Approximately 15% to 30% of all childhood fractures are growth plate fractures. Because the growth plate determines the length and shape of a mature bone, this type of fracture may result in severe growth abnormalities in children. Pathologically, the growth abnormality is caused by the formation of a bony bridge in the injured growth plate cartilage. Currently, the clinical treatment of growth plate fractures includes the surgical removal of the bony bridge and insertion of autologous fat or cartilage tissue into the empty space to discourage bony bridge reformation. Such surgical procedures are invasive and result in unsatisfactory outcomes. In addition, this treatment is only useful after the bony bridge has formed. Our long-term goal is to understand how to prevent bony bridge formation and improve growth plate cartilage regeneration at cellular and molecular levels and develop the first preventive and therapeutic approach for growth plate fracture. Specifically, the primary objective of this proposal is to evaluate the therapeutic effects of a nano-matrix assembled from matrilin-3 (MATN3) and rosette nanotube (RNT) in a preclinical growth plate fracture model. Our central hypothesis is that the MATN3/RNT nano-matrix specifically promotes chondrocyte growth and enhances chondrogenesis of mesenchymal stem cells (MSCs), while it also inhibits vascularization and osteogenesis at the fracture site. This is the cellular basis for such nano-matrix to improve growth plate cartilage regeneration and prevent bony bridge formation. We will test our central hypothesis and achieve the objective of the proposal by pursuing two specific aims: 1) to determine the ability of MATN3/RNT to prevent bony bridge formation; and 2) to determine the ability of MATN3/RNT to deliver growth factors for further improvement of chondrogenesis and growth plate cartilage regeneration. To achieve the two aims, our overall research strategy includes: 1) optimization of the ratio and dose of MATN3/RNT and its ability and bioactivity for loading growth factors in vitro; and 2) determination of the therapeutic efficay of the nano-matrix in our established growth plate fracture model in rats in long term. The proposed research is innovative: 1) biologically, it simultaneously promotes cartilage regeneration and inhibits bony bridge formation; 2) therapeutically, MATN3 and RNT can be injected as a liquid in a minimally invasive manner, and form a nano- matrix at the fracture site; 3) structurally, the nano-matrix concentrates bioactive MATN3 locally at the fracture site as well as binds TGF-?1 and IGF-1 to achieve multi-functional delivery. With the results of the two specific aims, we expect to 1) realize a synergistic strategy to specifically promote chondrogenesis while inhibiting osteogenesis and vascularization; and 2) develop an injectable approach for the localized delivery of cartilage growth factors. These outcomes have an important positive impact in developing novel, perhaps the first, preventive and therapeutic approach for growth plate cartilage repair.
The proposed research is relevant to public health because this project will determine the therapeutic efficacy of the nano-matrix for growth plate cartilage repair, and it will provide important insights in developing the first preventive and therapeutic approach for the treatment of growth plate fracture. Thus, the proposed research is relevant to the part of NIH's mission that translating scientific discovery into health that will help to reduc the burdens of human disability.
|Liu, Qihai; Wang, Jun; Chen, Yupeng et al. (2018) Suppressing mesenchymal stem cell hypertrophy and endochondral ossification in 3D cartilage regeneration with nanofibrous poly(l-lactic acid) scaffold and matrilin-3. Acta Biomater 76:29-38|
|Jayasuriya, Chathuraka T; Chen, Yupeng; Liu, Wenguang et al. (2016) The influence of tissue microenvironment on stem cell-based cartilage repair. Ann N Y Acad Sci 1383:21-33|
|Chen, Yupeng; Cossman, Jack; Jayasuriya, Chathuraka T et al. (2016) Deficient Mechanical Activation of Anabolic Transcripts and Post-Traumatic Cartilage Degeneration in Matrilin-1 Knockout Mice. PLoS One 11:e0156676|