Microparticles-in-Thermoresponsive/Bioadhesive Hydrogels as a Novel Integrated Platform for Effective Intra-articular Delivery of Triamcinolone Acetonide

Abstract

Intra-articular (IA) injection of thermoresponsive hydrogels coupled with microparticles (MPs) possess the benefit of sustaining the anti-inflammatory drug effect within the joint cavity for rheumatoid arthritis treatment. Star-shaped thermoresponsive poly(polyethylene glycol) methacrylate [Poly(PEGMA)] copolymers were synthesized using free radical polymerization technique and fully characterized. Triamcinolone acetonide (TA)-loaded PLA/mPEG−PDL MPs, previously optimized, were integrated into the synthesized copolymer solutions at various concentrations and tested for their gelation temperatures. The MPs-in-hydrogel formulations were characterized using scanning electron microscope (SEM), viscosity measurements, ex vivo bioadhesion, and in vitro release studies. The anti-inflammatory effect of integrated systems was assessed in adjuvant-induced monoarthritic rat knee joints and compared to Kenacort and TA-loaded MPs. Two copolymers were successfully synthesized; G-1 = poly(PEGMA 188 -ME-co-PEGMA 475 -ME) and G-2 = poly(PEGMA 246 -EE-co-PEGMA 475 -ME). Using the tube inversion technique, the gel formation was found dependent on copolymer concentration. An irreversible aggregation was obtained at copolymer concentrations ≤10% (w/v), while a gel was formed at 20 and 30% (w/v) of both copolymers upon increasing temperature. The MP-hydrogel formulations were optimized at 20 and 30% (w/v) of G-1 and G-2 with gelation temperatures of 33 and 37 °C, respectively. SEM images revealed the porous microstructures of hydrogels and their adsorption on MP surfaces. The integrated formulas showed pseudoplastic behaviors, while the bioadhesion study confirmed their bioadhesiveness on excised cartilage. The in vitro release study confirmed drug sustainment from MPs-hydrogels compared to MPs. In vivo studies proved the superiority of MP-in-hydrogels in treatment of induced arthritis, relative to Kenacort and MPs alone, suggesting the applicability of this integrated platform in IA drug delivery.

Thermosensitive In Situ Gels for Joint Disorders: Pharmaceutical Considerations in Intra-Articular Delivery

“…Triamcinolone acetonide was loaded in thermoresponsive hydrogels with microparticles for the treatment of rheumatoid arthritis [ 83 ]. The in vitro release study confirmed the sustained release of the drug from hydrogels when compared to microparticles.…”

Recent Developments of Nanomaterials in Hydrogels: Characteristics, Influences, and Applications

“…The drug delivery system (DDS) allows the drug to be directed to transfer to the wounded site and improves the therapeutic effect of the drug. [130] Due to the unique physical and chemical properties of hydrogels, it has become an attractive structure for designing controlled-release drug delivery systems. [131] With the development of nanotechnology, the response of nanoparticle-modified hydrogels to new stimuli can be adjusted in many ways.…”

Bioadhesives for musculoskeletal tissue regeneration

“…Despite successful engineering of functional cartilaginous tissues in vitro [105], integration with adjacent host tissue has been one of the outstanding challenges to achieve long-lasting success in cartilage regeneration [106]. Similarly, the integration issue was also involved with the injectable hydrogels with or without cells and/or bioactive cues [107]. Thus, bioadhesives have been applied to facilitate integration between cartilage implants and host tissues [108].…”

“…Application of bioadhesives as a delivery vehicle is an emerging idea in the field [7,13,14,19]. Even with suboptimal mechanical properties compared to target tissues, the intrinsic adhesive force on a tissue surface is likely beneficial for a localized delivery of cells, growth factors and small molecules on the target area.…”

“…Functionality of most bioadhesives is highly attributed to its adhesion properties on tissues, grafts, or materials, providing secure graft fixation, wound closure or dressing. Recently, the application of bioadhesives has been expanded for tissue repair, tissue engineering, and regenerative medicine [7][8][9][10][11][12][13][14]. To support repair and healing, particularly for musculoskeletal tissues, the adhesion strength of bioadhesives is being challenged to move up to the next level [8,9,[14][15][16].…”