Abstract
.Significance: Morphological collagen signatures are important for tissue function, particularly in the tumor microenvironment. A single algorithmic framework with quantitative, multiscale morphological collagen feature extraction may further the use of collagen signatures in understanding fundamental tumor progression.Aim: A modification of the 2D wavelet transform modulus maxima (WTMM) anisotropy method was applied to both digitally simulated collagen fibers and second-harmonic-generation imaged collagen fibers of mouse skin to calculate a multiscale anisotropy factor to detect collagen fiber organization.Approach: The modified 2D WTMM anisotropy method was initially validated on synthetic calibration images to establish the robustness and sensitivity of the multiscale fiber organization tool. Upon validation, the algorithm was applied to collagen fiber organization in normal wild-type skin, melanoma stimulated skin, and integrin skin.Results: Normal wild-type skin collagen fibers have an increased anisotropy factor at all sizes scales. Interestingly, the multiscale anisotropy differences highlight important dissimilarities between collagen fiber organization in normal wild-type skin, melanoma stimulated, and integrin skin. At small scales ( to ), the integrin skin was vastly different than normal skin (), whereas the melanoma stimulated skin was vastly different than normal at large scales ( to , ).Conclusions: This objective computational collagen fiber organization algorithm is sensitive to collagen fiber organization across multiple scales for effective exploration of collagen morphological alterations associated with melanoma and the lack of integrin binding.
Highlights
Collagen is the most abundant protein in our body, with estimates of at least 28 different subtypes identified as a primary protein component of the extracellular matrix (ECM)
At small scales (∼2 to 3 μm), the integrin α10 knockout mice (α10KO) skin was vastly different than normal skin (p-value ∼ 10−8), whereas the melanoma stimulated skin was vastly different than normal at large scales (∼30 to 40 μm, p-value ∼ 10−15)
This objective computational collagen fiber organization algorithm is sensitive to collagen fiber organization across multiple scales for effective exploration of collagen morphological alterations associated with melanoma and the lack of α10 integrin binding
Summary
Collagen is the most abundant protein in our body, with estimates of at least 28 different subtypes identified as a primary protein component of the extracellular matrix (ECM). Collagen molecules are stabilized via hydrogen binding and are further stabilized into both fibril and fiber structures via covalent bounds.[1,2,3] This unique structure of collagen provides a noncentrosymmetric organization of permanent dipole moments on the size scale of ∼300 to 500 nm,[4] creating an ideal “harmonophore” for second-harmonic generation (SHG). Tilbury et al.: Multiscale anisotropy analysis of second-harmonic generation collagen imaging of mouse skin tensor, which requires a permanent dipole moment with a noncentrosymmetric organization on the size-sale of the wavelength λSHG.[5] SHG imaging microscopy is a coherent process in which two photons interact with the noncentrosymmetric structure and create a single photon with exactly twice the frequency (half the wavelength, λSHG) of the incident/excitation laser. SHG microscopy has been used to explore the natural remodeling of the collagen in the cervix during child-birth[8,9] and the reorganization of collagen in the skin due to aging,[10] as well as various diseased states including fibrotic diseases such as idiopathic pulmonary fibrosis[11,12] and several distinct cancer types including breast, ovarian, pancreatic, colon, and melanoma.[13,14,15,16,17,18,19]
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