title: Repair of dense connective tissues via biomaterial-mediated matrix reprogramming of the wound interface.
abstract: Repair of dense connective tissues in adults is limited by their intrinsic hypocellularity and is exacerbated by a dense extracellular matrix (ECM) that impedes cellular migration to and local proliferation at the wound site. Conversely, healing in fetal tissues occurs due in part to an environment conducive to cell mobility and division. Here, we investigated whether the application of a degradative enzyme, collagenase, could reprogram the adult wound margin to a more fetal-like state, and thus abrogate the biophysical impediments that hinder migration and proliferation. We tested this concept using the knee meniscus, a commonly injured structure for which few regenerative approaches exist. To focus delivery and degradation to the wound interface, we developed a system in which collagenase was stored inside poly(ethylene oxide) (PEO) electrospun nanofibers and released upon hydration. Through a series of in vitro and in vivo studies, our findings show that partial digestion of the wound interface improves repair by creating a more compliant and porous microenvironment that expedites cell migration to and/or proliferation at the wound margin. This innovative approach of targeted manipulation of the wound interface, focused on removing the naturally occurring barriers to adult tissue repair, may find widespread application in the treatment of injuries to a variety of dense connective tissues.
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA; Comparative Orthopaedic Research Laboratory, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348, USA.
authors.forename: Feini
authors.initials: F
authors.lastname: Qu
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pintauro
authors.affiliation: Comparative Orthopaedic Research Laboratory, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348, USA.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Haughan
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Henning
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Esterhai
authors.affiliation: Comparative Orthopaedic Research Laboratory, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Schaer
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA. Electronic address: lemauck@mail.med.upenn.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Mauck
authors.affiliation: McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA. Electronic address: mbfisher@ncsu.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D003238:Connective Tissue / Q000502:physiology*; D018625:Microscopy, Atomic Force; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D012756:Sheep; D054457:Tissue Scaffolds / Q000737:chemistry*; D014945:Wound Healing / Q000502:physiology
chemical_list: D001672:Biocompatible Materials; D011092:Polyethylene Glycols
keywords: Connective tissue; Drug delivery; ECM (extracellular matrix); In vivo test; Scaffold; Wound healing