Tailoring Stimuli Responsiveness using Dynamic Covalent Cross-Linking of Poly(vinyl alcohol)-Heparin Hydrogels for Controlled Cell and Growth Factor Delivery

Abstract

Heparin-based hydrogels are attractive for cell encapsulation and drug delivery because of the ability of heparin to bind native proteins. However, heparin-based hydrogels have received little attention for their potential as stimuli-sensitive materials. Biosynthetic, poly(vinyl alcohol) (PVA)-heparin hydrogels were formed using dynamic, covalent crosslinking. Hydrogel stimuli-sensitivity was tailored by tuning the concentration of heparin to PVA. Relatively thermally and pH stable hydrogels were produced when formed from only the synthetic, nonionic PVA polymer cross-linked via hydrazone bonds. Cross-linking in the ionic biopolymer heparin, to form PVA-heparin gels, has a profound impact on thermal stability, with degradation ranging from over 6 months to only 4 days across 25−50 °C. PVA-heparin hydrogels degrade within 18 days at basic pH (10), while not fully degrading over 6 months at lower pH (4, 7.4). This finding is attributed to the anionic repulsion of carboxyls and sulfates in heparin. PVA-heparin macromers were cytocompatible and enabled mild cell encapsulation, in addition to providing pH-controlled growth factor release. Overall, it is demonstrated that the biopolymer heparin can be used to create pH and temperature-responsive hydrogel biomaterials for cell and drug delivery.

In situ formation of poly(vinyl alcohol)–heparin hydrogels for mild encapsulation and prolonged release of basic fibroblast growth factor and vascular endothelial growth factor

“…oxidized amino-glycerol) as previously described. 28,30,31 Heparin was functionalized with an aldehyde of the same oxidized amino-glycerol moiety, using a regio-selective modification method that does not oxidize (i.e. cleave) the native polymer.…”

“…cleave) the native polymer. 9,28 Retaining the native heparin polymer structure may be important to provide sufficient heparin-binding sites for encapsulated growth factors. 34,35 The hydrazide and aldehyde containing macromers were dissolved separately from each other and with any molecules for encapsulation (e.g.…”

“…28 Briefly, to synthesize PVA-HY, PVA was dissolved in DMSO with CDI. Glycine ethyl ester hydrochloride and triethylamine were added and the reaction was stirred overnight.…”

“…30 Moreover, hydrazone bonding is advantageous because it provides for injectable, in situ hydrogel formation within a clinically relevant time frame of several minutes. 28 …”

Tissue engineering of retina and Bruch’s membrane: a review of cells, materials and processes

“…Properties such as degradation, biocompatibility, melting point, transitional temperature and mechanical strength can be built directly into their chain 35. Polymers as such can be manipulated to degrade under very specific conditions such as pH36 and temperature,37 depending on its intended applications. One such example of a synthetic polymer is poly(lactic-co-glycolic) acid (PLGA) 38.…”