title: Optimization of intrinsic and extrinsic tendon healing through controllable water-soluble mitomycin-C release from electrospun fibers by mediating adhesion-related gene expression.
abstract: To balance intrinsic and extrinsic healing during tendon repair is challenging in tendon surgery. We hypothesized that by mediating apoptotic gene and collagen synthesis of exogenous fibroblasts, the adhesion formation induced by extrinsic healing could be inhibited. With the maintenance of intrinsic healing, the tendon could be healed with proper function with no adhesion. In this study, we loaded hydrophilic mitomycin-C (MMC) into hyaluronan (HA) hydrosols, which were then encapsulated in poly(L-lactic acid) (PLLA) fibers by micro-sol electrospinning. This strategy successfully provided a controlled release of MMC to inhibit adhesion formations with no detrimental effect on intrinsic healing. We found that micro-sol electrospinning was an effective and facile approach to incorporate and control hydrophilic drug release from hydrophobic polyester fibers. MMC exhibited an initially rapid, and gradually steadier release during 40 days, and the release rates could be tuned by its concentration. In vitro studies revealed that low concentrations of MMC could inhibit fibroblast adhesion and proliferation. When lacerate tendons were healed using the MMC-HA loaded PLLA fibers in vivo, they exhibited comparable mechanical strength to the naturally healed tendons but with no significant presence of adhesion formation. We further identified the up-regulation of apoptotic protein Bax expression and down-regulation of proteins Bcl2, collage I, collagen III and α-SMA during the healing process associated with minimum adhesion formations. This approach presented here leverages new advances in drug delivery and nanotechnology and offers a promising strategy to balance intrinsic and extrinsic tendon healing through modulating genes associated with fibroblast apoptosis and collagen synthesis.
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute, Soochow University, 708 Renmin Rd, Suzhou, Jiangsu 215006, PR China; Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge 02139, MA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai 200233, PR China.
authors.forename: Shichao
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai 200233, PR China.
authors.forename: Shen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai 200233, PR China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge 02139, MA, USA.
authors.forename: Zhi Yuan William
authors.initials: ZY
authors.lastname: Lin
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute, Soochow University, 708 Renmin Rd, Suzhou, Jiangsu 215006, PR China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Pan
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute, Soochow University, 708 Renmin Rd, Suzhou, Jiangsu 215006, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai 200233, PR China.
authors.forename: Fengfeng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai 200233, PR China. Electronic address: fancunyi888@hotmail.com.
authors.forename: Cunyi
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute, Soochow University, 708 Renmin Rd, Suzhou, Jiangsu 215006, PR China; Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge 02139, MA, USA. Electronic address: wgcui80@hotmail.com.
authors.forename: Wenguo
authors.initials: W
authors.lastname: Cui
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis*; D004058:Diffusion; D004595:Electroplating / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D016685:Mitomycin / Q000008:administration & dosage* / Q000737:chemistry; D041681:NIH 3T3 Cells; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D057139:Nanofibers / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D052256:Tendinopathy / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000267:Tissue Adhesions / Q000378:metabolism / Q000517:prevention & control; D016896:Treatment Outcome; D014867:Water / Q000737:chemistry; D014945:Wound Healing / Q000187:drug effects
chemical_list: D015815:Cell Adhesion Molecules; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D014867:Water; D016685:Mitomycin
keywords: Adhesion formation; Electrospun fibers; Micro-sol; Tendon healing; Water-soluble drug