Responsive Hydrogel-Based Drug Delivery Platform for Osteoarthritis Treatment

Abstract

Osteoarthritis (OA) is the most prevalent chronic joint disorder and is a major cause of disability among the elderly population. The degeneration and damage of articular cartilage associated with OA can result in a diminished range of motion in joints, subsequently impacting fundamental activities such as ambulation, standing, and grasping objects. In severe cases, it may culminate in disability. Traditional pharmacological treatments are often accompanied by various side effects, while invasive surgical procedures increase the risk of infection and thrombosis. Consequently, identifying alternative new methods for OA treatment remains a formidable challenge. With advancements in responsive hydrogel drug delivery platforms, an increasing number of strategies have emerged to enhance OA treatment protocols. Injectable response hydrogel drug delivery platforms show many advantages in treating OA, including improved biocompatibility, prolonged drug release duration, elevated drug loading capacity and enhanced sensitivity. This article reviews the recent progress of injectable responsive hydrogel drug delivery platform for OA treatment over the past few years. These innovative methodologies present new strategies and directions for future OA treatment while summarizing a series of challenges faced during the clinical transformation of injectable response hydrogel drug delivery platforms. Overall, injectable responsive hydrogel drug delivery platforms show great potential in treating OA, especially regarding improving drug retention time and stimulus-responsive release at the lesion sites. These innovative methods provide new hope for future OA treatment and point the way for clinical applications.

Keywords: drug delivery; injectable hydrogel; osteoarthritis; stimuli responsive.

Scheme 1

Responsive factors and their properties of hydrogels for OA treatment.

Figure 1

(a) Schematic illustration showing the injectable hydrogel of HA/PRP/BM fabricated via Schiff base reaction, and its synergetic treatment of OA owing to viscosupplementation, ROS elimination, inflammation relief, and cartilage repair promotion. (b) The cumulative release profile of BM from HA/BM hydrogel in PBS with different pH values. Depletion test of hydrogels for (c) hydrogen peroxide (H₂O₂), (d) hydroxyl radical (·OH), and (e) superoxide anion radical (O₂) (** p < 0.01 and *** p < 0.001) [26]. Copyright 2022 Elsevier.

Figure 2

(a) The synthesis of the itaconate (IA)-encapsulated zeolitic imidazolate framework-8 (IA-ZIF-8) nanoparticles. (b) The fabrication of IA-ZIF-8-loaded hydrogel microspheres (IA-ZIF-8@HMs) by one-step microfluidic technology under ultraviolet (UV) light. (c) The design of IA-ZIF-8@HMs for treating OA. (d) The results of cell viability about chondrocyte co-cultured with H₂O₂, H₂O₂ + ZIF-8, H₂O₂ + IA-ZIF-8, and H₂O₂ + IA-ZIF-8@HM. Enzyme-linked immunosorbent assay (ELISA) analyses of TNF-α (e) and IL-6 (f) concentration in cell supernatants (** p < 0.01, *** p < 0.001) [27]. Copyright 2023 Multidisciplinary Digital Publishing Institute.

Figure 3

(a) Schematic representation of the potential application of mPEG-TK-GLX@PVA-MMA to mitigate macrophage inflammation and ferroptosis. (b) Expression of pro-inflammatory genes evaluated by RT-qPCR (* p < 0.05 and ** p < 0.01) [28]. Copyright 2024 Elsevier.

Figure 4

(a) The fabrication of the KGN/Dex-TSPBA nanoparticles. (b) The fabrication of KGN/Dex-TSPBA@WHMs. (c) The mechanism of KGN/ Dex-TSPBA@WHMs in the treatment of OA. The levels of (d) TNF-α and (e) IL-6 secreted from ATDC5 cells after being treated with PBS, IL-1β, IL-1β+HM, IL-1β+TSPBA@WHMs, IL-1β+KGN/Dex-M@WHMs, and IL1β+KGN/Dex-TSPBA@WHMs. (f) Release behavior of KGN from free KGN, KGN/Dex-TSPBA, and KGN/Dex-TSPBA@ WHMs in PBS for 32 days. (g) Release behavior of Dex from free Dex, KGN/Dex-TSPBA, and KGN/Dex-TSPBA@WHMs in PBS for 32 days. (h) Release behavior of KGN from free KGN, KGN/Dex-TSPBA, and KGN/Dex-TSPBA@WHMs in PBS in the first 24 h. (i) Release behavior of Dex from free Dex, KGN/Dex-TSPBA, and KGN/Dex-TSPBA@WHMs in PBS in the first 24 h (** p < 0.01, *** p < 0.001) [29]. Copyright 2020 BioMed Central.

Figure 5

(a) The principle and production of anti-ageing Hydrogels@MVs/iMVs43. (b,c) SA-β-Gal staining and percentage of senescent cells after ageing induction and intervention with different factors. (d,e) Cell cycle analysis and percentage of proliferating cells after the same treatment using flow cytometry (* p < 0.05, *** p < 0.001, **** p < 0.0001) [30]. Copyright 2023 BioMed Central.

Figure 6

(a–c) Concentration of M1-secreted pro-inflammatory cytokines (including TNF-a, IL-1b, and IL-6) in the synovium tissues by ELISA. (d) Concentration of M2-secreted anti-inflammatory cytokines (IL-10) in the synovium tissues by ELISA. (e) Release profiles of rapamycin incorporated in the P-HA hydrogel (* p < 0.05, *** p < 0.001) [31]. Copyright 2023 Elsevier. (f) Hydrocortisone accumulated release-time for standard solution, base formulation, and formulations of MMH-T, MMH-C, MMH-S, and MMH-B [32]. Copyright 2023 Elsevier. (g) Schematic illustration of redox-active injectable hydrogel (RIG) system. Concentration of (h) tumor necrosis factor α (TNF-α) and (i) interleukin 1β (IL-1β) in the hind paw tissue of mice (* p < 0.05 as compared with control. # p < 0.05 as compared with RIG. ** p < 0.05 as compared with RIG@Carr.) [33]. Copyright 2013 Elsevier.

Figure 7

Gene-hydrogel microspheres for the treatment of OA. (a) Synthesis of G5-AHP and G5-AHP/miR-140. (b) Gene-hydrogel MSs. (c) MS@G5-AHP/miR140 was injected into the articular space to alleviate the progression of OA. (d) Endocytosis of G5-AHP/miR-140 polyplexes and the release of miR-140. (e–g) qRT-PCR analyses indicated the mRNA expression of COL2, MMP13 and Adamts5 in chondrocytes (** p < 0.01, *** p < 0.001.) [34]. Copyright 2022 nature.

Figure 8

(a) Schematic diagram of manufacturing ChsMA+CLX@Lipo@GelMA bilayer microspheres and the effect mechanism after intraarticular injection. The outer layer (GelMA) rapidly degrades in response to MMPs in the OA microenvironment, releasing CLX-loaded liposomes. The released CLX exerts an anti-inflammatory effect, and the inner core structure containing ChsMA microspheres is exposed and begins degrading, promoting the repair of OA cartilage that has undergone degenerative injury. (b–d) The mRNA expression levels of TNF-α, IL-6 and MMP-13 in IL-1β-treated chondrocytes co-cultured with ChsMA, CLX@Lipo@GelMA, and ChsMA+CLX@Lipo@ GelMA hydrogel microspheres for 24 h analyzed by qRT-PCR (*** p < 0.001, **** p < 0.0001, ns: represents no significance compared to the PBS and IL-1β groups) [35]. Copyright 2024 Elsevier.

Figure 9

(a) BI-4394 release from Gel@10 in the presence and absence of esterase (200 U mL⁻¹); (b) esterase dependent BI-4394 release from Gel@10. (c) Dosing pattern for the treatments; (d) quantification of standing position on their hindleg after treatment. (e) % Change in the knee thickness of rat after treatment (*** p ≤ 0.0001, ** p ≤ 0.01 and * p ≤ 0.05) [36]. Copyright 2024 Royal Society of Chemistry. Sustained release and enzyme-responsive release of zingerone from TGMS hydrogels encapsulated with (f) 5 mg/mL, (g) 10 mg/mL, and (h) 20 mg/mL of zingerone. For each panel, first 2 days release was plotted separately (right side panels) [37]. Copyright 2022 wiley.