Injectable mechanical pillows for attenuation of load-induced post-traumatic osteoarthritis

Abstract

Osteoarthritis (OA) of the knee joint is a degenerative disease initiated by mechanical stress that affects millions of individuals. The disease manifests as joint damage and synovial inflammation. Post-traumatic osteoarthritis (PTOA) is a specific form of OA caused by mechanical trauma to the joint. The progression of PTOA is prevented by immediate post-injury therapeutic intervention. Intra-articular injection of anti-inflammatory therapeutics (e.g. corticosteroids) is a common treatment option for OA before end-stage surgical intervention. However, the efficacy of intra-articular injection is limited due to poor drug retention time in the joint space and the variable efficacy of corticosteroids. Here, we endeavored to characterize a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system as a ‘mechanical pillow’ to cushion the load-bearing joint, withstand repetitive loading and improve the efficacy of intra-articular injections of nanoparticles containing dexamethasone, an anti-inflammatory agent. PEG-4MAL hydrogels maintained their mechanical properties after physiologically relevant cyclic compression and released therapeutic payload in an on-demand manner under in vitro inflammatory conditions. Importantly, the on-demand hydrogels did not release nanoparticles under repetitive mechanical loading as experienced by daily walking. Although dexamethasone had minimal protective effects on OA-like pathology in our studies, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from cartilage degradation and inhibit osteophyte formation in an in vivo load-induced OA mouse model.

An Intelligent Transdermal Formulation of ALA‐Loaded Copolymer Thermogel with Spontaneous Asymmetry by Using Temperature‐Induced Sol–Gel Transition and Gel–Sol (Suspension) Transition on Different Sides

“…During the recent decades, intelligent hydrogels have been investigated extensively [1][2][3][4] and widely applied in biomedicine. [5][6][7][8][9][10][11][12] While many efforts have been made to prepare various hydrogels as sustained release carriers of drugs, [13][14][15][16][17][18][19] little is known about the unique role of any intelligent hydrogel in a transdermal formulation for local photodynamic therapy (PDT) of a skin disease, where a sustained release is, however, usually not required.…”

Prevention of posttraumatic osteoarthritis at the time of injury: Where are we now, and where are we going?

“…Four recent studies published after the systematic PubMed search (Table 3, 2019–2020) exclusively use nonsurgical trauma models where treatment is given at the time of injury either orally (Doxycycline 23 or GKT137831 24 ) or as i.a. injection (dexamethasone, 25 2,3‐Dioxo‐6‐nitro‐1,2,3,4‐tetrahydrobenzo[f]quinoxaline‐7‐sulfonamide [NBQX] 26 ). Oral doxycycline reduced OARSI score by 30%, improved synovitis by 30%–40% and improved weight‐bearing 23 .…”

Recent Advances in Clinical Translation of Intra‐Articular Osteoarthritis Drug Delivery Systems

“…Reproduced under the terms of the Creative Commons CC BY License. [ 175 ] Copyright 2019, The Authors.…”

“…To this end, Holyoak et al pursued a 4-armed maleimide-functionalized PEG (PEG-4MAL) hydrogel-based "mechanical pillow" system loaded with PLGA-Dex NPs (≈203 nm) ( Figure 14A). [175] The PEG-4MAL hydrogels was cross-linked with 50% non-degradable dithiothreitol (DTT) and 50% MMP-degradable peptide crosslinker (GCRD-VPMSMRGGDRCG, VDM). This formulation was resistant to mechanical load-induced release but susceptible to collagenaseinduced release for on-demand drug delivery in the joint.…”