Bioresponsive microspheres for on‐demand delivery of anti‐inflammatory cytokines for articular cartilage repair

Abstract

Despite innovations in surgical interventions, treatment of cartilage injury in osteoarthritic joints remains a challenge due to concomitant inflammation. Obstructing a single dominant inflammatory cytokine has shown remarkable clinical benefits in rheumatoid arthritis, and similar strategies are being suggested to target inflammatory pathways in osteoarthritis (OA). Here, we describe the utility of gelatin microspheres that are responsive to proteolytic enzymes typically expressed in arthritic flares, resulting in on-demand and spatiotemporally controlled release of antiinflammatory cytokines for cartilage preservation and repair. These microspheres were designed with a net negative charge to sequester cationic anti-inflammatory cytokines, and the magnitude of the negative charge potential increased with an increase in crosslinking density. Collagenase-mediated degradation of the microspheres was dependent on the concentration of the enzyme. Release of antiinflammatory cytokines from the loaded microspheres directly correlated with the degradation of the gelatin matrix. Exposure of the IL-4 and IL-13 loaded microspheres reduced the inflammation of chondrocytes up to 80%. Hence, the delivery of these microspheres in an OA joint can attenuate the stimulation of chondrocytes and the resulting secretion of catabolic factors such as proteinases and nitric oxide. The microsphere format also allows for minimally invasive delivery and is less susceptible to mechanically induced drug release. Consequently, bioresponsive microspheres can be an effective tool for cartilage preservation and arthritis treatment.

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

“…For example, T/C-28a2 and SW-1353 human cell lines are not suitable for studying NO release and iNOS expression because, in comparison to ATDC-5 cells, these cells are incapable of producing NO and expressing iNOS in response to LPS, IL-1α, or IL-1β treatment [ 113 ]. ATDC5 cells are an acceptable alternative as they imitate the articular chondrocyte phenotype and they have been successfully used in inflammatory in vitro models of OA [ 113 , 114 , 115 , 116 , 117 ]. However, an important question remains; namely, how the accumulated data translate to the clinical outcome.…”

“…Other anti-inflammatory cytokines, such as IL-4 and IL-13, were also absent [ 21 ]. Notably, inflammatory and blood-induced injury models showed that maintaining concentrations of anti-inflammatory cytokines [ 12 , 76 , 77 , 114 , 141 , 142 , 224 , 225 ] or IL-1ra [ 226 , 227 , 228 ] not only modulated the inflammatory response by reducing inflammation, but additionally stimulated chondro- and cartilage-protective effects. Moreover, IL-10 promoted the regeneration of cartilage tissue [ 142 ].…”

Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment

“…Nevertheless, current research has already identified a broad range of promising therapeutics, allowing initial harm reduction and preventing ongoing detrimental events. One important future task is to bring the most promising of them into clinical studies-which includes intelligent strategies of administration e.g., though intraarticular application with prolonged or even on-demand release kinetics [208]. In combination with optimal surgical intervention, the early modulation of cellular and biological processes seems to have the potential to alleviate the acute situation, thus reducing the risk of PTOA development.…”

Advanced Polymer-Based Drug Delivery Strategies for Meniscal Regeneration

“…139,142 Indeed, in vitro studies have demonstrated that key inflammatory cytokines, such as tumor necrosis factor alpha (TNF-a) and interleukin-1b (IL-1b), attenuate or eliminate the integration of adjacent meniscal edges, 142,143 while the addition of matrix metalloproteinase (MMP) inhibitors can restore the integration capacity. 144 Furthermore, the delivery of anti-inflammatory and/or antioxidative agents has been widely used for the treatment of joint disease and has achieved effective knee function restoration, [145][146][147] which suggests that anti-inflammatory drugs may prevent disease progression and improve reparative activity.…”