Immunomodulatory biomaterials for osteoarthritis: Targeting inflammation and enhancing cartilage regeneration

Abstract

Osteoarthritis (OA) is a prevalent joint disorder characterized by progressive cartilage degradation, impaired mesenchymal stem cell (MSC) function, and chronic inflammation, ultimately leading to irreversible structural damage and functional impairment. Despite its high global burden, no regulatory agency has yet approved a disease-modifying therapy for OA, and effective interventions to halt or delay its progression remain a major challenge. Recent research highlights the pivotal role of the immune system in OA pathogenesis, with immunomodulatory biomaterials emerging as a promising strategy to simultaneously regulate inflammatory responses and promote tissue regeneration. These biomaterials, by leveraging their biocompatibility and immunoregulatory properties, offer a transformative alternative to conventional OA therapies, which predominantly focus on symptom management rather than targeting the underlying disease mechanisms. In this review, we comprehensively examine various immunomodulatory biomaterial strategies designed to mitigate OA progression. We first elucidate the immune landscape of OA, detailing the interplay between inflammation and disease pathophysiology. Next, we explore the latest advancements in immunomodulatory biomaterials, including nanoparticles (NPs), hydrogels, and scaffolds, highlighting their potential to reshape OA treatment. Finally, we discuss existing challenges and propose future directions for optimizing biomaterial-based immunotherapies to enhance OA management.

Keywords: Cartilage regeneration; Drug delivery; Immune response; Immunomodulatory biomaterials; Osteoarthritis; Responsive biomaterials.

Graphical abstract

Fig. 1

Pathophysiology and clinical therapies of OA. The immune cells involved in OA highlight M1 and M2 macrophages, with M1 promoting inflammation via Th1 activation and M2 exerting anti-inflammatory effects. Other immune cells, including DCs, NK cells, neutrophils, and Tregs, contribute to disease progression. Elevated levels of TNF-α, IL-1β, and IL-6 indicate an intensified inflammatory state in joint tissues. The treatment strategies of OA divide into two parts according to the clinical stages. Early-stage interventions include NSAIDs, glucocorticoids, and hyaluronic acid (HA) to reduce inflammation and improve joint function. In advanced cases, surgical options such as arthroscopic debridement, total joint replacement, microfracture surgery, and autologous chondrocyte implantation (ACI) address structural damage. The progression from pharmacological to surgical treatments reflects the disease's worsening nature and the need for stage-specific management strategies.

Fig. 2

The mechanism of common nano-drug delivery system. The drug-loaded nanoparticles can be combined with target cells by surface modification and other means, and the drug can be accurately delivered to the target cells. To achieve sustained drug release and to regulate drug release by pH change and oxidative stress imbalance response.

Fig. 3

Immunomodulation-based nanomaterials for OA therapy. (A) Schematic diagram of the preparation of conditioning NPs IgG/Bb@BRPL and their application in OA therapy. Copyright 2022, Elsevier [86]. (B) Cellular uptake of IgG/C6@BRPL in M0 and M1 macrophages. Fluorescence images showing the uptake characteristics of free C6, C6@BRPL, BSA/C6@BRPL and IgG/C6@BRPL in (a) M0 and (c) M1. Results of (b) M0 and (d) M1 were quantified using Image J (n = 3). Copyright 2022, Elsevier [86]. (C) Chondrocytes 6 h after transfection with miR-330-3p@DiO-LNP and KGN@DiI-LNP, miR-330-3p@DiO-FA-LNP and KGN@DiI-W-LNP and representative images of macrophage uptake. Copyright 2024, Elsevier [88]. (D) Schematic of KGN@HMZC@HA nano-enzymes preparation with the specific mechanism of microenvironmental remodeling for the treatment of OA. Copyright 2024, Elsevier [89].

Fig. 4

Immunomodulation-based hydrogel for OA therapy. (A) Schematic diagram of piezoelectric hydrogel used for OA patients. Copyright 2023, NATURE PORTFOLIO [154]. (B) Stem cell migration study assessed by scratch test, which was accomplished by filling the wound bed with Piezo, Non-Piezo, and collagen hydrogels. Copyright 2023, NATURE PORTFOLIO [154]. (C) Preparation of multifunctional PCCGA hydrogel for OA relief and cartilage protection. Copyright 2024, WILEY [159].

Fig. 5

Immunomodulation-based hydrogels for OA therapy. (A) Schematic diagram of hydrogel design and application for promoting OA-induced cartilage defect repair. Copyright 2023, American Chemical Society [251]. (B) Schematic Illustration of Preparation and Application of the Hydrogel for Treatment of Cartilage Degradation Induced by Meniscal Tears. Copyright 2023 American Chemical Society [252]. (C) ATR-FTIR spectra of the free hydrogel, meloxicam loaded nanoparticles, meloxicam, N2 and S2 hydrogels (a) the scanning range 4000-600 cm⁻¹, and (b) the enlarged overlay range 1600-600 cm⁻¹. Copyright 2019, Elsevier [253]. (D) SB permeation of SCT-HA in vivo. (a) Whole joint, meniscus, cartilage, SB, and bone marrow cavities of mouse knee joint sections were visualized by laser scanning confocal observation and 3D surface reconstruction after CQ-HA and SCT-HA were injected into the joint cavity. (b) Fluorescence intensity analysis of CQ-HA and SCT-HA penetrating the meniscus, cartilage, SB, and bone marrow cavities of mouse knee joints. Copyright 2024, John Wiley and Sons [254].

Fig. 6

The classification, utilization and therapeutic effects of immumodulatory scaffolds for OA. The immumodulatory scaffolds are divided into four groups, including natural polymer scaffolds, synthetic polymer scaffolds, bioceramic scaffolds and metal-based scaffolds. They play anti-inflammatory and cartilage repair functions through the properties described in this picture to promote OA prognosis.

Fig. 7

Immunomodulation-based scaffolds for OA therapy. (A) Schematic procedure for the synthesis of MIP-modified magnetic GO and its application for the cyclic extraction of atropine. Copyright 2019, Elsevier [285]. (B) Schematic illustration of 3D-printed Co-ClAP/PLGA scaffolds for the treatment of osteochondral defects containing excess ROS. Copyright 2023, John Wiley and Sons [286]. (C) Scaffolds with porous sulfonated PEEK scaffolds for macrophage polarization modulation: immunofluorescence staining of macrophages (RAW264.7) cultured with PEEK, SPK-15, SPK-30, and SPK-60 for 4 days. Copyright 2023, Elsevier [287]. (D) Confocal microscopy imaging of internalized releases from PLA-Exo scaffolds into pro-inflammatory macrophages. Exo. Cells were stained with DAPI (blue) and examined by confocal laser scanning microscopy. Copyright 2023, EMC [288]. (E) Mechanisms by which DNA-Col promotes Treg differentiation through the TLR4-p38-PGC-1α pathway. By using the TLR4 inhibitor TAK-242, the investigators found that the promotion of PGC-1α expression and p38 phosphorylation by DNA-Col was attenuated, suggesting that DNA-Col may regulate T-cell metabolism and differentiation by activating TLR4. Copyright 2023, Elsevier (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)