The use of bioinspired alterations in the glycosaminoglycan content of collagen–GAG scaffolds to regulate cell activity

Abstract

The design of biomaterials for regenerative medicine can require biomolecular cues such as growth factors to induce a desired cell activity. Signal molecules are often incorporated into the biomaterial in either freely-diffusible or covalently-bound forms. However, biomolecular environments in vivo are often complex and dynamic. Notably, glycosaminoglycans (GAGs), linear polysaccharides found in the extracellular matrix, are involved in transient sequestration of growth factors via charge interactions. Biomaterials mimicking this phenomenon may offer the potential to amplify local biomolecular signals, both endogenously produced and exogenously added. GAGs of increasing sulfation (hyaluronic acid, chondroitin sulfate, heparin) were incorporated into a collagen–GAG (CG) scaffold under development for tendon tissue engineering. Manipulating the degree of GAG sulfation significantly impacts sequestration of growth factors from the media. Increasing GAG sulfation improved equine tenocyte metabolic activity in normal serum (10% FBS), low serum (1% FBS), and IGF-1 supplemented media conditions. Notably, previously reported dose-dependent changes in tenocyte bioactivity to soluble IGF-1 within the CG scaffold were replicated by using a single dose of soluble IGF-1 in scaffolds containing increasingly sulfated GAGs. Collectively, these results suggest that CG scaffold GAG content can be systematically manipulated to regulate the sequestration and resultant enhanced bioactivity of growth factor signals on cell behavior within the matrix.

The effect of glycosaminoglycan content on polyethylenimine-based gene delivery within three-dimensional collagen-GAG scaffolds

“…12, 15, 16, 40 Recently, we demonstrated that modifying the GAG content of collagen-GAG (CG) scaffolds imparts differential capacity for non-covalent, electrostatic growth factor binding. 41 Notably, by incorporating highly sulfated heparin into the CG scaffold, we saw increased growth factor sequestration and positive impacts on cellular bioactivity compared to scaffolds containing lesser charged GAGs (hyaluronic acid, chondroitin sulfate). While modifying the degree of GAG-sulfation within three-dimensional biomaterials has been shown to impact both biomolecule sequestration and resultant cell response, its impact on the activity of cationic-polymer gene delivery vectors remains poorly understood.…”

Synthesis of the New-Type Vascular Endothelial Growth Factor–Silk Fibroin–Chitosan Three-Dimensional Scaffolds for Bone Tissue Engineering and In Vitro Evaluation

“…This indicates that the growth factor remained bioactive within the matrix in a long time. 42 The time course of osteoblast cells, SF-CS, adhesion clearly demonstrated adhesion of hFOB1.19 to SF-CS scaffolds within minutes. The rapid time course of osteoblast cells adhesion to SF-CS scaffolds was significant, characterized by 29% adhesion by 60 minutes postseeding.…”

Strategies to balance covalent and non-covalent biomolecule attachment within collagen-GAG biomaterials

“…Such a need may only be magnified for studies leveraging bioinspired approaches to transiently immobilize growth factors within the biomaterial through the use of glycosaminoglycan or heparin binding peptides. 32, 36, 38 …”

“…1, 32, 34–36 Notably, while GAG content had previously been shown to impact the regenerative capacity of CG scaffolds in full thickness skin wounds, 14, 37 we recently demonstrated that selective alteration of the GAG content can also be used to impact transient sequestration of growth factors within the matrix as well as resultant cell bioactivity. 38 …”