To Cross-Link or Not to Cross-Link? Cross-Linking Associated Foreign Body Response of Collagen-Based Devices

Abstract

Collagen-based devices, in various physical conformations, are extensively used for tissue engineering and regenerative medicine applications. Given that the natural cross-linking pathway of collagen does not occur in vitro, chemical, physical, and biological cross-linking methods have been assessed over the years to control mechanical stability, degradation rate, and immunogenicity of the device upon implantation. Although in vitro data demonstrate that mechanical properties and degradation rate can be accurately controlled as a function of the cross-linking method utilized, preclinical and clinical data indicate that cross-linking methods employed may have adverse effects on host response, especially when potent cross-linking methods are employed. Experimental data suggest that more suitable cross-linking methods should be developed to achieve a balance between stability and functional remodeling.

Temporal and spatial distribution of macrophage phenotype markers in the foreign body response to glutaraldehyde-crosslinked gelatin hydrogels

“…Many studies have been performed over the years to evaluate the FBR to glutaraldehyde-crosslinked biomaterials [42–45]. While the concentrations of glutaraldehyde used in the present work were substantially lower than those used in the preparation of clinically utilized bioprosthetic heart valves [30] and wound dressings [32], it is likely that the lowest concentration of glutaraldehyde studied here was sufficient to induce as much inflammation as the highest concentration.…”

Extracellular matrix-based biomaterial scaffolds and the host response

“…Evidence supporting this hypothesis can be found through investigation of host responses to cross-linked collagen implants, rendering their degradation and removal more difficult. Analysis of host responses to cross-linked collagen is detailed elsewhere [45]. Numerous studies conclude that prolonged degradation rates from increasing crosslink density are associated with more severe host FBRs as evidenced by the presence of FBGC’s, and fibrous capsule formation around the implanted material [39, 45–47].…”

“…Analysis of host responses to cross-linked collagen is detailed elsewhere [45]. Numerous studies conclude that prolonged degradation rates from increasing crosslink density are associated with more severe host FBRs as evidenced by the presence of FBGC’s, and fibrous capsule formation around the implanted material [39, 45–47]. The method of crosslinking seems to be largely irrelevant to the FBR intensity achieved.…”

“…Interestingly, there has been little research into naturally cross-linked collagen host FBRs. While collagen crosslinking via lysyl oxidase, an enzyme responsible for natural collagen crosslinking in vivo, has not been feasible ex vivo, other natural cross-linking methods such as the use of transglutaminases have not been studied with respect to the host FBR [45, 48–50]. This would substantiate the operative hypothesis that unnatural, therefore difficult-to-breakdown, crosslinking leads to the observed increased FBR to crosslinked collagen implants [45].…”

Recreating complex pathophysiologies in vitro with extracellular matrix surrogates for anticancer therapeutics screening

“…These findings (rigidity) are of significant importance, given that the matrix rigidity stimulates epithelial-mesenchymal transition and endorses tumour invasion and metastasis, following mechano-signalling pathways [156,[160][161][162][163]. Nevertheless, the high water content and the fast degradation rate of low-density cross-linked hydrogels and the low water content, low degradation rate, high cytotoxicity and low diffusion of high cross-linking density hydrogels [164,165] have triggered investigation into alternative scaffold-based models.…”