Synthetic design of growth factor sequestering extracellular matrix mimetic hydrogel for promoting in vivo bone formation

Abstract

Synthetic scaffolds that possess an intrinsic capability to protect and sequester sensitive growth factors is a primary requisite for developing successful tissue engineering strategies. Growth factors such as recombinant human bone morphogenetic protein-2 (rhBMP-2) is highly susceptible to premature degradation and to provide a meaningful clinical outcome require high doses that can cause serious side effects. We discovered a unique strategy to stabilize and sequester rhBMP-2 by enhancing its molecular interactions with hyaluronic acid (HA), an extracellular matrix (ECM) component. We found that by tuning the initial protonation state of carboxylic acid residues of HA in a covalently crosslinked hydrogel modulate BMP-2 release at physiological pH by minimizing the electrostatic repulsion and maximizing the Van der Waals interactions. At neutral pH, BMP-2 release is primarily governed by Fickian diffusion, whereas at acidic pH both diffusion and electrostatic interactions between HA and BMP-2 become important as confirmed by molecular dynamics simulations. Our results were also validated in an in vivo rat ectopic model with rhBMP-2 loaded hydrogels, which demonstrated superior bone formation with acidic hydrogel as compared to the neutral counterpart. We believe this study provides new insight on growth factor stabilization and highlights the therapeutic potential of engineered matrices for rhBMP-2 delivery and may help to curtail the adverse side effects associated with the high dose of the growth factor.

Controlling Cell Behavior through the Design of Biomaterial Surfaces: A Focus on Surface Modification Techniques

“…Overall, the design of growth factor releasing substrates can not only influence cellular responses but also increase therapeutic activity and stability of growth factors in coping with chemical enzymatic or chemical degradation . On the other hand, changeability of growth factors in response to biologically relevant stimuli such as light, temperature, pH, and enzymatic degradation makes them appropriate candidates for the design of smart scaffolds …”

An Unexpected Role of Hyaluronic Acid in Trafficking siRNA Across the Cellular Barrier: The First Biomimetic, Anionic, Non‐Viral Transfection Method

“…We have recently demonstrated that subtle changes in the ionic state of HA affect molecular interactions with large proteins,s uch as recombinant human bone morphogenetic protein-2 (rhBMP2). [10] Asimilar model system was adopted to identify the binding parameters of the interaction between the double-stranded siRNAs equence and HA (i.e.R NA fragment interacting with as mall HA oligomer composed of six units) from atheoretical point of view by means of molecular dynamics (MD) simulations.A ne xhaustive overview of the computational protocol is presented in the Supporting Information. Briefly,t welve possible complex structures were obtained through molecular docking (in which major groove,m inor groove,a nd overhangs were considered as potential binding sites) and used as input for MD simulations.…”

Biomaterials for Sequestration of Growth Factors and Modulation of Cell Behavior

“…Finally, novel synthetic platforms with abiotic affinity are envisioned to constitute the next-generation of affinity-binding systems, by allowing a less costly and larger scale production. stimulated the use of materials based, for example, on hyaluronic acid (HA), [47,48] collagen type I, [49] or gelatin, a product of collagen hydrolysis. [50][51][52][53] Besides ECM molecules, other natural polymers widely researched in the field of tissue engineering have also been studied recently for GF delivery.…”