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Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.

Osteoarthritis (OA) is the most common joint disorder and currently affects >500 million patients worldwide, with ~60% of them also suffering from obesity. There is no drug approved for human use that changes the course of OA progression. OA is one of the most common comorbidities of obesity, and obesity-related OA (ObOA) is a serious health concern because it shows heightened severity of tissue damage and also predominantly affects the working population. Unresolved inflammation is a major driver of ObOA, thus, resolving disease-associated inflammation is a viable strategy to treat ObOA. Resolvins are highly potent molecules that play a role in the resolution of inflammation and promote tissue healing. However, small molecules (like Resolvin D1; RvD1) have to be administered frequently or prior to injury because they lose their in vivo activity rapidly either by lymphatic clearance, or oxidation-mediated deactivation. In this study, we have encapsulated RvD1 in liposomes and established its efficacy in the mouse model of ObOA at much lower dosages than freely administered RvD1. Liposomal RvD1 (lipo-RvD1) acted as a source of the RvD1 molecules for ~11 days in vitro in synovial fluid derived from patients. When administered prophylactically or therapeutically, lipo-RvD1 suppressed cartilage damage in male C57BL/6 mice compared to untreated and free RvD1 treatments. This efficacy was achieved by increasing the proportion of the proresolution M2 macrophages over proinflammatory M1 macrophages in the synovial membrane. These results show the potential of lipo-RvD1 as an anti-OA agent., (© 2023 Wiley Periodicals LLC.)

Poor adherence to drug dosing schedule is responsible for ∼50% of hospitalization cases. Most patients fail to adhere to a strict dosing schedule due to invasive drug administration, off-target toxicities, or medical conditions like dementia. The emerging concept of wearable devices (WDs), implantable devices (IDs) and combined wearable and implantable devices (WIDs) for drug delivery has created new opportunities for treating patients with chronic diseases needing repeated and long-term medical attention like diabetes, ocular disorders, cancer, wound healing, cardiovascular diseases, and contraception. WDs, worn on the body surface have created appealing non-invasive, self-administrable drug delivery platforms which receive huge patient compliance. Microneedle-skin patches, wound healing patches, drug-eluting contact lenses, mouth guards, intra-vaginal rings, pharmaceutical jewelry, and drug-loaded self-care textiles are popular WDs explored in drug delivery. In contrast, IDs are surgically placed inside body tissue allowing higher payload and enhanced localized effect for an extended duration. Hormone micropumps, hydrogel/nanofibrous depot, coronary stents, intravitreal devices, and intrauterine devices are some representative examples of IDs. In this review, we have described the past 10 years of research progress on drug-delivering WDs and IDs in the context of treating diseases that demand repeated and long-term medication, especially those affecting soft tissues. We highlighted several technical challenges that need to be addressed before considering the translation of such technologies to clinics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Inflammatory disease (ID) is an umbrella term encompassing all illnesses involving chronic inflammation as the central manifestation of pathogenesis. These include, inflammatory bowel diseases, hepatitis, pulmonary disorders, atherosclerosis, myocardial infarction, pancreatitis, arthritis, periodontitis, psoriasis. The IDs create a severe burden on healthcare and significantly impact the global socio-economic balance. Unfortunately, the standard therapies that rely on a combination of anti-inflammatory and immunosuppressive agents are palliative and provide only short-term relief. In contrast, the emerging concept of immunomodulatory nanosystems (IMNs) has the potential to address the underlying causes and prevent reoccurrence, thereby, creating new opportunities for treating IDs. The IMNs offer exquisite ability to precisely modulate the immune system for a therapeutic advantage. The nano-sized dimension of IMNs allows them to efficiently infiltrate lymphatic drainage, interact with immune cells, and subsequently to undergo rapid endocytosis by hyperactive immune cells (HICs) at inflamed sites. Thus, IMNs serve to restore dysfunctional or HICs and alleviate the inflammation. We identified that different IMNs exert their immunomodulatory action via either of the seven mechanisms to modulate; cytokine production, cytokine neutralization, cellular infiltration, macrophage polarization, HICs growth inhibition, stimulating T-reg mediated tolerance and modulating oxidative-stress. In this article, we discussed representative examples of IMNs by highlighting their rationalization, design principle, and mechanism of action in context of treating various IDs. Lastly, we highlighted technical challenges in the application of IMNs and explored the future direction of research, which could potentially help to overcome those challenges., (Copyright © 2021. Published by Elsevier Ltd.)

A young female with pure red cell aplasia with brisk response to prednisolone therapy is described. The patient has remained in remission on a small dose of prednisolone for 10 months.