Injectable Hydrogel Therapy for Osteoarthritis and Cartilage Repair

Osteoarthritis (OA) remains one of the most challenging degenerative joint diseases, characterized by cartilage breakdown and abnormal subchondral bone formation. Current treatments primarily offer symptomatic relief without addressing the underlying pathology. Our recent study introduces a novel therapeutic approach using a sclerostin-inspired short peptide (SC-3) delivered through an injectable hydrogel system, designed to restore joint homeostasis and regenerate cartilage.

The Science Behind SC-3

Sclerostin, a natural inhibitor of Wnt signaling, plays a protective role in joint health by preventing excessive bone formation and preserving cartilage integrity. Mimicking this function, SC-3 was engineered from sclerostin’s loop 3 region to inhibit Wnt signaling and promote chondrogenic differentiation. Preclinical studies confirmed SC-3’s ability to suppress osteoblast activity while enhancing cartilage matrix synthesis, making it a promising candidate for OA therapy.

Why Hydrogel Delivery?

While weekly intra-articular injections of SC-3 demonstrated significant efficacy in reducing OA progression, frequent dosing poses practical challenges for patient compliance. To overcome this, we developed a pre-formed, injectable hydrogel system capable of sustained peptide release, reducing the need for repeated interventions.

Design and Optimization of the Hydrogel

The hydrogel formulation (SC-3-F) was created using covalent crosslinking between hyaluronic acid (HA) and gelatin (Ge) via EDC/NHS chemistry. Among six tested formulations, B-F-5 emerged as the optimal candidate due to its superior viscoelastic properties, injectability, and thermal stability. Rheological analysis confirmed its shear-thinning behavior, ensuring smooth injection, while FTIR spectroscopy validated successful crosslinking.

Thermal analysis revealed a glass transition temperature of 143°C and degradation onset at 180°C, which increased to 200°C upon SC-3 incorporation, indicating enhanced stability. These properties collectively ensure that SC-3-F is robust enough for intra-articular delivery while maintaining biocompatibility.

Sustained Release for Long-Term Efficacy

In vitro release studies using rhodamine B as a model drug demonstrated controlled release over 25 days, with RF-5 and RF-6 formulations achieving cumulative releases of approximately 57% and 53%, respectively. This sustained release profile predicts therapeutic peptide availability for up to eight weeks, matching the efficacy of multiple weekly injections with a single administration.

Preclinical Validation in OA Model

Using the anterior cruciate ligament transection (ACLT) rat model, we compared the effects of weekly SC-3 injections and a single SC-3-F hydrogel injection. Both approaches significantly reduced OA severity, as evidenced by improved OARSI scores, preserved cartilage integrity (Safranin-O staining), and absence of osteophyte formation in µCT scans. Furthermore, SC-3-F normalized epiphyseal bone volume and trabecular thickness, effectively mitigating pathological subchondral bone remodeling.

Discussion: A Paradigm Shift in OA Management

Our findings underscore the potential of SC-3 as a disease-modifying agent for OA. By combining sclerostin-mimetic activity with hydrogel-based sustained delivery, this approach addresses two critical challenges: halting disease progression and improving patient adherence. Unlike conventional therapies, SC-3 not only alleviates symptoms but also restores cartilage and prevents aberrant bone formation.

The hydrogel system offers additional advantages, including biocompatibility, injectability, and customizable release kinetics. This innovation could pave the way for next-generation OA treatments that are minimally invasive, long-acting, and tailored to patient needs.

Future Perspectives

While preclinical results are promising, clinical translation will require further studies on long-term safety, pharmacokinetics, and dose optimization. Exploring SC-3’s potential in early-stage OA and inflammatory arthritis models could broaden its therapeutic scope. Additionally, integrating imaging and biomarker-based monitoring will enhance precision in treatment delivery.

Disclaimer: This article was originally authored by researchers from NanoBio Research Lab, collaborating with other labs and institutes. The original article was published in Biomedicine & Pharmacotherapy

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