells exhibited adipogenic, osteogenic, and chondrogenic differentiation potential, as revealed by staining assays.\u003c/p\u003e\n\u003ch3\u003eSVF Injection\u003c/h3\u003e\n\u003cp\u003eAll injections were performed using the same technique by an experienced senior orthopedic surgeon. Patients lay down on the table in a supine position with their knees extended during intra-articular injection. An arthrocentesis was performed to eliminate a knee effusion, before SVF was administered by transversely inserting a needle between the articular surface and patellofemoral joint in the midpoint of the patella, after pushing the patella upwards and shifting it to the lateral side. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] The patients were advised against additional treatments including physical therapy, acupuncture, steroid injection, and opioid or strong analgesics until 1 year after the injection. They were also told to avoid weight-bearing motions that impose an excessive burden on the affected knee, such as standing for prolonged periods, jogging, and lifting heavy objects, for the first 3 days.\u003c/p\u003e\n\u003ch3\u003eOutcome Assessment\u003c/h3\u003e\n\u003cp\u003eAll patients were evaluated clinically and radiologically before injection and during follow-up(s). For clinical evaluation, the visual analog scale (VAS) for pain was collected and all patients were asked how soon after receiving injection treatment they began to feel improvement in pain. Adverse events were recorded for safety evaluation. Radiological evaluations included a weight-bearing anterior-posterior (AP) view, true lateral view at 30\u0026deg; of knee flexion, and hip-to-ankle standing AP radiograph on a long cassette. To avoid potential bias, an independent observer, who was a musculoskeletal-trained radiologist not involved in the care of patients and blinded to the intention of this study, performed the radiological evaluation. The K-L grading system [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] was used to assess the AP radiographs\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe principal dependent variable was the VAS scores during the follow-up visits. Descriptive statistics were calculated as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations unless otherwise indicated. The Wilcoxon signed-rank test was used to evaluate differences between the preoperative and final follow-up values. The Spearman\u0026rsquo;s rank-order correlation test was used to evaluate potential bivariate associations between different factors to identify significant correlations. Statistical analyses were performed using SPSS, Version 13.0 (IBM Corp., Armonk, NY, USA), and a \u003cem\u003eP\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePain Scores and Radiological Outcomes\u003c/h2\u003e \u003cp\u003eThe mean VAS score significantly improved from 37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.3 at baseline to 67.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5 at the final follow-up (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Patients reported a mean time to perceived pain improvement of 18.9\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5 days following SVF injection. No clinically significant adverse events were observed during the 12-month follow-up period. Although mild knee stiffness accompanied by swelling was reported in 9 patients, these symptoms resolved spontaneously without the need for additional intervention.\u003c/p\u003e \u003cp\u003eRadiographic evaluation using the Kellgren\u0026ndash;Lawrence (K\u0026ndash;L) grading system demonstrated that, prior to treatment, most knees were classified as grade II (94 knees, 43.3%), grade III (86 knees, 39.6%), or grade IV (37 knees, 17.1%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At the 1-year follow-up, the distribution of K\u0026ndash;L grades remained largely unchanged, with grade II observed in 91 knees (41.9%), grade III in 87 knees (40.1%), and grade IV in 39 knees (18.0%), and no statistically significant difference was identified compared with baseline (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.096).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Associations\u003c/h2\u003e \u003cp\u003eCorrelation analyses were performed to evaluate the associations between pain-related outcomes and SVF cell number, as well as radiographic disease severity assessed by the Kellgren\u0026ndash;Lawrence (K\u0026ndash;L) grading system (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No significant correlation was observed between SVF cell number and baseline VAS score (Spearman\u0026rsquo;s ρ\u0026thinsp;=\u0026thinsp;0.088, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.195). In contrast, SVF cell number demonstrated a significant negative correlation with VAS score at the final follow-up (ρ = \u0026minus;0.262, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating that a higher SVF cell number was associated with lower pain levels at 1 year after injection. Additionally, the magnitude of pain improvement, defined as the difference between baseline and final follow-up VAS scores, showed a moderate positive correlation with SVF cell number (ρ\u0026thinsp;=\u0026thinsp;0.370, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A significant positive correlation was also identified between SVF cell number and the duration until symptom improvement (ρ\u0026thinsp;=\u0026thinsp;0.219, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), suggesting that patients receiving higher numbers of SVF cells tended to report symptom improvement over a longer time period (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAssociations between K\u0026ndash;L grade and pain-related outcomes were generally weak (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Baseline K\u0026ndash;L grade demonstrated a weak but statistically significant positive correlation with baseline VAS score (ρ\u0026thinsp;=\u0026thinsp;0.151, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026), indicating higher baseline pain levels in patients with more advanced radiographic osteoarthritis. Similarly, final follow-up K\u0026ndash;L grade was weakly correlated with baseline VAS score (ρ\u0026thinsp;=\u0026thinsp;0.166, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014). However, neither baseline nor final follow-up K\u0026ndash;L grade showed significant correlations with final follow-up VAS score, the degree of pain improvement, or the duration until symptom improvement (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), suggesting that radiographic severity was not strongly associated with post-treatment pain outcomes following SVF injection.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelations between Pain Outcomes and SVF Number\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eSVF Number\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS rho\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.195\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal follow-up VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDifference between initial and final follow-up VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.370\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration until symptom improvement, days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cem\u003ea\u003c/em\u003e \u003c/sup\u003eCalculated using the Spearman rank-order test. VAS, visual analogue scale; S, Spearman; SVF, stromal vascular fraction.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelations between Pain Outcomes and K-L Grade at Baseline and at the Final Follow-up\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eK-L Grade\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eFinal Follow-up\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS rho\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS rho\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal follow-up VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDifference between initial and final follow-up VAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.885\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.990\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration until symptom improvement, days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.414\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cem\u003ea\u003c/em\u003e \u003c/sup\u003eCalculated using the Spearman rank-order test. VAS, visual analogue scale; S, Spearman; K-L, Kellgren-Lawrence.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe most notable finding of the present study is the rapid improvement in pain following intra-articular injection of autologous stromal vascular fraction (SVF), with patients reporting symptomatic relief at a mean of approximately 3 weeks after treatment. This early clinical response distinguishes our results from many previously published SVF studies and may be attributable, at least in part, to the relatively high SVF cell number administered in our cohort.\u003c/p\u003e \u003cp\u003ePrevious clinical studies and systematic reviews have consistently demonstrated that intra-articular SVF injection is safe and effective for reducing pain and improving function in patients with knee osteoarthritis; however, the onset of symptom relief has typically been reported at follow-up intervals of 1 to 3 months rather than within the first few weeks. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Several trials and reviews have described meaningful improvements in pain scores beginning at 4\u0026ndash;12 weeks after injection, highlighting substantial variability in the timing of clinical response across studies. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn a double-blind randomized self-controlled trial, Hong et al. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] reported that patients with Kellgren\u0026ndash;Lawrence (K\u0026ndash;L) grade II\u0026ndash;III knee osteoarthritis experienced significant improvements in VAS and WOMAC scores beginning at 1 month after SVF injection, with continued improvement at subsequent follow-up visits. Notably, the SVF preparations used in that study generally yielded approximately 1\u0026ndash;3 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e total SVF cells per knee, which is substantially lower than the SVF cell number administered in the present study. Similarly, Lapuente et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] demonstrated significant clinical improvement at 1-year follow-up, with pain relief occurring progressively over the first several postoperative months rather than within weeks after injection. These findings suggest that, in most prior studies, early pain improvement within the first few weeks was not a predominant feature of SVF therapy.\u003c/p\u003e \u003cp\u003eSystematic reviews further support these observations. Shanmugasundaram et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] analyzed 11 clinical studies of SVF therapy and reported that the earliest consistent improvements in pain were observed between 4 and 12 weeks after treatment, with most studies administering SVF cell numbers in the range of 10\u003csup\u003e6\u003c/sup\u003e to low 10\u003csup\u003e7\u003c/sup\u003e cells. Likewise, Goncharov et al. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] highlighted the substantial heterogeneity in SVF preparation protocols and cell yields, noting that few studies directly examined the relationship between injected SVF cell number and the timing of pain relief, with most clinical improvements reported at 1\u0026ndash;3 months after injection. A comparison of SVF cell dose and the timing of pain improvement across previously published studies and the present cohort is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of SVF Cell Number and Time to Pain Improvement Across Studies\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design / OA grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReported SVF cell number (per knee)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReported time to pain improvement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKey notes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHong et al., 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDouble-blind randomized self-controlled trial / K\u0026ndash;L II\u0026ndash;III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026asymp;\u0026thinsp;1\u0026ndash;3 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e total SVF cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFrom 1 month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVAS and WOMAC improvement reported at 1, 3, 6, and 12 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLapuente et al., 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort / moderate\u0026ndash;severe OA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLower SVF yield; exact number not standardized\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSeveral months; primary endpoint at 1 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFocus on immunomodulatory and long-term effects\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShanmugasundaram et al., 2021 (Systematic review)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 clinical studies / mixed OA grades\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTypically 10\u003csup\u003e6\u003c/sup\u003e to low 10\u003csup\u003e7\u003c/sup\u003e cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u0026ndash;12 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMarked heterogeneity in SVF preparation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGoncharov et al., 2023 (Systematic review)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 studies / knee OA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMostly within 10\u003csup\u003e6\u003c/sup\u003e\u0026ndash;10\u003csup\u003e7\u003c/sup\u003e cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u0026ndash;3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDose\u0026ndash;response relationship rarely analyzed\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYokota et al., 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParallel single-arm trials / K\u0026ndash;L II\u0026ndash;IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSVF dose lower than cultured ASC protocols\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEarlier than ASCs, but not within weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eASC superior for long-term outcomes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort / K\u0026ndash;L II\u0026ndash;IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.4 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e total SVF cells (\u0026asymp;\u0026thinsp;7.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e stromal cells)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.9\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5 days (\u0026asymp;\u0026thinsp;3 weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eShortest time to pain improvement among compared studies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003eSVF, stromal vascular fraction; ASC, adipose-derived stromal cell; OA, osteoarthritis; K\u0026ndash;L, Kellgren\u0026ndash;Lawrence; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn contrast to these prior reports, the present study employed a higher mean SVF cell dose of approximately 7.4 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e total SVF cells, including approximately 7.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e stromal cells, administered per knee, and demonstrated a significantly shorter time to perceived pain improvement, with patients reporting symptom relief at a mean of 18.9\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5 days (approximately 3 weeks) after treatment. Correlation analysis further revealed that higher SVF cell numbers were significantly associated with greater reductions in VAS scores, supporting a potential dose-dependent relationship between SVF cell number and pain relief.\u003c/p\u003e \u003cp\u003eImportantly, radiographic disease severity assessed using the K\u0026ndash;L grading system was not significantly associated with pain outcomes, including pain at final follow-up, the magnitude of pain improvement, or the time to perceived symptom relief (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This finding suggests that the observed pain reduction following SVF injection may occur independently of structural disease severity, as reflected by radiographic grading. Several previous studies have similarly reported a discordance between radiographic severity and clinical pain outcomes following SVF therapy, indicating that pain relief may precede or occur independently of structural cartilage repair. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eFrom a mechanistic perspective, accumulating evidence indicates that the primary early therapeutic effects of SVF are mediated through anti-inflammatory and paracrine mechanisms rather than direct structural regeneration of cartilage. SVF is a heterogeneous cell population comprising adipose-derived stromal cells, endothelial progenitor cells, pericytes, macrophages, and various immune cells. Experimental and translational studies have shown that SVF, particularly through its enrichment of M2-polarized macrophages, rapidly enhances the secretion of anti-inflammatory cytokines such as interleukin-10, interleukin-1 receptor antagonist, and transforming growth factor\u0026ndash;β, while suppressing pro-inflammatory mediators including interleukin-1β and tumor necrosis factor\u0026ndash;α. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eLapuente et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] further provided clinical and biochemical evidence supporting this mechanism by demonstrating significant reductions in pro-inflammatory cytokines and matrix metalloproteinases within the synovial fluid following SVF injection, accompanied by increases in anabolic and anti-inflammatory mediators. Importantly, these molecular changes occurred in parallel with clinical pain improvement, reinforcing the concept that symptom relief is driven primarily by immunomodulation rather than immediate cartilage regeneration.\u003c/p\u003e \u003cp\u003eClinical comparative studies further corroborate the predominance of paracrine effects in SVF therapy. Yokota et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] reported that although both SVF and cultured adipose-derived stromal cell injections significantly improved pain and function, SVF-treated knees exhibited earlier symptomatic improvement, whereas stromal cell therapy demonstrated more sustained long-term structural and functional benefits. Similarly, a recent systematic review focusing on K\u0026ndash;L grade II\u0026ndash;III osteoarthritis concluded that SVF therapy is characterized by rapid paracrine-driven pain reduction, while cartilage regeneration, when present, likely contributes to longer-term outcomes rather than early symptom improvement. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eFrom a clinical standpoint, the ability to achieve early pain relief is highly relevant. Rapid symptom improvement may enhance patient satisfaction, reduce reliance on analgesic medications, and facilitate earlier engagement in rehabilitation and daily activities. The early analgesic effect observed across a range of K\u0026ndash;L grades in the present study suggests that SVF therapy with an adequate cell dose may be broadly applicable in patients with knee osteoarthritis.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, its retrospective design and the absence of a control group limit the ability to draw definitive causal conclusions regarding the observed clinical improvements. Second, although a significant association between SVF cell number and pain reduction was identified, the optimal SVF cell dose required to maximize both early and long-term clinical benefits remains undefined. Third, radiographic outcomes were assessed using conventional grading systems, which may not fully capture subtle structural changes or biological remodeling within the joint. Finally, heterogeneity in patient characteristics and SVF preparation techniques may have influenced treatment response. Future prospective, randomized, dose-comparison studies with standardized SVF processing protocols and longer follow-up are warranted to address these limitations.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, intra-articular injection of autologous SVF resulted in rapid and clinically meaningful pain relief, with symptom improvement occurring within approximately 3 weeks after treatment. The lack of association between radiographic disease severity and pain outcomes, together with evidence from prior clinical and experimental studies, suggests that this early analgesic effect is predominantly mediated by the anti-inflammatory and paracrine actions of SVF, rather than by immediate structural cartilage regeneration. These findings highlight the potential of high-dose SVF therapy as an effective, biologically active, and broadly applicable treatment option for patients with knee osteoarthritis, particularly for achieving early symptomatic benefit.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Yonsei Sarang Hospital (YSSR IRB 2025-12-001). Written informed consent was obtained from all participants prior to enrollment.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003eWritten informed consent was obtained from all participants.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eClinical trial number\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo external funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eY.S.K. and Y.G.K. conceptualized the study. D.S.S. and Y.B.K. performed methodology. Y.B.K. conducted analysis. J.H.C. collected data. Y.S.K. drafted the manuscript. Y.B.K. and Y.G.K. revised it. All authors had given final approval of the version to be submitted and agreed on the journal to be published.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAvailable from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGoncharov EN, Koval OA, Nikolaevich Bezuglov E, Encarnacion Ramirez MJ, Engelgard M, Igorevich EI, Saporiti A, Valentinovich Kotenko K, Montemurro N. Stromal Vascular Fraction Therapy for Knee Osteoarthritis: A Systematic Review. 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J Orthop Surg Res. 2020;15(1):137. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13018-020-01664-z\u003c/span\u003e\u003cspan address=\"10.1186/s13018-020-01664-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Knee osteoarthritis, Stromal vascular fraction, Intra-articular injection, Pain relief, Dose–response relationship","lastPublishedDoi":"10.21203/rs.3.rs-8572223/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8572223/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIntra-articular injection of adipose-derived stromal vascular fraction (SVF) has emerged as a promising regenerative treatment for knee osteoarthritis (OA) because of its heterogeneous cellular composition and potent anti-inflammatory paracrine effects. However, the timing of pain relief and the influence of SVF cell dose on early clinical outcomes remain incompletely defined.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included 146 patients (217 knees) with Kellgren\u0026ndash;Lawrence (K\u0026ndash;L) grade II\u0026ndash;IV knee OA who underwent intra-articular injection of autologous SVF and completed a minimum follow-up of 1 year. Pain was assessed using the visual analog scale (VAS), and patients reported the time to perceived pain improvement after treatment. Radiographic severity was evaluated using the K\u0026ndash;L grading system. Correlation analyses were performed to assess associations between pain-related outcomes, SVF cell number, and radiographic severity.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eVAS scores improved significantly from baseline to the final follow-up (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Patients reported perceived pain improvement at a mean of 18.9\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5 days after SVF injection. The mean injected dose was 7.4 \u0026times; 10⁷ total SVF cells per knee, including approximately 7.0 \u0026times; 10⁶ stromal cells. Higher SVF cell numbers were significantly associated with greater pain improvement and lower VAS scores at final follow-up (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both). Radiographic severity was not significantly correlated with pain outcomes. No clinically relevant adverse events were observed.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIntra-articular injection of high-dose autologous SVF was associated with rapid and clinically meaningful pain relief, with symptom improvement occurring within approximately 3 weeks after treatment. The dose-dependent association and the lack of correlation with radiographic severity suggest that early pain relief is primarily mediated by the anti-inflammatory and paracrine effects of SVF rather than immediate structural cartilage regeneration.\u003c/p\u003e","manuscriptTitle":"Rapid pain relief after intra-articular injection of adipose-derived stromal vascular fraction in patients with knee osteoarthritis: a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-18 13:04:42","doi":"10.21203/rs.3.rs-8572223/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eae0c275-5334-4dc5-b2d7-485ecfd8dc3c","owner":[],"postedDate":"January 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T11:42:31+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-18 13:04:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8572223","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8572223","identity":"rs-8572223","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}