Research ArticleExperimental Studies
Open Access

The Protective Effect of Decellularized Extracellular Matrix in Osteoarthritis: An In Vitro and In Vivo Study in Rat Model

SAKYENG SHIN and JAE YEON LEE
In Vivo January 2026, 40 (1) 274-284; DOI: https://doi.org/10.21873/invivo.14190

Abstract

Background/Aim: Osteoarthritis (OA) is a degenerative joint disease affecting both humans and companion animals, characterized by progressive cartilage destruction, inflammation, and functional impairment. Current therapies provide mainly symptomatic relief, emphasizing the need for regenerative strategies. Decellularized extracellular matrix (dECM) hydrogels preserve native biochemical cues and biocompatibility, making them potential candidates for cartilage protection and regeneration. This study aimed to evaluate the biocompatibility, anti-inflammatory activity, and chondroprotective potential of meniscus-derived dECM (Meni-dECM) hydrogel.

Materials and Methods: Meniscus tissue was decellularized and processed into hydrogel form. In vitro cytocompatibility and chondrogenic potential were assessed using stem cells cultured within the hydrogel. For in vivo evaluation, OA was induced in rats by intra-articular monosodium iodoacetate (MIA) injection. The therapeutic efficacy of intra-articularly injected Meni-dECM hydrogel was compared with control using gross joint assessment, cytokine analysis, and histological evaluation.

Results: In vitro assays confirmed excellent cell viability, proliferation, and upregulation of chondrogenic gene expression within the Meni-dECM hydrogel. In vivo, Meni-dECM-treated rats exhibited significantly reduced joint swelling, lower serum levels of IL-1β, IL-6, and TNF-α, and improved cartilage preservation compared with control. Histological analysis revealed decreased synovial hyperplasia, reduced inflammatory infiltration, and enhanced proteoglycan retention in Meni-dECM-treated joints.

Conclusion: Meni-dECM hydrogels demonstrated protective effects against OA progression by modulating inflammation and preserving cartilage architecture. These findings support Meni-dECM hydrogel as a promising injectable biomaterial for OA management in both veterinary and translational medicine. Further studies are warranted to confirm long-term stability, elucidate molecular mechanisms, and evaluate clinical feasibility.

Keywords:

Introduction

Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive deterioration of articular cartilage, leading to chronic pain and impaired mobility. It has a high prevalence not only in humans but also in various veterinary patients, including companion animals. OA is particularly common in elderly dogs and cats, and the resulting decline in quality of life is a major concern for both pet owners and clinical veterinarians (1). To date, most treatments for osteoarthritis have focused on symptomatic relief, with limited therapeutic options available to inhibit disease progression or promote cartilage regeneration (2).

Recent advancements in tissue engineering and biomaterials have highlighted the potential use of hydrogels as novel therapeutic strategies for cartilage regeneration (3-6). Hydrogels possess high water content and tissue-friendly physical properties, making them suitable for a wide range of biomedical applications, including drug delivery systems, cell scaffolds, and tissue regeneration platforms. In particular, decellularized extracellular matrix-derived hydrogels (dECM hydrogels) are fabricated by decellularizing native tissues and processing them into a gel form (7). These hydrogels retain the biochemical components and biocompatibility of the original tissue, offering unique advantages for regenerative applications (3, 8, 9).

In the field of veterinary medicine, the development of osteoarthritis treatments based on dECM hydrogels is still in its early stages. Further research is needed to explore regenerative medicine approaches that can be applied to actual veterinary patients. This study aimed to investigate the physicochemical properties and biological efficacy of the Meni-dECM hydrogels in veterinary models, including companion animals, and to evaluate their potential as therapeutic agents for osteoarthritis. It aimed to demonstrate the practical applicability of hydrogel-based therapeutics from a veterinary perspective by: 1) fabricating and characterizing tissue-derived hydrogels, 2) analyzing cellular responses in chondrocytes and osteoarthritis models, and (3) verifying their anti-inflammatory and cartilage-regenerative effects.

Materials and Methods

Preparation of meniscus-derived extracellular matrix (Meni-dECM). Meniscal tissue was harvested from the posterior knee joints of slaughtered pigs (7-month-old males). For preparation of the Meni-dECM, the meniscal samples were rinsed in phosphate-buffered saline (PBS) and cut into small pieces approximately 1-2 mm3 in size. The tissue fragments were treated in 0.01 M acetic acid solution (pH 2) at 4°C for 48 h, followed by a freeze-thaw cycle consisting of freezing at −80°C for 24 h and thawing at room temperature for 4 h.

Subsequently, the samples underwent decellularization by stirring in 2% sodium dodecyl sulfate (SDS) and 10 mM Tris at 25 °C for three cycles, each lasting 24 h. This was followed by treatment with 0.1% peracetic acid for 3 h. The samples were then washed by stirring for 12 h in sterile water and PBS containing aprotinin. The decellularized tissue was freeze-dried to obtain sponge-like Meni-dECM. The resulting material was digested in a solution containing 0.1% pepsin in 0.01 M hydrochloric acid (HCl, pH 2) at a concentration of 50 mg/ml, under stirring at 25°C for 12 h to produce the Meni-dECM digest. The digested Meni-dECM was further treated with 200 U/ml DNase and 50 U/ml RNase (Sigma Aldrich, Saint Louis, MO, USA) at 37°C for 24 h, followed by two 1-min washes with PBS.

Prior to use, the pH of the Meni-dECM solution was neutralized using 0.5 mol/l sodium hydroxide (NaOH), and the concentration was adjusted to 3 mg/ml using 1×PBS. The final Meni-dECM solution was stored at 4°C until further use. To quantify the growth factors present in Meni-dECM hydrogels, we employed the DuoSet® ELISA kit (R&D Systems, Bio-Techne, Minneapolis, MN, USA) following the manufacturer’s instructions.

Cell viability and cytotoxicity assessment. Cell viability was evaluated using a cytotoxicity assay involving test frames and the Meni-dECM hydrogels. Cells (C57BL/6 Mouse Bone Marrow Mesenchymal Stem Cells, MUBMX-01001, Cyagen, Santa Clara, CA, USA) were seeded at a density of 5×104 cells per well into two wells of a 6-well plate. One well was used for live/dead staining, and the other for a Cell Counting Kit-8 (CCK-8) assay. Simultaneously, twelve 0.5 μl Meni-dECM hydrogel samples were prepared in a 96-well plate and crosslinked at 37°C for 30 min. All samples were placed into cell culture inserts within the 6-well plate and incubated at 37°C in a humidified atmosphere containing 5% CO2 and air. For the CCK-8 assay, 10% (v/v) CCK-8 solution was added to each well and incubated for 4 h. The absorbance of each sample was measured at a wavelength of 450 nm. For the live/dead cell viability assay, cells were stained according to the manufacturer’s protocol using the Live/Dead Cell Viability Assay Kit (Invitrogen Life Technologies, Waltham, MA, USA).

Establishment of OA model and intra-articular injection treatment. As part of the in vivo study, twenty-two adult male Sprague-Dawley rats weighing 260±10 g were used. The rats were randomly assigned to three groups: normal control group without OA induction (n=2), OA induction without treatment (n=10), OA induction with the Meni-dECM hydrogel (n=10). The animals were acclimatized to the facility environment for seven days prior to the experiment. All animal procedures were approved by the Institutional Animal Care and Use Committee of Daegu Haany University (DHU2021-033), in accordance with the guidelines for the care and use of laboratory animals for biomedical research.

To establish the osteoarthritis (OA) model, rats were anesthetized via intraperitoneal injection with a 1:1 mixture of tiletamine and zolazepam (Zoletil 50; Virbac, Carros, France) and xylazine (Rompun; Bayer, Leverkusen, Germany), at doses of 30 mg/kg Zoletil and 10 mg/kg Rompun. For the chemically induced OA model, monosodium iodoacetate (MIA; Bioworld, Dublin, OH, USA) was dissolved in saline at a concentration of 100 μg/μl, filtered through a syringe filter, and injected into the right knee joint cavity at a volume of 100 μl using a 26-gauge needle. Four weeks after MIA injection, OA development was confirmed, and rats in the experimental group received 200 μl of Meni-dECM injected into the joint cavity, while the control group received 200 μl of saline. Eight weeks post-treatment, the rats were euthanized, and histopathological analysis of the joint tissues was performed.

Joint inflammation analysis and serum cytokine profiling. Joint Inflammation Analysis: MIA was injected into the rat knee joint to induce osteoarthritis. Joint swelling was measured at baseline (day 0) and subsequently on days 3, 7, 14, 28, and 36 post-treatment using digital calipers. Changes in joint diameter were compared between the control and Meni-dECM hydrogel-treatment groups.

Serum Cytokine Profiling: Blood samples were collected at 1, 2, 4, and 8 weeks post-treatment. Serum levels of IL-1β, IL-6, and TNF-α were quantified using commercial ELISA kits (R&D Systems, Bio-Techne, Minneapolis, MN, USA) according to the manufacturer’s protocols.

Histological analysis. The knee joints were removed from mice and subsequently fixed in 10% EDTA solution for 6 weeks after 4% paraformaldehyde fixation for 24 h. Next, with the specimens dehydrated by a series of alcohol gradients and finally embedded in paraffin wax blocks. The embedded tissues were sectioned sagittally at 5 μm thickness through the femoral condyle. Femoral and tibial slides were stained with H&E (Solarbio, Beijing, PR China) and Safranin-O/Fast Green (Solarbio). Morphological evaluation of the meniscal tissues was performed using a double-blinded method under a microscope (Olympus, Tokyo, Japan).

Statistical analysis. All statistical analyses of the data (mean±standard deviation) were performed using SPSS version 64.0 (SPSS Inc., Chicago, IL, USA). Comparisons between the control and treatment groups were conducted using one-way analysis of variance (ANOVA) followed by Tukey’s HSD post-hoc test. A p-value of less than 0.05 was considered statistically significant. Sample sizes are indicated in the figure legends.

Results

DNA/GAG analysis, growth factor quantification, and gelation assays. We evaluated Meni-dECM using DNA and glycosaminoglycan (GAG) quantification, live/dead assay, cell proliferation assay (CCK assay), real-time PCR, and immunofluorescence staining. Following the decellularization process, the residual DNA and GAG contents of the Meni-dECM were analyzed. The DNA content of the decellularized tissue was reduced to approximately 26.2% of that in the native meniscus, while the GAG content was decreased to 25.2% (Figure 1A). For gelation analysis, Meni-dECM was solubilized in a pepsin/0.5 M acetic acid solution, followed by a neutralization process. The pre-gel solution was incubated at 37°C to induce gelation. As a result, Meni-dECM successfully formed a stable hydrogel within 40 min of incubation (Figure 1B).

Figure 1.
Figure 1.

Quantification of biochemical components and gelation behavior of Meni-dECM. (A) Residual DNA and glycosaminoglycan (GAG) content in native meniscus versus decellularized tissue, confirming effective decellularization. (B) Representative images demonstrating temperature-induced gelation of solubilized Meni-dECM at 37°C. Data are presented as mean±SD (n=3) (*p<0.05 versus native).

The concentrations of selected growth factors were measured in both native meniscal tissue and Meni-dECM. As summarized in Table I, all tested growth factors were present at substantially higher levels in native tissue compared with Meni-dECM, reflecting the expected reduction following the decellularization process. Specifically, basic fibroblast growth factor (bFGF) decreased from 52.5 pg/mg in native tissue to 8.1 pg/mg in Meni-dECM. Bone morphogenetic protein 5 (BMP-5) and BMP-7 showed marked decreases from 512.6 to 140.1 pg/mg and from 100.4 to 21.2 pg/mg, respectively. Fibroblast growth factor 4 (FGF-4) was reduced from 200.6 to 53.9 pg/mg, while fibroblast growth factor 7 (FGF-7) decreased from 64.4 to 16.7 pg/mg.

View this table:
Table I.

Growth factor quantification.

Cell viability and cytotoxicity assessment. To evaluate the cytocompatibility of Meni-dECM, a live/dead assay was performed (Figure 2A). The results demonstrated high cell viability, indicating that the hydrogel scaffold exerted no apparent cytotoxic effects. Cell proliferation was further assessed using the CCK assay (Figure 2B), which revealed a time-dependent increase in cell number, confirming that Meni-dECM provided a supportive microenvironment for cell growth. Gene expression analysis using real-time PCR revealed upregulation of fibrocartilaginous markers in cells cultured within the Meni-dECM hydrogel (Figure 2C).

Figure 2.
Figure 2.

In vitro biocompatibility and chondrogenic response of stem cells cultured with Meni-dECM. (A) Live/Dead fluorescence staining showing high cell viability at days 1, 4, 7, and 14. (B) Cell proliferation assessed by CCK-8 assay at days 7 and 14 demonstrating time-dependent growth (*p<0.05 versus day 1). (C) Relative expression of chondrogenic markers analyzed via RT-PCR at days 7 and 14. Results are shown as mean±SD (n = 3) (*p<0.05 versus collagen).

Effect of Meni-dECM hydrogels on cartilage damage in rat osteoarthritis model. After four weeks of MIA injection, the rats were divided into two groups: control [phosphate-buffered saline (PBS)] and the Meni-dECM Hydrogel treatment.

Joint inflammation. Joint swelling analysis on day 3 after MIA injection showed a significant increase in joint diameter compared today-0 groups (before MIA injection), indicating synovitis of the knee joint. No significant difference was observed in the groups on day 3 post treatment. On days 7, 14, 28 and 36 post treatments, knee swelling in the Meni-dECM Hydrogel group was lower compared to control group (Figure 3).

Figure 3.
Figure 3.

Joint swelling analysis. Changes in knee joint diameter measured on days 3, 7, 14, 28, and 36 after treatment. Meni-dECM-treated rats exhibited significantly reduced swelling at later time points compared to untreated controls. Data are expressed as mean±SD (n=10 per OA group; p<0.05 versus control).

Serum cytokine profiling. Overall, cytokine profiling revealed that the control group maintained persistently elevated levels of IL-1β, IL-6, and TNF-α, reflecting sustained systemic inflammation associated with osteoarthritis progression (Figure 4). Conversely, the Meni-dECM-treatment group consistently exhibited significantly lower cytokine expression, with reductions ranging from 3-fold (TNF-α, IL-1β) to nearly 7-fold (IL-6) (Figure 4). These findings indicate that Meni-dECM exerts a potent immunomodulatory effect, attenuating pro-inflammatory cytokine signaling in vivo and thereby establishing a biochemical environment more conducive to cartilage protection and regeneration.

Figure 4.
Figure 4.

Serum cytokine levels during osteoarthritis progression. Quantification of IL-1β, IL-6, and TNF-α at weeks 1, 2, 4, and 8 post-treatment. Meni-dECM hydrogel significantly reduced systemic pro-inflammatory cytokines compared with untreated controls. Data are shown as mean±SD (n=10) (*p<0.05 versus control).

Histological analysis. In the control group, sections obtained after MIA injection revealed marked synovial hyperplasia, inflammatory cell infiltration, and structural disorganization of the articular cartilage. Safranin-O/Fast Green staining demonstrated a progressive loss of proteoglycan content, as indicated by the diminished red staining intensity within the cartilage matrix, along with surface fibrillation and erosion of the articular layer. These degenerative changes became more evident at later time points (Figure 5). In contrast, the Meni-dECM hydrogel-treatment group exhibited notably reduced pathological alterations. Hematoxylin and Eosin (H&E) staining showed decreased synovial proliferation and reduced inflammatory infiltration compared to controls. Moreover, Safranin-O/Fast Green staining demonstrated better preservation of cartilage matrix integrity, with stronger Safranin-O positivity indicating higher proteoglycan retention. Histopathological analysis demonstrated that the Meni-dECM hydrogel-treatment group exhibited markedly better preservation of the articular cartilage architecture, with smoother cartilage surfaces, minimal chondrocyte clustering, and attenuated extracellular matrix degradation, in contrast to the pronounced degenerative changes observed in the control group.

Figure 5.
Figure 5.

Gross appearances of articular surface and histological analysis. Normal control: without osteoarthritis induction, Control (OA only): Osteoarthritis induced group without treatment, OA+Meni-dECM: Osteoarthritis induced group with the Meni-dECM treatment. H & E and Safranin-O/fast green stain, ×40. scale bar 200 μm. Cartilage matrix loss and microfracture (fibrocartilaginous) were observed (arrows) in the Control (OA only) group. Although partial cartilage matrix loss was noted, overall bone remodeling with evidence of osseous repair (stars) was observed in the OA + Meni-dECM group.

Overall, histological analysis confirmed that Meni-dECM hydrogel treatment mitigated synovial inflammation and cartilage degeneration, consistent with the reductions in joint swelling and systemic pro-inflammatory cytokines observed in the biochemical assays.

Discussion

The present study demonstrated that Meni-dECM hydrogels exerted protective effects against OA progression in a rat model induced by MIA injection. Three major findings support the therapeutic potential of Meni-dECM: 1) reduced joint swelling at later time points, 2) significant suppression of systemic pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and 3) preservation of cartilage structure and matrix integrity observed in histological analyses.

Joint swelling analysis revealed that both groups exhibited synovial inflammation on day 3 after MIA injection, indicating successful induction of OA pathology. However, from day 7 onward, the Meni-dECM-treatment group showed significantly lower knee swelling compared to controls. This finding suggests that Meni-dECM hydrogels facilitated the resolution of acute synovitis and limited chronic inflammatory progression within the joint. These results are consistent with previous reports that ECM-derived scaffolds can attenuate inflammatory cascades by modulating macrophage polarization and synovial fibroblast activity (10-12). Similarly, Turner et al. demonstrated that dECM-based biomaterials reduced inflammatory joint swelling in a murine arthritis model, highlighting their potential as local immunomodulatory agents (13).

Serum cytokine profiling further supported the immunomodulatory effects of the Meni-dECM. In the control group, IL-1β, IL-6, and TNF-α levels remained persistently elevated, reflecting systemic inflammation associated with OA. In contrast, the Meni-dECM group exhibited consistently lower cytokine concentrations across all time points, with reductions of approximately 3-7 fold. This pattern aligns with previous findings that IL-1β and TNF-α drive chondrocyte catabolism through NF-κB-mediated signaling (12, 14), while IL-6 contributes to proteoglycan degradation and cartilage erosion (15). The observed suppression of these mediators in the Meni-dECM group therefore provides a plausible mechanistic explanation for the cartilage protection observed histologically. Importantly, similar cytokine attenuation has been reported in ECM hydrogel therapies for myocardial infarction and liver injury (16, 17), suggesting that dECM exerts systemic anti-inflammatory actions irrespective of tissue origin.

Histological evaluation reinforced the biochemical findings. Control animals exhibited classical OA-associated degenerative features, including cartilage erosion, proteoglycan depletion, and inflammatory infiltration. Conversely, the Meni-dECM-treatment group maintained relatively intact cartilage architecture, with stronger Safranin-O staining and reduced synovitis. These results are in line with previous studies demonstrating that dECM scaffolds preserve chondrocyte phenotype and enhance proteoglycan retention in osteochondral defects (3, 18). Furthermore, the presence of bioactive ECM components such as glycosaminoglycans and collagen fragments may have contributed to maintaining cartilage homeostasis, consistent with reports that ECM-derived signals support chondrocyte viability and matrix synthesis (18, 19).

The therapeutic benefits of dECM hydrogels may arise from multiple mechanisms. First, bioactive components of ECM are known to modulate immune cell responses, particularly by shifting macrophages from a pro-inflammatory M1 phenotype to a reparative M2 phenotype (11, 20, 21). Second, ECM degradation products have been reported to act as damage-associated molecular patterns (DAMPs) with anti-inflammatory potential, reducing cytokine release (22). Third, the hydrogel form of dECM may provide a structural microenvironment that supports cartilage tissue integrity by stabilizing local mechanical stresses and promoting chondroprotective cell-matrix interactions (13, 14, 22). The results of growth factor levels in this study demonstrate that although the decellularization procedure effectively diminishes the overall content of growth factors, measurable amounts of bioactive molecules are retained within the dECM scaffold. This residual presence may contribute to the biological activity of the matrix and could play a role in supporting cell adhesion, proliferation, and tissue regeneration.

From a translational standpoint, the dual ability of dECM to suppress inflammation and preserve cartilage suggests that it may serve as an injectable, minimally invasive therapeutic for early to moderate OA (23). Compared to conventional pharmacological interventions such as nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroid injections, which primarily alleviate symptoms (24), dECM offers a biomimetic strategy that targets both the inflammatory and structural aspects of OA pathology. This dual action may provide longer-term benefits in slowing disease progression, potentially reducing the need for surgical interventions such as joint replacement.

Despite these promising findings, the present study has several limitations. First, the OA model was induced chemically via MIA injection, which may not fully capture the multifactorial etiology of human OA, including biomechanical and metabolic factors (25). Second, the study focused on outcomes up to 8 weeks; long-term regenerative capacity and durability of the Meni-dECM treatment remain to be determined. Third, molecular mechanisms such as macrophage polarization, NF-κB signaling inhibition, and growth factor activation were not directly assessed. Future work should employ transcriptomic profiling, immunohistochemical analyses, and biomechanical testing to delineate the cellular pathways involved in dECM-mediated protection.

Conclusion

The Meni-dECM hydrogels demonstrated protective effects against OA progression by modulating inflammation and preserving cartilage architecture. These findings support Meni-dECM hydrogel as a promising injectable biomaterial for OA management in both veterinary and translational medicine. Further studies are warranted to confirm long-term stability, elucidate molecular mechanisms, and evaluate clinical feasibility.

Acknowledgements

The authors would like to express sincere gratitude to the technical staff of the participating institutions, whose contributions were indispensable to the collection of animal experimental data.

Footnotes

  • Authors’ Contributions

    All authors contributed to the study conception and design. Sakyeng Shin and Jae Yeon Lee were responsible for performing material preparation, data collection, and data analysis. Sakyeng Shin wrote the first draft of the manuscript. Jae Yeon Lee contributed to the study methodology, secured funding acquisition, supervised the overall research process, and was responsible for writing, reviewing, and editing the manuscript. All Authors provided feedback on previous versions of the manuscript. All Authors have read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest related to this work.

  • Funding

    This work was supported by a research grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2020R1A2C2009127) and was supported by a grant from Daegu Haany University Kylin Foundation in 2024.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received October 11, 2025.
  • Revision received October 29, 2025.
  • Accepted November 3, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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The Protective Effect of Decellularized Extracellular Matrix in Osteoarthritis: An In Vitro and In Vivo Study in Rat Model
SAKYENG SHIN, JAE YEON LEE
In Vivo Jan 2026, 40 (1) 274-284; DOI: 10.21873/invivo.14190
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