Shape-Defined microPlates for the Sustained Intra-articular Release of Dexamethasone in the Management of Overload-Induced Osteoarthritis.

Martina Di Francesco,Luca Ceseracciu,Craig Duvall,Sean K Bedingfield,Lauren E Himmel,Fang Yu,Elena Bellotti,Daniele Di Mascolo,Juan M Colazo,Miguel Ferreira,Valentina Di Francesco,Paolo Decuzzi

doi:10.1021/acsami.1c02082

Abstract

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.

Highlights

Osteoarthritis (OA) is a prevalent disease that causes chronic pain and disability, especially among the elderly.[1,2] OA can affect younger patients, often due to post-traumatic osteoarthritis (PTOA), a form of OA which can occur after joint, ligament, and bone injury or surgery.[3]
Excessive inflammation reduces the synthesis of extracellular matrix components and increases matrix degradation, driven principally by aggrecanases and matrix metalloproteinase (MMP), resulting in lesions on the articular cartilage surface that progress toward full cartilage erosion and complete joint dysfunction.[4,5]
This sacrificial template presents a 2D matrix of wells, identical to that of the original master template, which are filled with the polymeric paste (PLGA) containing the drug payload (Figure 1c)

Summary

Introduction

Osteoarthritis (OA) is a prevalent disease that causes chronic pain and disability, especially among the elderly.[1,2] OA can affect younger patients, often due to post-traumatic osteoarthritis (PTOA), a form of OA which can occur after joint, ligament, and bone injury or surgery.[3]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are typically the first line of pharmaceutical treatment but are only marginally effective at pain relief, can cause gastrointestinal complications, and do not slow cartilage deterioration.[6,7] one challenge for NSAID systemic administration is the insufficient accumulation in the joints, which are relatively avascular, making local injection a good alternative for increasing bioavailability and decreasing systemic exposure.[7] In the current clinical practice, the Osteoarthritis Research Society International (OARSI) and the American College of Rheumatology recommend articular injection of anti-inflammatory corticosteroids for symptomatic knee OA with dexamethasone (DEX) as one of the five FDA-approved corticosteroids for this use.[7−9] A limitation of the intra-

Results

Discussion

Conclusion