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. 2013 Jan;34(4):1033-40.
doi: 10.1016/j.biomaterials.2012.10.062. Epub 2012 Nov 16.

Hydrogels derived from central nervous system extracellular matrix

Christopher J Medberry  1 , Peter M Crapo, Bernard F Siu, Christopher A Carruthers, Matthew T Wolf, Shailesh P Nagarkar, Vineet Agrawal, Kristen E Jones, Jeremy Kelly, Scott A Johnson, Sachin S Velankar, Simon C Watkins, Michel Modo, Stephen F Badylak
Affiliations

Hydrogels derived from central nervous system extracellular matrix

Christopher J Medberry et al. Biomaterials. 2013 Jan.

Abstract

Biologic scaffolds composed of extracellular matrix (ECM) are commonly used repair devices in preclinical and clinical settings; however the use of these scaffolds for peripheral and central nervous system (CNS) repair has been limited. Biologic scaffolds developed from brain and spinal cord tissue have recently been described, yet the conformation of the harvested ECM limits therapeutic utility. An injectable CNS-ECM derived hydrogel capable of in vivo polymerization and conformation to irregular lesion geometries may aid in tissue reconstruction efforts following complex neurologic trauma. The objectives of the present study were to develop hydrogel forms of brain and spinal cord ECM and compare the resulting biochemical composition, mechanical properties, and neurotrophic potential of a brain derived cell line to a non-CNS-ECM hydrogel, urinary bladder matrix. Results showed distinct differences between compositions of brain ECM, spinal cord ECM, and urinary bladder matrix. The rheologic modulus of spinal cord ECM hydrogel was greater than that of brain ECM and urinary bladder matrix. All ECMs increased the number of cells expressing neurites, but only brain ECM increased neurite length, suggesting a possible tissue-specific effect. All hydrogels promoted three-dimensional uni- or bi-polar neurite outgrowth following 7 days in culture. These results suggest that CNS-ECM hydrogels may provide supportive scaffolding to promote in vivo axonal repair.

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Figures

Figure 1
Figure 1
Collagen and sGAG composition in B-ECM and SC-ECM scaffolds. (A) SC-ECM contains a significantly higher percentage of collagen than B-ECM. (B) B-ECM contains a significantly higher concentration of sGAGs than SC-ECM.
Figure 2
Figure 2
B-ECM, SC-ECM, and UBM-ECM Hydrogels and their respective Scanning Electron Micrographs (6mg/mL). (A) B-ECM hydrogel; (B) SC-ECM hydrogel; (C) UBM-ECM hydrogel; (D) B-ECM 1000x; (E) SC-ECM 1000x; (F) UBM-ECM 1000x; (G) B-ECM 10000x; (H) SC-ECM 10000x; (I) UBM-ECM 10000x.
Figure 3
Figure 3
B-ECM and SC-ECM representative turbidimetric and normalized turbidimetric curves. (A) Example absorbance curve and the metrics analyzed. (B) Normalized absorbance for B-ECM (diamonds), SC-ECM (squares), and UBM-ECM (triangles). (C) Lag time comparison for B-ECM, SC-ECM, and UBM-ECM. (D) Time to 50% complete gelation for B-ECM, SC-ECM, and UBM-ECM. (E) Time to 95% complete gelation for B-ECM, SC-ECM, and UBM-ECM. (F) Velocity to complete gelation for B-ECM, SC-ECM, and UBM-ECM following the lag time.
Figure 4
Figure 4
Representative rheologic gelation kinetics for B-ECM and SC-ECM hydrogels (4, 6, and 8 mg/mL). G′ represents the storage modulus and G″ represents the loss modulus. SC-ECM is significantly stiffer than B-ECM at each hydrogel concentration. (A) Storage modulus time sweep for B-ECM, SC-ECM, and UBM-ECM at 8mg/mL. (C) Storage modulus time sweep for B-ECM, SC-ECM, and UBM-ECM at 6mg/mL. (C) Storage modulus time sweep for B-ECM, SC-ECM, and UBM-ECM at 4mg/mL. (D) Final storage modulus for B-ECM, SC-ECM, and UBM-ECM at each concentration. * Indicates statistical significance of p<0.05.
Figure 5
Figure 5
B-ECM and SC-ECM pre-gel solutions increase the number of cells with neurite extensions. All Scaffolds show a dose dependent increase for the number of cells with neurite extension, while only B-ECM shows a dose dependent increase in neurite length with increasing concentrations of ECM. * Indicates statistical significance of p<0.05.
Figure 6
Figure 6
Neurite Extension in B-ECM, SC-ECM, and UBM-ECM in 6mg/mL hydrogels in a 3-D cube or compressed Z-stack. (A) N1E-115 cell extension following 7 days culture in B-ECM in 3-D cube. (B) N1E-115 cell extension following 7 days culture in SC-ECM in 3-D cube. (C) N1E-115 cell extension following 7 days culture in UBM-ECM in 3-D cube. The compressed Z-stack shows B-ECM has short arborizing extensions at two days, while SC-ECM and UBM-ECM have uni- or bi-polar extensions. At 7 days all ECM hydrogels support uni- or bi-polar N1E-115 cell extensions. For 3-D cubes the major tick mark represents 50μm and the minor tick mark represents 10μm. For the Z-stacks the scale bar represents 50μm.
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