Local BMP2 hydrogel therapy for robust bone regeneration in a porcine model of Legg-Calvé-Perthes disease

AUTHORS

Chi Ma, Min Sung Park, Felipe Alves do Monte, Vishal Gokani, Olumide O. Aruwajoye, Yinshi Ren, Xiaohua Liu & Harry K. W. Kim

ABSTRACT

Legg-Calvé-Perthes disease is juvenile idiopathic osteonecrosis of the femoral head (ONFH) that has no effective clinical treatment. Previously, local injection of bone morphogenetic protein-2 (BMP2) for ONFH treatment showed a heterogeneous bone repair and a high incidence of heterotopic ossification (HO) due to the BMP2 leakage. Here, we developed a BMP2-hydrogel treatment via a transphyseal bone wash and subsequential injection of BMP2-loaded hydrogel. In vitro studies showed that a hydrogel of gelatin-heparin-tyramine retained the BMP2 for four weeks. The injection of the hydrogel can efficiently prevent leakage. With the bone wash, the injected hydrogel had a broad distribution in the head. In vivo studies on pigs revealed that the BMP2-hydrogel treatment produced a homogeneous bone regeneration without HO. It preserved the subchondral contour and restored the subchondral endochondral ossification, although it increased growth plate fusions. In summary, the study demonstrated a promising BMP2-hydrogel treatment for ONFH treatment, especially for teenagers.

Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply

AUTHORS

Houyi Sun, Weicheng Zhang, Ning Yang, Yi Xue, Tianhao Wang, Hongzhi Wang, Kai Zheng, Yijun Wang, Feng Zhu, Huilin Yang, Wei Xu, Yaozeng Xu & Dechun Geng

ABSTRACT

In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

Differences in the Microarchitectural and Histomorphologic Characteristics Between Glucocorticoid-induced Osteonecrosis of Femoral Head and Alcohol-induced Osteonecrosis of Femoral Head

AUTHORS

Yiwei Chen, Kexin Liu, Yu Miao, Bin Zhu, Feng Xue, Junhui Yin, Minghao Zheng, guangyi li, Changqing Zhang

ABSTRACT

Aims

To analyze microarchitecture and histomorphology characteristics of different regions in femoral heads from patients with glucocorticoid-induced osteonecrosis of femoral head (GIONFH) and alcohol-induced osteonecrosis of femoral head (AIONFH).

Methods

Patients diagnosed with GIONFH and AIONFH were recruited. Femoral heads were obtained after total hip replacement. Micro-CT was applied to evaluate the microstructure of 9 regions of interest (ROIs) in the femoral head. Along the supero-inferior orientation, the femoral head was divided into necrotic region, reactive interface, and normal region; along the medio-lateral orientation, the femoral head was divided into medial region, central region and lateral region. Decalcified and undecalcified bone histology were then performed to assess histopathological alterations and bone remodeling levels.

Results

42 GIONFH patients (50 hips) and 43 AIONFH patients (50 hips) anticipated in the study. In the necrotic region, most of the microarchitectural parameters did not differ significantly between GIONFH and AIONFH, whereas both the reactive interface and normal region illustrated significant differences in the microstructure and histomorphometry. The reactive interface and normal region exhibited a less sclerotic microarchitecture, but a higher bone remodeling level in GIONFH as compared with AIONFH. Despite similar necrotic pathological manifestations, subchondral trabecular microfracture in the necrotic region was more severe and vasculature of the reactive interface was more abundant in GIONFH.

Conclusions

Although these two subtypes of ONFH shared similar microarchitecture and pathological features in the necrotic region, GIONFH exhibited a less sclerotic microarchitecture and a more active bone metabolic status in both the reactive interface and normal region.