Osteoarthritis
(OA) is treated with the intra-articular
injection of steroids such as dexamethasone (DEX) to provide short-term
pain management. However, DEX treatment suffers from rapid joint clearance.
Here, 20 × 10 μm, shape-defined poly(d,l-lactide-co-glycolide)acid microPlates (μPLs) are created and
intra-articularly deposited for the sustained release of DEX. Under
confined conditions, DEX release is projected to persist for several
months, with only ∼20% released in the first month. In a highly
rigorous murine knee overload injury model (post-traumatic osteoarthritis),
a single intra-articular injection of Cy5-μPLs is detected in
the cartilage surface, infrapatellar fat pad/synovium, joint capsule,
and posterior joint space up to 30 days. One intra-articular injection
of DEX-μPL (1 mg kg–1) decreased the expression
of interleukin (IL)-1β, tumor necrosis factor (TNF)-α,
IL-6, and matrix metalloproteinase (MMP)-13 by approximately half
compared to free DEX at 4 weeks post-treatment. DEX-μPL also
reduced load-induced histological changes in the articular cartilage
and synovial tissues relative to saline or free DEX. In sum, the μPLs
provide sustained drug release along with the capability to precisely
control particle geometry and mechanical properties, yielding long-lasting
benefits in overload-induced OA. This work motivates further study
and development of particles that provide combined pharmacological
and mechanical benefits.
A variety of microparticles have been proposed for the sustained and localized delivery of drugs with the objective of increasing therapeutic indexes by circumventing filtering organs and biological barriers. Yet, the geometrical, mechanical, and therapeutic properties of such microparticles cannot be simultaneously and independently tailored during the fabrication process to optimize their performance. In this work, a top-down approach is employed to realize micron-sized polymeric particles, called microplates (μPLs), for the sustained release of therapeutic agents. μPLs are square hydrogel particles, with an edge length of 20 μm and a height of 5 μm, made out of poly(lactic- co-glycolic acid) (PLGA). During the synthesis process, the μPL Young's modulus can be varied from 0.6 to 5 MPa by changing the PLGA amounts from 1 to 7.5 mg, without affecting the μPL geometry while matching the properties of the surrounding tissue. Within the porous μPL matrix, different classes of therapeutic payloads can be incorporated including molecular agents, such as anti-inflammatory dexamethasone (DEX), and nanoparticles containing imaging and therapeutic molecules themselves, thus originating a truly hierarchical platform. As a proof of principle, μPLs are loaded with free DEX and 200 nm spherical polymeric nanoparticles, carrying DEX molecules (DEX-SPNs). Electron and fluorescent confocal microscopy analyses document the uniform distribution and stability of molecular and nanoagents within the μPL matrix. This multiscale, hierarchical microparticle releases DEX for at least 10 days. The inclusion of DEX-SPNs serves to minimize the initial burst release and modulate the diffusion of DEX molecules out of the μPL matrix. The biopharmacological and therapeutic properties together with the fine tuning of geometry and mechanical stiffness make μPLs a unique polymeric depot for the potential treatment of cancer, cardiovascular, and chronic, inflammatory diseases.
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