Biomaterial-engineered intra-articular drug delivery systems for osteoarthritis therapy

Abstract

Osteoarthritis (OA) is a progressive and degenerative disease, which is no longer confined to the elderly. So far, current treatments are limited to symptom relief, and no valid OA disease-modifying drugs are available. Additionally, OA relative joint is challenging for drug delivery, since the drugs experience rapid clearance in joint, showing a poor bioavailability. Existing therapeutic drugs, like non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, are not conducive for long-term use due to adverse effects. Though supplementations, including chondroitin sulfate and glucosamine, have shown beneficial effects on joint tissues in OA, their therapeutic use is still debatable. New emerging agents, like Kartogenin (KGN) and Interleukin-1 receptor antagonist (IL-1 ra), without a proper formulation, still will not work. Therefore, it is urgent to establish a suitable and efficient drug delivery system for OA therapy. In this review, we pay attention to various types of drug delivery systems and potential therapeutic drugs that may escalate OA treatments.

Keywords: Drug delivery system; delayed release; nanomedicine; osteoarthritis; retention time.

Figure 1.

Introduction of OA. (A) Current OA treatment, including surgery, drugs, diet, patient education, and exercise. (B) Normal parasagittal section of the knee. (C) Schematic illustration of osteoarthritis. The pathobiology of OA and potential occurring sites in human body. Compared to (B), it demonstrates that OA is a disease that affects the entire joint structure, including the articular cartilage, synovium, subchondral bone, joint capsule, and other components of the joint.

Figure 2.

Ex vivo cartilage retention studies for PLGA NPs, indicating the interaction between NPs and cartilage. (A) Histological sections for (i) health cartilage and (ii) enzymatically digested OA cartilage. (B) Cytotoxicity of PLGA NPs to the cartilage (n = 6). (C) Quantified analysis of NPs’ retained in explant cartilage after incubation (n = 5). (D) Cross section of health and OA sample after incubated with NPs observed with a fluorescence microscopy (Scale bar = 100 µm). α, p < 0.05, β, p < .01 representing the significance between saline and synovial fluid treatments. Reprinted with permission from Brown et al. (2019).

Figure 3.

Cartilage persistence of conventional HA and thermosensitive HA Nano 1 conjugated with cyanine 5. In vivo imaging system showed the retention of HA and HA Nano 1 after (A, B) intra-articular injection in an OA mouse model and (C, D) subcutaneous injection in healthy mice (n = 4). (E) Fluorescence micrographs of right knee 2 months after OA induction (F: femur, T: tibia, scale bar = 300 µm). (F) Fluorescence micrographs of the skin at 21 days after injection (D: Dermis, scale bar = 500 µm), and mice received an injection of PBS as the sham group. Reprinted with permission from Maudens et al. (2018).

Figure 4.

Morphology of hydrogels and evaluation using 3D cultured chondrocytes via histological analysis. (A) SEM images of hydrogels showing the interior morphology of hydrogels (upper images, scale bar = 5 µm) and cell adhesion to the hydrogels (lower images, scale bar = 10 µm). (B) Histological analysis of chondrocytes in hydrogel systems during 6-week culture, including H&E (top images and quantified data of aggregate area at 6 weeks), safranin-O (middle images and quantified data of sGAG at 6 weeks), and immunohistochemical staining of Col II (bottom images and quantified data of Col II at 6 weeks) (scale bar = 200 µm). n = 3; *p < .05 and **p < .01 compared with MeGC; ^##p < .01 compared with other groups. Reprinted with permission from Choi et al. (2014).