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tendon.1−4 The protein is responsive to mechanical stress both during the fibrillogenesis process and later in tissue as a response to fatigue,5 loa...
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The Relationship of Collagen Structural and Compositional Heterogeneity to Tissue Mechanical Properties: A Chemical Perspective Junjie Chen,† Taeyong Ahn,‡ Isabel D. Colón-Bernal,† Jinhee Kim,† and Mark M. Banaszak Holl*,†,‡,§ †

Department of Chemistry, ‡Macromolecular Science and Engineering, and §Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States ABSTRACT: Collagen is the primary protein component in mammalian connective tissues. Over the last 20 years, evidence has mounted that collagen matrices exhibit substantial heterogeneity in their hierarchical structures and that this heterogeneity plays important roles in both structure and function. Herein, an overview of studies addressing the nanoscale compositional and structural heterogeneity is provided and connected to work exploring the mechanical implications for a number of tissues.

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collagen-containing tissues and how this fatigue impacts nanoscale structure.

ollagen is the most common protein in mammals and plays a key structural role in many tissues including bone, cartilage, cornea, ligament, skin, teeth, and tendon.1−4 The protein is responsive to mechanical stress both during the fibrillogenesis process and later in tissue as a response to fatigue,5 loading,6 and injury.7 Collagen molecules contain a right-handed triple helix of three polypeptide chains with the repeating amino acid sequence Gly−X−Y in which X is most likely proline and Y is most likely hydroxyproline. Fibril-forming collagens are particularly important molecules for forming tissue scaffolds with the Type I collagen molecule (1.5 nm in diameter and 300 nm in length) being the most common size and present in bone, ligament, skin, and teeth. Self-assembly of Type I collagen molecules with other types of collagens, proteins, and hydroxyapatite minerals into microfibrils, fibrils, and fibers spanning dimensions ranging from a few nanometers to meters in size yields complex hierarchical materials that serve a wide range of structural and mechanical roles.1,8 Understanding the structural and compositional relationships that yield nanomechanical to bulk mechanical properties has been a challenge to the field since early observations of the nanoscale fibril structure.9,10 In this Perspective, we discuss recent advances in experimental and theoretical analysis of collagen microfibril and fibril structure and the challenges inherent in analyzing materials with intrinsic heterogeneity present at the atomic to nanoscale. Changes in nanoscale structure that occur as a function of disease are addressed. We then discuss efforts to understand how nanoscale material heterogeneity relates to mechanical properties of tissue. Finally, we address the issue of material fatigue in © 2017 American Chemical Society

In this Perspective, we discuss recent advances in experimental and theoretical analysis of collagen microfibril and fibril structure and the challenges inherent in analyzing materials with intrinsic heterogeneity present at the atomic to nanoscale. Heterogeneity in collagen-based tissues originates at the level of the collagen molecule.3,11 Although Type I collagen is most common, other types have been proposed to be critical for fibrillogenesis and/or to have importance for certain tissue types. For example, Type V collagen is commonly found with Type I in most tissues, with particularly high levels in cornea. Type II collagen is the primary component of cartilage in combination with smaller levels of Type XI collagen. In addition to heterogeneity at the level of the amino acid sequence, a given collagen molecule can vary on the level of post-translational modification. Finally, collagen fibrils can vary on the level of chemical cross-linking induced by lysyl oxidase. All of these molecular level sources of chemical and structural heterogeneity have the potential to induce heterogeneity at higher hierarchical levels in the tissue, including features such as Published: November 7, 2017 10665

DOI: 10.1021/acsnano.7b06826 ACS Nano 2017, 11, 10665−10671

Perspective

Cite This: ACS Nano 2017, 11, 10665-10671

ACS Nano

Perspective

Figure 1. Hierarchical structure of Type I collagen in bone, skin, and tendon. Reprinted from ref 35. Copyright 2012 American Chemical Society.

tissues is genetic mutation, as exemplified by diseases such as Alport syndrome,12 Ehlers-Danlos syndrome,13 Kniest dysplasia,14 and Osteogenesis imperfecta.15 The Interplay between Nanoscale Heterogeneity and Methods of Characterization. In order to understand how these molecular level drivers of chemical heterogeneity affect the nano- to microscale structure of tissue, it is critical to understand the strengths and limitations of the various physical methods used to characterize collagen structures in tissue. Electron microscopy (EM), the first method used to characterize collagen fibrils, evaluates modulation of electron density in space. Electron microscopy provides structural data on the level of the individual fibril; however, it is important to keep in mind that the electron density patterns reported are typically not of the Type I collagen fibril directly but rather reflect the electron density of a negative or positive stain. X-ray diffraction (XRD) is similar to EM in that it measures the spatial electron density of the sample; however, XRD is an ensemble method that averages over micron to millimeter spatial dimensions and does not provide data on the structure of individual Type I collagen microfibrils or fibrils. X-ray diffraction data were employed to develop the two-dimensional Hodge−Petruska16 model of the collagen fibril. These ideas were further refined and extended to three dimensions17,18 and found their current expression in an average model that consists of five-stranded microfibrils supertwisted in the axial direction and quasi-hexagonally packed in the equatorial plane (Figure 1).19−21 Although the development of these models has been critically important for the progress of the field, XRD averages over length scales far greater than that of the known chemical heterogeneity (