Research Papers

Spatiotemporal Characterization of Extracellular Matrix Microstructures in Engineered Tissue: A Whole-Field Spectroscopic Imaging Approach

[+] Author and Article Information
Zhengbin Xu

Weldon School of Biomedical Engineering,
Purdue University,
West Lafayette, IN 47907

Altug Ozcelikkale

School of Mechanical Engineering,
Purdue University,
West Lafayette, IN 47907

Young L. Kim

Weldon School of Biomedical Engineering,
Purdue University,
West Lafayette, IN 47907
e-mail: youngkim@purdue.edu

Bumsoo Han

School of Mechanical Engineering,
and Weldon School of Biomedical Engineering,
Purdue University,
West Lafayette, IN 47907e-mail: 

1Corresponding authors.

Manuscript received October 23, 2012; final manuscript received March 28, 2013; published online July 11, 2013. Assoc. Editor: Liang Zhu.

J. Nanotechnol. Eng. Med 4(1), 011003 (Jul 11, 2013) (9 pages) Paper No: NANO-12-1129; doi: 10.1115/1.4024130 History: Received October 23, 2012; Revised March 28, 2013

Quality and functionality of engineered tissues are closely related to the microstructures and integrity of their extracellular matrix (ECM). However, currently available methods for characterizing ECM structures are often labor-intensive, destructive, and limited to a small fraction of the total area. These methods are also inappropriate for assessing temporal variations in ECM structures. In this study, to overcome these limitations and challenges, we propose an elastic light scattering approach to spatiotemporally assess ECM microstructures in a relatively large area in a nondestructive manner. To demonstrate its feasibility, we analyze spectroscopic imaging data obtained from acellular collagen scaffolds and dermal equivalents as model ECM structures. For spatial characterization, acellular scaffolds are examined after a freeze/thaw process mimicking a cryopreservation procedure to quantify freezing-induced structural changes in the collagen matrix. We further analyze spatial and temporal changes in ECM structures during cell-driven compaction in dermal equivalents. The results show that spectral dependence of light elastically backscattered from engineered tissue is sensitively associated with alterations in ECM microstructures. In particular, a spectral decay rate over the wavelength can serve as an indicator for the pore size changes in ECM structures, which are at nanometer scale. A decrease in the spectral decay rate suggests enlarged pore sizes of ECM structures. The combination of this approach with a whole-field imaging platform further allows visualization of spatial heterogeneity of EMC microstructures in engineered tissues. This demonstrates the feasibility of the proposed method that nano- and micrometer scale alteration of the ECM structure can be detected and visualized at a whole-field level. Thus, we envision that this spectroscopic imaging approach could potentially serve as an effective characterization tool to nondestructively, accurately, and rapidly quantify ECM microstructures in engineered tissue in a large area.

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Grahic Jump Location
Fig. 1

Schematic diagram of the spectroscopic imaging setup. This system obtains three-dimensional data sets as a function of (x, y, λ). Back-directional gating in the imaging arm significantly reduces cross-talk among adjacent (x, y) locations and allows large-area imaging.

Grahic Jump Location
Fig. 2

(a) Representative spectra of elastically backscattered light from unfrozen and frozen/thawed regions of each collagen scaffold. (b) Comparison of spectral decay rates β for each scaffold region. Error bar represents standard deviations (n ≥ 3 for all data points).

Grahic Jump Location
Fig. 3

(a)–(c) Representative SEM images of the scaffold microstructures from unfrozen and frozen/thawed regions. (d) Comparison of mean void areas for each scaffold region. (e) Correlation between the mean void areas and the spectral decay rates β for three distinct cases. Error bar represents standard deviations (n ≥ 3 for all data points).

Grahic Jump Location
Fig. 4

Representative 2D planar spectroscopic images using the spectral decay rate β for unfrozen and frozen/thawed regions of each scaffold

Grahic Jump Location
Fig. 5

Representative cryo-SEM images of engineered scaffolds. (a) Dermal equivalent—white area is zoomed and shown on the right. (b) Acellular collagen matrix. Dermal equivalent has compacted matrix structure with thinner collagen fibrils. Very fine fibril structures are observed around the cell, which is not observed in acellular matrix.

Grahic Jump Location
Fig. 6

Time-lapse spectroscopic images of dermal equivalent ((a) and (b)) and acellular matrix ((c) and (d)) for 2.5 h time period. (a) The spectral decay rate β increases over time. (b) Pseudocolor spectroscopic images after subtracting the image at the initial time-point (T1). The red color represents locally dense ECM structure, which is thought to be caused by the cell-driven compaction. (c) and (d) The spectral signal from acellular matrix showed no change over the same time period.



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