Articular cartilage is a remarkable tissue whose sophisticated composition and architecture allow it to withstand complex stresses within the joint. Once injured, cartilage lacks the capacity to selfrepair, and injuries often progress to joint wide osteoarthritis (OA) resulting in debilitating pain and loss of mobility. Current palliative and surgical management provides short-term symptom relief, but almost always progresses to further deterioration in the long term. A number of bioactive factors, including drugs, corticosteroids, and growth factors, have been utilized in the clinic, in clinical trials, or in emerging research studies to stabilize the inflamed joint environment or to promote new cartilage tissue formation. However, these therapies remain limited in their duration and effectiveness. For this reason, current efforts are focused on improving the localization, retention, and activity of these bioactive factors. The purpose of this review is to highlight recent advances in drug delivery for the treatment of damaged or degenerated cartilage. First, we summarize material and modification techniques to improve the delivery of these factors to damaged tissue and enhance their retention and action within the joint environment. Second, we synthesize recent studies using novel methods to promote new cartilage formation via biofactor delivery, that have potential for improving future long-term clinical outcomes. Lastly, we review the emerging field of orthobiologics, using delivered and endogenous cells as drug-delivering "factories" to preserve and restore joint health. Enhancing drug delivery systems can improve both restorative and regenerative treatments for damaged cartilage.

Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor–α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.

The field of articular cartilage repair has made significant advances in recent decades; yet current therapies are generally not evaluated or tested, at the time of pivotal trial, in patients with a variety of common comorbidities. To that end, we systematically reviewed cartilage repair clinical trials to identify common exclusion criteria and reviewed the literature to identify emerging regenerative approaches that are poised to overcome these current exclusion criteria. The term "knee cartilage repair" was searched on clinicaltrials.gov. Of the 60 trials identified on initial search, 33 were further examined to extract exclusion criteria. Criteria excluded by more than half of the trials were identified in order to focus discussion on emerging regenerative strategies that might address these concerns. These criteria included age (<18 or >55 years old), small defects (<1 cm 2), large defects (>8 cm 2), multiple defect (>2 lesions), BMI >35, meniscectomy (>50%), bilateral knee pathology, ligamentous instability, arthritis, malalignment, prior repair, kissing lesions, neurologic disease of lower extremities, inflammation, infection, endocrine or metabolic disease, drug or alcohol abuse, pregnancy, and history of cancer. Finally, we describe emerging tissue engineering and regenerative approaches that might foster cartilage repair in these challenging environments. The identified criteria exclude a majority of the affected population from treatment, and thus greater focus must be placed on these emerging cartilage regeneration techniques to treat patients with the challenging "red knee".

This meniscus replacement scaffold has the potential to improve surgical treatment and provide better long-term outcomes for those suffering from severe meniscus damage.