Optimization of Collagen Chemical Crosslinking to Restore Biocompatibility of Tissue-Engineered Scaffolds.

Mohammad Mirazul Islam,Pablo Argüeso,James Chodosh,Hirak K Patra,Alexandru Chivu,Dina B Abusamra,Claes H Dohlman,Miguel González-Andrades

doi:10.3390/pharmaceutics13060832

Abstract

Collagen scaffolds, one of the most used biomaterials in corneal tissue engineering, are frequently crosslinked to improve mechanical properties, enzyme tolerance, and thermal stability. Crosslinkers such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) are compatible with tissues but provide low crosslinking density and reduced mechanical properties. Conversely, crosslinkers such as glutaraldehyde (GTA) can generate mechanically more robust scaffolds; however, they can also induce greater toxicity. Herein, we evaluated the effectivity of double-crosslinking with both EDC and GTA together with the capability of sodium metabisulfite (SM) and sodium borohydride (SB) to neutralize the toxicity and restore biocompatibility after crosslinking. The EDC-crosslinked collagen scaffolds were treated with different concentrations of GTA. To neutralize the free unreacted aldehyde groups, scaffolds were treated with SM or SB. The chemistry involved in these reactions together with the mechanical and functional properties of the collagen scaffolds was evaluated. The viability of the cells grown on the scaffolds was studied using different corneal cell types. The effect of each type of scaffold treatment on human monocyte differentiation was evaluated. One-way ANOVA was used for statistical analysis. The addition of GTA as a double-crosslinking agent significantly improved the mechanical properties and enzymatic stability of the EDC crosslinked collagen scaffold. GTA decreased cell biocompatibility but this effect was reversed by treatment with SB or SM. These agents did not affect the mechanical properties, enzymatic stability, or transparency of the double-crosslinked scaffold. Contact of monocytes with the different scaffolds did not trigger their differentiation into activated macrophages. Our results demonstrate that GTA improves the mechanical properties of EDC crosslinked scaffolds in a dose-dependent manner, and that subsequent treatment with SB or SM partially restores biocompatibility. This novel manufacturing approach would facilitate the translation of collagen-based artificial corneas to the clinical setting.

Highlights

Data from the World Health Organization (WHO) indicate that the current transplantation rate of 100,800 solid organs per year fulfills less than 10% of the global demand [1].any advancement in the development of new biomaterials holds tremendous potential to fill the gap between the supply and demand of donated organs
The treatments were performed on the base materials and untreated samples served as controls (Figure 1)
The compressive modulus was measured to evaluate the mechanical properties of the hydrogel; strong materials exhibit a higher compressive modulus

Summary

Introduction

Any advancement in the development of new biomaterials holds tremendous potential to fill the gap between the supply and demand of donated organs. Engineered organ development is based on the selection of appropriate biomaterials, which usually. Pharmaceutics 2021, 13, 832 requires polymerization processes to form apposite structure of the target organ. Natural biomaterials, such as collagen, show superior biocompatibility but lack optimal mechanical properties. Collagen-based biomaterials are widely used for tissue engineering because of their excellent properties for creating regenerative cell-free scaffolds for tissue engineering as seen in early clinical evaluations [2,3,4]. The clinical success of collagen scaffolds is based on their excellent biocompatibility. Bioactivity is hindered mostly by poor mechanical behavior and a high vulnerability to enzymatic digestion [5]

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