Incorporation of sulfated hyaluronic acid macromers into degradable hydrogel scaffolds for sustained molecule delivery

Abstract

Synthetically sulfated hyaluronic acid (HA) has been shown to bind proteins with high affinity through electrostatic interactions. While HA-based hydrogels have been used widely in recent years for drug delivery and tissue engineering applications, incorporation of sulfated HA into these networks to attenuate the release of proteins has yet to be explored. Here, we developed sulfated and methacrylate-modified HA macromers and incorporated them into HA hydrogels through free radical-initiated crosslinking. The sulfated HA macromers bound a heparin-binding protein (i.e., stromal cell-derived factor 1-α, SDF-1α) with an affinity comparable to heparin and did not alter the gelation behavior or network mechanics when copolymerized into hydrogels at low concentrations. Further, these macromers were incorporated into electrospun nanofibrous hydrogels to introduce sulfate groups into macroporous scaffolds. Once incorporated into either uniform or fibrous HA hydrogels, the sulfated HA macromers significantly slowed encapsulated SDF-1α release over 12 days. Thus, these macromers provide a useful way to introduce heparin-binding features into radically-crosslinked hydrogels to alter protein interactions for a range of applications.

Hyaluronan/Collagen Hydrogels with Sulfated Hyaluronan for Improved Repair of Vascularized Tissue Tune the Binding of Proteins and Promote Endothelial Cell Growth

“…HA‐AC/sHA1‐AC/coll possessed the lowest water content after crosslinking and displayed the lowest volume changes after lyophilization compared to HA‐AC/coll. The swelling ratio of the HA‐AC gels, which represents the gel mass increase due to water binding relative to the initial weight of the gels after freeze‐drying, was significantly reduced in the presence of coll type I (HA‐AC/coll), while it increased in the presence of sGAG‐AC compared to HA‐AC/coll (Figure C), which is in line with previous observations for sHA‐containing gels compared to pure HA‐based hydrogels . Gels containing coll type I and sGAG‐AC had a comparable swelling ratio like HA‐AC without coll type I.…”

“…In contrast to Guo et al, who used an analog preparation techniques to develop collagen‐based hydrogels with crosslinked methacrylated HA and CS for cartilage tissue engineering, we prepared HA‐based hydrogels with much higher GAG to collagen mass ratios (20:1 vs 1:2 in the case of Guo et al) aiming to improve the regeneration of vascularized tissues such as skin. Thereby, we strongly limit the usage of collagen as animal‐derived biomaterial component, while at the same time provide also in contrast to other HA‐based hydrogels with sHA, ligands required for cell adhesion. Furthermore, we were able to generate hydrogels with about 43–150% higher sHA percentages compared to previous publications, which we expect to be favorable to modulate the interaction with proteins and cells since a higher number of potential interaction sites are available.…”

“…Thereby, we strongly limit the usage of collagen as animal‐derived biomaterial component, while at the same time provide also in contrast to other HA‐based hydrogels with sHA, ligands required for cell adhesion. Furthermore, we were able to generate hydrogels with about 43–150% higher sHA percentages compared to previous publications, which we expect to be favorable to modulate the interaction with proteins and cells since a higher number of potential interaction sites are available.…”

Hyaluronic Acid Graft Copolymers with Cleavable Arms as Potential Intravitreal Drug Delivery Vehicles

“…Most of the esterification methods reported for HA involve a pretreatment of the polysaccharide (acidification or hydrophobic salt) in order to solubilize it into polar aprotic solvents, such as DMSO . This additional step is time‐consuming, may lead to degradation of the chains and complicates the purification of the products, hence we explored ways to functionalize the commercially available sodium salt of HA directly.…”

Tissue engineering strategies for promoting vascularized bone regeneration

“…Immunomodulation by the MSCs is accomplished by secretion of immunosuppressive and antiinflammatory cytokines, such as interleukin-10 131 , nitric oxide 132 and prostaglandins 133 . MSCs can also regulate T-cells in an antigen-independent manner 89 through the suppression of the primary and secondary T-cell responses by inhibiting cell proliferation 134–136 .…”