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Reversing Rheumatoid Arthritis With Nitric Oxide-Scavenging Hydrogels
A new, injectable hybrid hydrogel has been designed to remove nitric oxide and alleviate inflammatory symptoms, paving the way for rheumatoid arthritis treatment.

Tender, swollen joints that are especially stiff in the morning, accompanied by fever, fatigue, and loss of appetite. These are the daily struggles of someone suffering from rheumatoid arthritis – a common, chronic inflammatory joint disorder that affects one’s hands, wrists, feet, and ankles. Despite being known to affect the joints, 40 per cent of people who suffer from the disease also experience signs and symptoms that do not involve the joints. This is because rheumatoid arthritis can spread and damage a wide variety of body systems, including the skin, eyes, lungs, heart, and blood vessels. If left untreated, this disease can also become debilitating.

Given these severe effects, scientists have sought to develop treatments for rheumatoid arthritis, many of which are focused on eliminating inflammation at affected sites. However, because the cause of the disease remains unknown, there has yet to be a treatment that can completely remove inflammation. To this, researchers from Pohang University of Science and Technology, in collaboration with OmniaMed Co., Ltd., have proposed a new therapeutic approach that can pinpoint and remove inflammation by safely delivering drugs that deplete nitric oxides at targeted areas.

In a number of inflammatory diseases, including rheumatoid arthritis, the overproduction of nitric oxides can cause painful inflammation and aggravate symptoms by abnormally upregulating inflammatory immune cells. Therefore, selectively removing the overproduced nitric oxides is key to eliminate inflammation. One way to do this is to use nitric oxide-scavenging hydrogels. However, previously developed hydrogels have failed to completely deplete nitric oxide from affected areas because they cannot be directly injected into the local area. And even when injected as a small molecule, the hydrogel molecules can easily escape and inadvertently deplete nitric oxides in other areas instead. This can cause serious side effects as nitric oxide is needed to relax blood vessels and smooth muscles as well as reduce blood pressure among other functions.

In this study, Professor Won Jong Kim, Ph.D. candidate Taejeong Kim of the Department of Chemistry, and colleagues have designed a new nitric oxide-scavenging hydrogel that can be easily injected into the inflammatory site and selectively control the anti-inflammatory agent according to the degree of inflammation. Their hydrogel has also been shown to be long-lasting upon injection into the local site.

“The concept of [nitric oxide]-scavenging hydrogel platform developed in this study is a breakthrough because it specifically responds to the [nitric oxide], a major substance that causes an inflammatory reaction in autoimmune diseases such as rheumatism. It releases the drugs in response to the [nitric oxides] and treats diseases by depleting them,” explained Professor Won Jong Kim who led the study.

During the development of this hydrogel, the researchers first prepared a liquid that can be directly injected using a syringe. They then cross-linked polymeric aggregates that can self-assemble and carry anti-inflammatory drugs. Upon administering both the liquid and the aggregates into the injected site via a dual-syringe, the mixture was then rapidly transformed into a hydrogel material. Their findings showed that the hydrogel could collect and eliminate the overproduced nitric oxide at the target site. Additionally, because the hydrogel includes nanometre-sized polymeric aggregates that can self-heal even if damaged by external pressure, it can also help to replenish the viscosity of joints.

To validate the potency of their creation, the research team proceeded to test the hydrogel in animal models. The results indicated that the hybrid hydrogel could collect abnormally high levels of nitric oxide at the inflammatory site. The scientists were also able to confirm how the hydrogel works in vivo – the hydrogel is hydrolysed to release the drugs depending on the concentration of the nitric oxide. Further investigations revealed that inflammatory symptoms were also significantly alleviated when the anti-inflammatory drug dexamethasone was added to the hydrogel and injected into the rheumatoid arthritis model.

With these positive results, the team is hopeful to expand the applications of their hydrogel. As said by Professor Won Jong Kim, “This [nitric oxide]-scavenging hydrogel system can be applied to various inflammatory diseases with a simple process, presenting applicable potential to treatments currently on the market or in clinical trials.”

Source: Kim et al. (2021). Polymeric Aggregate-Embodied Hybrid Nitric-Oxide-Scavenging and Sequential Drug-Releasing Hydrogel for Combinatorial Treatment of Rheumatoid Arthritis. Advanced Materials, 33(34).

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