title: Substrate topography: A valuable in vitro tool, but a clinical red herring for in vivo tenogenesis.
abstract: Controlling the cell-substrate interactions at the bio-interface is becoming an inherent element in the design of implantable devices. Modulation of cellular adhesion in vitro, through topographical cues, is a well-documented process that offers control over subsequent cellular functions. However, it is still unclear whether surface topography can be translated into a clinically functional response in vivo at the tissue/device interface. Herein, we demonstrated that anisotropic substrates with a groove depth of ∼317nm and ∼1988nm promoted human tenocyte alignment parallel to the underlying topography in vitro. However, the rigid poly(lactic-co-glycolic acid) substrates used in this study upregulated the expression of chondrogenic and osteogenic genes, indicating possible tenocyte trans-differentiation. Of significant importance is that none of the topographies assessed (∼37nm, ∼317nm and ∼1988nm groove depth) induced extracellular matrix orientation parallel to the substrate orientation in a rat patellar tendon model. These data indicate that two-dimensional imprinting technologies are useful tools for in vitro cell phenotype maintenance, rather than for organised neotissue formation in vivo, should multifactorial approaches that consider both surface topography and substrate rigidity be established.
  
  
  CONCLUSIONS
  Herein, we ventured to assess the influence of parallel groves, ranging from nano- to micro-level, on tenocytes response in vitro and on host response using a tendon and a subcutaneous model. In vitro analysis indicates that anisotropically ordered micro-scale grooves, as opposed to nano-scale grooves, maintain physiological cell morphology. The rather rigid PLGA substrates appeared to induce trans-differentiation towards chondrogenic and/or steogenic lineage, as evidence by TILDA gene analysis. In vivo data in both tendon and subcutaneous models indicate that none of the substrates induced bidirectional host cell and tissue growth. Collective, these observations indicate that two-dimensional imprinting technologies are useful tools for in vitro cell phenotype maintenance, rather than for directional neotissue formation, should multifactorial approaches that consider both surface topography and substrate rigidity be established.
authors: Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building (BRB), National University of Ireland Galway (NUI Galway), Galway, Ireland; Network of Excellence for Functional Biomaterials (NFB), BRB, NUI Galway, Galway, Ireland; Centre for Research in Medical Devices (CÚRAM), BRB, NUI Galway, Galway, Ireland.
authors: Andrew
authors: A
authors: English
authors: Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building (BRB), National University of Ireland Galway (NUI Galway), Galway, Ireland; Network of Excellence for Functional Biomaterials (NFB), BRB, NUI Galway, Galway, Ireland; Centre for Research in Medical Devices (CÚRAM), BRB, NUI Galway, Galway, Ireland.
authors: Ayesha
authors: A
authors: Azeem
authors: Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building (BRB), National University of Ireland Galway (NUI Galway), Galway, Ireland; Network of Excellence for Functional Biomaterials (NFB), BRB, NUI Galway, Galway, Ireland; Centre for Research in Medical Devices (CÚRAM), BRB, NUI Galway, Galway, Ireland.
authors: Kyriakos
authors: K
authors: Spanoudes
authors: School of Biological Sciences, University of East Anglia, Norwich, UK.
authors: Eleanor
authors: E
authors: Jones
authors: Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, Dublin, Ireland.
authors: Bhawana
authors: B
authors: Tripathi
authors: Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, Dublin, Ireland.
authors: Nandita
authors: N
authors: Basu
authors: Materials and Surface Science Institute (MSSI), Department of Physics and Energy, University of Limerick, Limerick, Ireland.
authors: Karrina
authors: K
authors: McNamara
authors: Materials and Surface Science Institute (MSSI), Department of Physics and Energy, University of Limerick, Limerick, Ireland.
authors: Syed A M
authors: SAM
authors: Tofail
authors: Proxy Biomedical, Galway, Ireland.
authors: Niall
authors: N
authors: Rooney
authors: School of Biological Sciences, University of East Anglia, Norwich, UK.
authors: Graham
authors: G
authors: Riley
authors: Tyndall National Institute, Cork, Ireland.
authors: Alan
authors: A
authors: O'Riordan
authors: Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, Dublin, Ireland.
authors: Graham
authors: G
authors: Cross
authors: Institute of Health & Biomedical Innovation, Queensland University of Technology, Australia.
authors: Dietmar
authors: D
authors: Hutmacher
authors: Network of Excellence for Functional Biomaterials (NFB), BRB, NUI Galway, Galway, Ireland; Centre for Research in Medical Devices (CÚRAM), BRB, NUI Galway, Galway, Ireland.
authors: Manus
authors: M
authors: Biggs
authors: Network of Excellence for Functional Biomaterials (NFB), BRB, NUI Galway, Galway, Ireland; Centre for Research in Medical Devices (CÚRAM), BRB, NUI Galway, Galway, Ireland.
authors: Abhay
authors: A
authors: Pandit
authors: Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biosciences Research Building (BRB), National University of Ireland Galway (NUI Galway), Galway, Ireland; Network of Excellence for Functional Biomaterials (NFB), BRB, NUI Galway, Galway, Ireland; Centre for Research in Medical Devices (CÚRAM), BRB, NUI Galway, Galway, Ireland. Electronic address: dimitrios.zeugolis@nuigalway.ie.
authors: Dimitrios I
authors: DI
authors: Zeugolis
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D019544:Equipment Failure Analysis; D006801:Humans; D008422:Materials Testing; D011474:Prosthesis Design; D013499:Surface Properties; D013710:Tendons / Q000166:cytology* / Q000254:growth & development*; D023822:Tissue Engineering / Q000295:instrumentation* / Q000379:methods; D054457:Tissue Scaffolds
chemical_list: D001672:Biocompatible Materials
keywords: Lithography; Substrate stiffness; Surface topography; Tendon; Tenocyte morphology; Tenocyte phenotype; Tenocyte trans-differentiation; Tissue regeneration