title: Mechanisms of lamellar collagen formation in connective tissues.
abstract: The objective of tissue engineering is to regenerate functional tissues. Engineering functional tissues requires an understanding of the mechanisms that guide the formation and evolution of structure in the extracellular matrix (ECM). In particular, the three-dimensional (3D) collagen fiber arrangement is important as it is the key structural determinant that provides mechanical integrity and biological function. In this review, we survey the current knowledge on collagen organization mechanisms that can be applied to create well-structured functional lamellar tissues and in particular intervertebral disc and cornea. Thus far, the mechanisms behind the formation of cross-aligned collagen fibers in the lamellar structures is not fully understood. We start with cell-induced collagen alignment and strain-stabilization behavior mechanisms which can explain a single anisotropically aligned collagen fiber layer. These mechanisms may explain why there is anisotropy in a single layer in the first place. However, they cannot explain why a consecutive collagen layer is laid down with an alternating alignment. Therefore, we explored another mechanism, called liquid crystal phasing. While dense concentrations of collagen show such behavior, there is little evidence that the conditions for liquid crystal phasing are actually met in vivo. Instead, lysyl aldehyde-derived collagen cross-links have been found essential for correct lamellar matrix deposition. Furthermore, we suggest that supra-cellular (tissue-level) shear stress may be instrumental in the alignment of collagen fibers. Understanding the potential mechanisms behind the lamellar collagen structure in connective tissues will lead to further improvement of the regeneration strategies of functional complex lamellar tissues.
authors.affiliation: Department of Orthopedic Surgery, VU University Medical Center, Amsterdam, The Netherlands; MOVE Research Institute, VU University, Amsterdam, The Netherlands; Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: s.ghazanfari@vumc.nl.
authors.forename: Samaneh
authors.initials: S
authors.lastname: Ghazanfari
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA; Department of Bioindustrial Technologies, College of Animal Bioscience and Technology, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, Republic of Korea; Department of Physics, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Khademhosseini
authors.affiliation: Department of Orthopedic Surgery, VU University Medical Center, Amsterdam, The Netherlands; MOVE Research Institute, VU University, Amsterdam, The Netherlands.
authors.forename: Theodoor H
authors.initials: TH
authors.lastname: Smit
mesh_terms: D000818:Animals; D003094:Collagen / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D003238:Connective Tissue / Q000378:metabolism*; D003956:Dialysis; D006801:Humans; D007267:Injections
chemical_list: D003094:Collagen
keywords: Arrangment; Collagen; Functional tissue; Lamellar structure; Liquid crystal behavior