Rationale: Osteoarthritis (OA) is a degenerative disease affecting cartilage, synovium and bone, that is a major cause of pain and disability. Intra-articular injection of hyaluronic acid (HA) derivatives, also known as viscosupplementation (VS), is a common treatment for the symptomatic management of knee OA. Despite its widespread use, the magnitude of the clinical benefit of VS remains controversial, with conflicting results due to methodological differences and possible differences in efficacy between products related to remanence and rheological properties. Methods: Here, to create an effective HA-based treatment, an injectable self-healing HA hydrogel with long-persistent radiopacity is formed by tethering a clinical iodine contrast agent to HA. The labeling conditions are tuned to obtain sufficient X-ray signal without altering the biocompatibility, rheological and injectability properties of the hydrogel. Results: The iodine labeling enabled to monitor not only delivery of the hydrogel but also its retention in mouse knees up to 5 weeks post-administration using synchrotron K-edge subtraction-computed tomography. We further demonstrated that the unique properties of this hydrogel enable creation of a transient HA network in vivo that attenuates OA progression in a mouse model of OA. Moreover, our data showed that the rate of HA-I disappearance appears to predict treatment response, likely because a rapid elimination serves as an indirect indicator of in situ inflammation. Conclusion: Collectively, these results show that our radiopaque HA-I hydrogel holds significant promise for improving patient management in the treatment of OA before clinical symptoms worsen. Its capacity for in vivo tracking over time allows for personalized treatment schedules based on observed retention and therapeutic effect. As a result, this theranostic hydrogel emerges as a strong candidate for precision medicine in OA.
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Cell therapy is promising to treat many conditions, including neurological and osteoarticular diseases. Encapsulation of cells within hydrogels facilitates cell delivery and can improve therapeutic effects. However, much work remains to be done to align treatment strategies with specific diseases. The development of imaging tools that enable monitoring cells and hydrogel independently is key to achieving this goal. Our objective herein is to longitudinally study an iodine-labeled hydrogel, incorporating gold-labeled stem cells, by bicolor CT imaging after in vivo injection in rodent brains or knees. To this aim, an injectable self-healing hyaluronic acid (HA) hydrogel with long-persistent radiopacity was formed by the covalent grafting of a clinical contrast agent on HA. The labeling conditions were tuned to achieve sufficient X-ray signal and to maintain the mechanical and self-healing properties as well as injectability of the original HA scaffold. The efficient delivery of both cells and hydrogel at the targeted sites was demonstrated by synchrotron K-edge subtraction-CT. The iodine labeling enabled to monitor the hydrogel biodistribution in vivo up to 3 days post-administration, which represents a technological first in the field of molecular CT imaging agents. This tool may foster the translation of combined cell-hydrogel therapies into the clinics.