Thiol-ene crosslinking polyamidoamine dendrimer-hyaluronic acid hydrogel system for biomedical applications

Abstract

A series of alkene functionalized polyamidoamine (PAMAM) dendrimers were synthesized to prepare in situ forming hydrogels with varied gelation time and mechanical properties through crosslinking with thiolated hyaluronic acid (HS-HA). By varying the alkenyl groups on the dendrimers, the gelation time displayed a large range from 8 seconds to 18 hours, and the modulus of the hydrogels ranged from 36 to 183 Pa under experimental conditions. Investigation by (1)H-NMR spectroscopy revealed that the gelation time and the stiffness of the hydrogels were governed by the degree of electron deficiency of alkenyl groups on the dendrimers. This research provided a systematic study on the relationship between chemical structures versus gelation time and mechanical properties of hydrogels, which could guide the way to synthesize in situ forming hydrogels with designated gelation time and stiffness for biomedical applications. Further, a RGD peptide was attached to the PAMAM dendrimers to enhance cell attachment and proliferation. Viability assays of Human Umbilical Vein Endothelial Cells (HUVEC) in the synthesized hydrogels demonstrated the biocompatibility of the hydrogels after 48 hours of culturing, and the RGD peptide improved the viability of HUVEC cells in hydrogels. We believe the PAMAM/HA hydrogel system is a tuneable and biocompatible system for diverse biomedical applications.

Crosslinkers for polysaccharides and proteins: Synthesis conditions, mechanisms, and crosslinking efficiency, a review

“…The different systems presented tailored gelation times and mechanical properties according to the electron density of the alkenyl end groups on the dendrimer. The storage modulus of the hydrogels decreased in the same order as for gelation time with functional groups on PAMAM from maleimide, to vinyl sulfone, acrylic, methacrylic, and alkene, respectively, ranging from 36 to 183 Pa under the experimental condition [300].…”

Methods for producing microstructured hydrogels for targeted applications in biology

“…In addition to the stabilization of emulsions, crosslinking is necessary in most cases to generate mechanically robust, microstructured hydrogels [72,204]. Multiple chemistries have been employed for this purpose, including Michael-type addition reactions between a nucleophile and an electron-poor unsaturated compound; thiols are the most commonly used nucleophiles whereas the unsaturated group could be acrylate, maleimide, and vinyl sulfone depending on the desired reactivity that can range from the tens of minutes for acrylic compounds to a couple of minutes and even few seconds for both maleimide and vinyl sulfone [145,205]. Due to the increase in nucleophilicity of the thiol group when it is deprotonated, pH is a factor influencing the time of reaction so it can be reduced to just some minutes in acrylates when the crosslinking is conducted under basic conditions [78,206].…”

Thiolated Hyaluronic Acid as Versatile Mucoadhesive Polymer: From the Chemistry Behind to Product Developments—What Are the Capabilities?

“…As thiolated HA has great potential within the medical field, some products are already available on the market. For instance, Glycosil ® [92] represents a thiol-modified hyaluronic acid and is utilized for 3D cell culturing and tissue engineering applications [93]. HyStem ® , a hydrogel kit containing Glycosil ® as a main component, could be applied for biomedical applications such as wound healing as mentioned previously [76].…”