A rat model of ischemic osteonecrosis for investigating local therapeutics using biomaterials

Osteonecrosis is one of the most disabling diseases affecting pediatric and adult populations. Local application of biomaterials is a promising therapeutic strategy for osteonecrosis. Currently, there is a lack of low-cost animal models of osteonecrosis for testing and developing biomaterials-driven therapeutics. To develop a rat model of ischemic osteonecrosis (IO), the distal femoral epiphysis was selected due to its size 7.7 folds larger than the proximal femoral epiphysis (p<0.0001). The feasibility of intraosseous drillings and the local application of biomaterials were determined. Four model biomaterials were successfully applied: injectable hydrogel, microsphere, bone cement, and implant. The IO was induced by surgically cauterizing the blood vessels supplying the distal femoral epiphysis. Osteonecrosis of the whole epiphysis was achieved with a complete absence of blood flow and near 100% of apoptotic osteocytes. At eight weeks after IO, severe bone deformity and osteoarthritis developed in the affected epiphysis. The histological analysis showed 50% lacunae empty in the IO group compared to 2% in the control group (p<0.0001). The μCT analysis showed the epiphyseal quotient decreased to 0.46 in the IO group compared to 0.53 in the control group (p<0.0001), and the distal femoral epiphysis in the IO group was 19% smaller than the control group (p<0.01). The Safranin O stained sections showed articular cartilage erosions and subchondral bone fractures in the IO group. In summary, we established a clinically relevant IO model on rats that is compatible with the application of biomaterials for treatment. Statement of significance: Osteonecrosis is one of the most serious orthopedic conditions, leading to permanent joint deformity and end-stage osteoarthritis. An efficient and low-cost animal model is essential for development and testing of new treatment strategies for osteonecrosis. This is the first study to develop a clinically relevant model of osteonecrosis on the distal femoral epiphysis of rats. The model is highly efficient in developing osteonecrosis with relatively low cost and it provides suitable skeletal size to apply various forms of biomaterials. More importantly, it mimicked the pathological features and progression of osteonecrosis in humans. The study is expected to have an important impact on the development and testing of innovative biological therapeutics for osteonecrosis.