title: Phytomolecule icaritin incorporated PLGA/TCP scaffold for steroid-associated osteonecrosis: Proof-of-concept for prevention of hip joint collapse in bipedal emus and mechanistic study in quadrupedal rabbits.
abstract: Steroid-associated osteonecrosis (SAON) may lead to joint collapse and subsequent joint replacement. Poly lactic-co-glycolic acid/tricalcium phosphate (P/T) scaffold providing sustained release of icaritin (a metabolite of Epimedium-derived flavonoids) was investigated as a bone defect filler after surgical core-decompression (CD) to prevent femoral head collapse in a bipedal SAON animal model using emu (a large flightless bird). The underlying mechanism on SAON was evaluated using a well-established quadrupedal rabbit model. Fifteen emus were established with SAON, and CD was performed along the femoral neck for the efficacy study. In this CD bone defect, a P/T scaffold with icaritin (P/T/I group) or without icaritin (P/T group) was implanted while no scaffold implantation was used as a control. For the mechanistic study in rabbits, the effects of icaritin and composite scaffolds on bone mesenchymal stem cells (BMSCs) recruitment, osteogenesis, and anti-adipogenesis were evaluated. Our efficacy study showed that P/T/I group had the significantly lowest incidence of femoral head collapse, better preserved cartilage and mechanical properties supported by more new bone formation within the bone tunnel. For the mechanistic study, our in vitro tests suggested that icaritin enhanced the expression of osteogenesis related genes COL1α, osteocalcin, RUNX2, and BMP-2 while inhibited adipogenesis related genes C/EBP-ß, PPAR-γ, and aP2 of rabbit BMSCs. Both P/T and P/T/I scaffolds were demonstrated to recruit BMSCs both in vitro and in vivo but a higher expression of migration related gene VCAM1 was only found in P/T/I group in vitro. In conclusion, both efficacy and mechanistic studies show the potential of a bioactive composite porous P/T scaffold incorporating icaritin to enhance bone defect repair after surgical CD and prevent femoral head collapse in a bipedal SAON emu model.
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China; Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, PR China. Electronic address: lingqin@cuhk.edu.hk.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yao
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Wai-Ching
authors.initials: WC
authors.lastname: Liu
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Peking University Shenzhen Hospital, Shenzhen, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Le
authors.initials: L
authors.lastname: Huang
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Xie
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China; Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, PR China.
authors.forename: Xinluan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, The Second People's Hospital of Shenzhen, Shenzhen, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, PR China.
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Yao
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China; Orthopaedic Research Institute, Chinese People's Liberation Army General Hospital, Beijing, PR China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Peng
authors.affiliation: School of Biological Science and Medical Engineering, Beihang University, Beijing, PR China.
authors.forename: He
authors.initials: H
authors.lastname: Gong
authors.affiliation: Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: James F
authors.initials: JF
authors.lastname: Griffith
authors.affiliation: Interdisciplinary Division of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, PR China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Interdisciplinary Division of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, PR China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Baylor College of Dentistry, Texas A&M University, Dallas, USA.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.affiliation: Baylor College of Dentistry, Texas A&M University, Dallas, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Shihui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Peking University Shenzhen Hospital, Shenzhen, PR China.
authors.forename: Deming
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Department of Orthopaedics, The Second People's Hospital of Shenzhen, Shenzhen, PR China.
authors.forename: Daping
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, The Second People's Hospital of Shenzhen, Shenzhen, PR China.
authors.forename: Jiangyi
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Guangzhou Institutes of Biomedical and Health, Chinese Academy of Sciences, Guangzhou, PR China.
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, The First Peoples' Hospital, Shenzhen, PR China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Mechanical Engineering, Tsinghua University, Beijing, PR China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Lee Hysan Clinical Research Laboratories, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Kwong-Man
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: Chun-Yiu
authors.initials: CY
authors.lastname: Cheng
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis; D000818:Animals; D020312:Dromaiidae; D020342:Finite Element Analysis; D005419:Flavonoids / Q000737:chemistry / Q000627:therapeutic use*; D005684:Gait; D006621:Hip Joint / Q000473:pathology*; D019344:Lactic Acid; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D010020:Osteonecrosis / Q000139:chemically induced / Q000188:drug therapy*; D010944:Plants / Q000737:chemistry; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011817:Rabbits; D013256:Steroids / Q000009:adverse effects*; D054457:Tissue Scaffolds
chemical_list: D005419:Flavonoids; D013256:Steroids; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C499403:icaritin
keywords: Bioactive composite porous scaffold; Bipedal emus; Hip collapse; Phytomolecule icaritin; Steroid-associated osteonecrosis