title: Alignment of collagen fiber in knitted silk scaffold for functional massive rotator cuff repair.
abstract: Rotator cuff tear is one of the most common types of shoulder injuries, often resulting in pain and physical debilitation. Allogeneic tendon-derived decellularized matrices do not have appropriate pore size and porosity to facilitate cell infiltration, while commercially-available synthetic scaffolds are often inadequate at inducing tenogenic differentiation. The aim of this study is to develop an advanced 3D aligned collagen/silk scaffold (ACS) and investigate its efficacy in a rabbit massive rotator cuff tear model. ACS has similar 3D alignment of collagen fibers as natural tendon with superior mechanical characteristics. Based on ectopic transplantation studies, the optimal collagen concentration (10mg/ml), pore diameter (108.43±7.25μm) and porosity (97.94±0.08%) required for sustaining a stable macro-structure conducive for cellular infiltration was determined. Within in vitro culture, tendon stem/progenitor cells (TSPCs) displayed spindle-shaped morphology, and were well-aligned on ACS as early as 24h. TSPCs formed intercellular contacts and deposited extracellular matrix after 7days. With the in vivo rotator cuff repair model, the regenerative tendon of the ACS group displayed more conspicuous native microstructures with larger diameter collagen fibrils (48.72±3.75 vs. 44.26±5.03nm) that had better alignment and mechanical properties (139.85±49.36vs. 99.09±33.98N) at 12weeks post-implantation. In conclusion, these findings demonstrate the positive efficacy of the macroporous 3D aligned scaffold in facilitating rotator cuff tendon regeneration, and its practical applications for rotator cuff tendon tissue engineering.
  
  
  
  Massive rotator cuff tear is one of the most common shoulder injuries, and poses a formidable clinical challenge to the orthopedic surgeon. Tissue engineering of tendon can potentially overcome the problem. However, more efficacious scaffolds with good biocompatibility, appropriate pore size, favorable inductivity and sufficient mechanical strength for repairing massive rotator cuff tendon injuries need to be developed. In this study, we developed a novel macroporous 3D aligned collagen/silk scaffold, and demonstrated that this novel scaffold enhanced the efficacy of rotator cuff tendon regeneration by inducing aligned supracellular structures similar to natural tendon, which in turn enhanced cellular infiltration and tenogenic differentiation of stem/progenitor cells from both the tendon itself and surrounding tissues. Hence, it can potentially be a clinically useful application for tendon tissue engineering.
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Zhejiang 310000, China; Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Orthopedic Surgery, The Children's Hospital, School of Medicine, Zhejiang University, Zhejiang 310052, China.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Orthopedics Research Institute of Zhejiang University, Zhejiang, China.
authors.forename: Jisheng
authors.initials: J
authors.lastname: Ran
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Orthopedics Research Institute of Zhejiang University, Zhejiang, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Zhejiang 310000, China; Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China.
authors.forename: Yejun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Zhejiang 310000, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang 310009, China; China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Zhejiang 310000, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang 310009, China.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Faculty of Dentistry, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Boon Chin
authors.initials: BC
authors.lastname: Heng
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Feng
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Orthopedics Research Institute of Zhejiang University, Zhejiang, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Le
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Orthopedics Research Institute of Zhejiang University, Zhejiang, China.
authors.forename: Chenqi
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Orthopedics Research Institute of Zhejiang University, Zhejiang, China.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Orthopedics Research Institute of Zhejiang University, Zhejiang, China.
authors.forename: Yangwu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Zhejiang 310000, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310003, China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of Biomechanical Orthopedics, EPFL, Lausanne, Switzerland.
authors.forename: Pioletti
authors.initials: P
authors.lastname: Dominique
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Zhejiang 310000, China; Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang 310009, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Sports Medicine, School of Medicine, Zhejiang University, Zhejiang 310000, China; Laboratory of Biomechanical Orthopedics, EPFL, Lausanne, Switzerland; China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, China; Department of Orthopedics Research Institute of Zhejiang University, Zhejiang, China. Electronic address: shenweiliang365@163.com.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Shen
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Zhejiang 310000, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang 310009, China; Department of Sports Medicine, School of Medicine, Zhejiang University, Zhejiang 310000, China; China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D012831:Bombyx; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D024022:Fibrillar Collagens / Q000737:chemistry* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020007:Implants, Experimental; D016062:Porosity; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration / Q000187:drug effects; D017006:Rotator Cuff / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D047011:Silk / Q000737:chemistry* / Q000494:pharmacology; D034421:Sus scrofa; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D024022:Fibrillar Collagens; D047011:Silk
keywords: Macroporous three-dimensional aligned collagen/silk scaffold; Regeneration; Rotator cuff; Tissue engineering