Polymeric Hydrogels for Controlled Drug Delivery to Treat Arthritis

Abstract

Rheumatoid arthritis (RA) and osteoarthritis (OA) are disabling musculoskeletal disorders that affect joints and cartilage and may lead to bone degeneration. Conventional delivery of anti-arthritic agents is limited due to short intra-articular half-life and toxicities. Innovations in polymer chemistry have led to advancements in hydrogel technology, offering a versatile drug delivery platform exhibiting tissue-like properties with tunable drug loading and high residence time properties This review discusses the advantages and drawbacks of polymeric materials along with their modifications as well as their applications for fabricating hydrogels loaded with therapeutic agents (small molecule drugs, immunotherapeutic agents, and cells). Emphasis is given to the biological potentialities of hydrogel hybrid systems/micro-and nanotechnology-integrated hydrogels as promising tools. Applications for facile tuning of therapeutic drug loading, maintaining long-term release, and consequently improving therapeutic outcome and patient compliance in arthritis are detailed. This review also suggests the advantages, challenges, and future perspectives of hydrogels loaded with anti-arthritic agents with high therapeutic potential that may alter the landscape of currently available arthritis treatment modalities.

Keywords: arthritis; hybrid hydrogel composite; nanoparticles/microparticles-embedded hydrogels; polymeric hydrogels; protein/polysaccharide polymers; synthetic polymers.

Figure 1

Overview of polymeric hydrogels used to deliver small molecule drugs, immunotherapeutics, and cells to joint sites for alleviating pain, swelling, inflammation, thus providing viscoelastic, lubrication, and cartilage repair advantages.

Figure 2

Chemical structure of protein/peptide–based polymers and their modifications (a) gelatin, (b) methacrylated gelatin (GelMA), (c) fibrin (protein structure), (d) silk fibroin (primary chemical structure and protein structure, (e) collagen, (f) methacrylated collagen, (g) silk-sericin, and (h) elastin-like protein.

Figure 3

Chemical structures of polysaccharide polymers: (a) alginate (sodium salt), (b) chitosan, (c) hyaluronic acid (HA) and their modifications such as (d) HA–tyramine, (e) HA–adipic acid dihydrazide, (f) HA–acrylate, (g) heparin, (h) dextran and its (i) tyramine conjugate, (j) chondroitin sulfate and its modification, (k) chondroitin sulfate–hydrazide, and (l) gellan gum and its (m) methacrylate derivative.

Figure 4

Schematic illustration of (a) the enzymatic cross-linked SF/HA-Tyr composite hydrogel, (b) the gelation time of the hydrogel was decreased with an increase in HA concentration, and (c) HA20/SF80 showed the maximum G′ values of 3.94 kPa among all the groups ** p <0.001 *** p < 0.0005 **** p < 0.0001. Immunohistochemical characterization revealed (d) maintenance of chondrocyte cell morphology on day 21 (Safranin-O staining) and (e) increased the accumulation of type II collagen (immunostaining). Adapted with permission from ref. [85], Copyright 2021 Elsevier.

Figure 5

(a) Preparation of nitrous oxide (NO)-scavenging nanogel (NO-Scv) to alleviate rheumatoid arthritis. (b) NO-Scv nanogel prevents NO-mediated cartilage damage, inflammation, and bone deformation. (c) In vivo efficacy studies with NO-Scv nanogel in collagen-induced arthritis mouse model suggest (d) reduction in paw volume and swelling. (e) Monitoring of bone and joint morphology by computer tomography revealed clear boundary of bone and less bone erosion in both the ankles and fingers of mice as compared to those in the saline and NOx gel-treated animal group. Adapted with permission from ref. [91], Copyright 2019 American Chemical Society.

Figure 6

Schematic of MMP-degradable PEG hydrogel (a,b) prepared with a 4-arm PEG-norbornene network and MMP-degradable peptide sequence/or with non-degradable (3.5-kDa PEG dithiol) linker. The chondrocyte-laden degradable hydrogel maintained cell viability and significantly increased (c) GAG and (d) collagen deposition after 28 days of culturing. Adapted with permission from ref. [98], Copyright 2015 John Wiley and Sons.

Figure 7

Anti-TNF α monoclonal antibody conjugated-chondroitin sulfate modified poly(amidoamine) dendrimer NP (Anti-TNF α mAb-CS/PAMAM dendrimer NP)-loaded GG-tyr and GG-tyr/SF hydrogel. (a) Representative images of GG-tyr and GG-tyr/SF hydrogel, where the fluorescence image shows a uniform distribution of NPs throughout the hydrogel. (b) Anti-TNF-α mAb conjugation to CS/PAMAM dendrimer NP. Effect of the hydrogel on THP-1 cell-based inflammation model, (c) metabolic activity, and (d) DNA concentration. (e) Measurement of the free TNF-α levels in cell culture media demonstrates that the anti-TNF α mAb-CS/PAMAM dendrimer NP-loaded hydrogel maintained cell viability, induced cell proliferation, and retained the capacity to neutralize TNF-α, even after 14 days. Adapted from [166] under the terms of the creative common attribution license, MDPI, 2021.

Figure 8

(a) Injectable methotrexate MP–hydrogel composite for anti-arthritic application. (b) T_sol–gel, gelation time, viscoelastic properties, and morphology. (c) Hydrogel-mediated controlled MTX release. (d) In vivo biocompatibility studies. Adapted with permission from ref. [157], Copyright 2021 Elsevier.