Injectable cell-free piezoelectric scaffold to treat osteoarthritis in large animal models

Abstract Millions of American suffer from osteoarthritis (OA) while the repair of large or major cartilage defects in severe OA is still a significant challenge. Current medicines including analgesics and anti-inflammatory drugs only alleviate the symptoms but do not completely cure the disease. The gold standard treatment is to use replacement auto- and allo- replacement cartilage grafts. These grafts however suffer from the problems of donor site morbidity, immune-rejection, infection and especially, limit of tissue supply. As such, regenerative engineering approaches, which rely on biomaterial scaffolds to construct “engineered” cartilage grafts, have emerged as an important field. Despite many encouraging results, the clinical use of engineered cartilage grafts has been limited due to the (1) the ineffectiveness to regenerate hyaline cartilage which can serve as a load- bearing tissue, (2) the toxicity and adverse events of growth factors or seeded stem cells which are often used to promote the cartilage regrowth, and (3) the invasive surgical procedure to implant the grafts. As an alternative to biochemical cues, electrical stimulation (ES) has been shown to significantly promote bone and cartilage growth, and can be used in combination with a biomaterial tissue graft to enhance tissue regeneration. Piezoelectric materials with an exciting ability to generate electricity under applied pressure, could be appealing to create self-powered electrical stimulators which can be mechanically activated to electrically induce cartilage re-growth. In this regard, the PI group has pioneered a novel piezoelectric nanofiber scaffold made of Poly-L- lactide (PLLA, a well-known safe erodible polymer) which can be implanted into cartilage defects and produce electrical cues under ultrasound activation to electrically drive cartilage re-growth. To avoid the invasive implantation surgery, we also developed an injectable piezoelectric scaffold which is comprised of a traditional collagen hydrogel and cryo-sectioned piezoelectric PLLA nanofibers. The hydrogel however provides only a modest chondrogenesis, preventing its ability to heal challenging load-bearing cartilage defects. Herein, we propose to (1) study a new injectable piezoelectric nanocomposite hydrogel scaffold, based on the piezoelectric PLLA nanofibers and magnesium oxide nanoparticles (MgO NPs) which could offer a significantly enhanced chondrogenesis, superior to the piezoelectric PLLA hydrogel alone, and (2) investigate how this piezoelectric MgO/PLLA nanocomposite hydrogel scaffold can be used to promote the healing of major load-bearing cartilage defects in large animal models. The success of this proposed work will be the key step towards a clinical trial for testing this novel injectable self-powered piezo-scaffold treatment in human OA patients with severe cartilage damages.