Osteoarthritis (OA), a chronic and degenerative joint disease, remains a challenge in treatment due to the lack of disease-modifying therapies. As a promising therapeutic agent, adipose-derived stem cells (ADSCs) have an effective anti-inflammatory and chondroprotective paracrine effect that can be enhanced by genetic modification. Unfortunately, direct cell delivery without matrix support often results in poor viability of therapeutic cells. Herein, a hydrogel implant approach that enabled intra-articular delivery of gene-engineered ADSCs was developed for improved therapeutic outcomes in a surgically induced rat OA model. An injectable extracellular matrix (ECM)-mimicking hydrogel was prepared as the carrier for cell delivery, providing a favorable microenvironment for ADSC spreading and proliferation. The ECM-mimicking hydrogel could reduce cell death during and post injection. Additionally, ADSCs were genetically modified to overexpress transforming growth factor-β1 (TGF-β1), one of the paracrine factors that exert an anti-inflammatory and pro-anabolic effect. The gene-engineered ADSCs overexpressing TGF-β1 (T-ADSCs) had an enhanced paracrine effect on OA-like chondrocytes, which effectively decreased the expression of tumor necrosis factor-alpha and increased the expression of collagen II and aggrecan. In a surgically induced rat OA model, intra-articular injection of the T-ADSC-loaded hydrogel markedly reduced cartilage degeneration, joint inflammation, and the loss of the subchondral bone. Taken together, this study provides a potential biomaterial strategy for enhanced OA treatment by delivering the gene-engineered ADSCs within an ECM-mimicking hydrogel.
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This content will become publicly available on January 24, 2025
Immunomodulatory Strategies for Cartilage Regeneration in Osteoarthritis
Osteoarthritis (OA) is the most prevalent musculoskeletal disorder and a leading cause of disability globally.
Although many efforts have been made to treat this condition, current tissue engineering (TE) and regenerative
medicine strategies fail to address the inflammatory tissue environment that leads to the rapid progression of
the disease and prevents cartilage tissue formation. First, this review addresses in detail the current antiinflammatory therapies for OA with a special emphasis on pharmacological approaches, gene therapy, and
mesenchymal stromal cell (MSC) intra-articular administration, and discusses the reasons behind the limited
clinical success of these approaches at enabling cartilage regeneration. Then, we analyze the state-of-the-art TE strategies and how they can be improved by incorporating immunomodulatory capabilities such as the optimization of biomaterial composition, porosity and geometry, and the loading of anti-inflammatory molecules
within an engineered structure. Finally, the review discusses the future directions for the new generation of TE
strategies for OA treatment, specifically focusing on the spatiotemporal modulation of anti-inflammatory agent
presentation to allow for tailored patient-specific therapies.
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- Award ID(s):
- 1944914
- NSF-PAR ID:
- 10488821
- Publisher / Repository:
- Mary Ann Liebert, Inc.
- Date Published:
- Journal Name:
- Tissue Engineering Part A
- ISSN:
- 1937-3341
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Objective To elucidate the role of decorin, a small leucine‐rich proteoglycan, in the degradation of cartilage matrix during the progression of post‐traumatic osteoarthritis (
OA ).Methods Three‐month–old decorin‐null (Dcn−/−) and inducible decorin‐knockout (Dcni
KO ) mice were subjected to surgical destabilization of the medial meniscus (DMM ) to induce post‐traumaticOA . TheOA phenotype that resulted was evaluated by assessing joint morphology and sulfated glycosaminoglycan (sGAG ) staining via histological analysis (n = 6 mice per group), surface collagen fibril nanostructure via scanning electron microscopy (n = 4 mice per group), tissue modulus via atomic force microscopy–nanoindentation (n = 5 or more mice per group) and subchondral bone structure via micro–computed tomography (n = 5 mice per group). Femoral head cartilage explants from wild‐type and Dcn−/−mice were stimulated with the inflammatory cytokine interleukin‐1β (IL ‐1β) in vitro (n = 6 mice per group). The resulting chondrocyte response toIL ‐1β and release ofsGAG s were quantified.Results In both Dcn−/−and Dcni
KO mice, the absence of decorin resulted in acceleratedsGAG loss and formation of highly aligned collagen fibrils on the cartilage surface relative to the control (P < 0.05). Also, Dcn−/−mice developed more salient osteophytes, illustrating more severeOA . In cartilage explants treated withIL ‐1β, loss of decorin did not alter the expression of either anabolic or catabolic genes. However, a greater proportion ofsGAG s was released to the media from Dcn−/−mouse explants, in both live and devitalized conditions (P < 0.05).Conclusion In post‐traumatic
OA , decorin delays the loss of fragmented aggrecan and fibrillation of cartilage surface, and thus, plays a protective role in ameliorating cartilage degeneration.
