Orthogonal Self-Assembly of Bioactive Hydrogels

Hydrogels are of great interest due to their ability to encapsulate and deliver bioactive molecules, mimic the extracellular matrix (ECM) and act as an artificial 3D scaffold. Here we report multi-component hydrogels based on low-molecular-weight gelators (LMWGs) and polymer gelators (PGs) incorporating heparin that can bind to self-assembled molecules, and their potential for controlled release and to mimic the ECM. These multi- component systems were characterised and the orthogonality of each individual component investigated.
Firstly, three cationic surfactants were synthesised and their ability to self-assemble and bind to polyanionic heparin was investigated. The systems consisted of an amine-based head group connected via an amide linkage to different saturated fatty acids. Self- assembled C14-DAPMA and C16-DAPMA formed highly organised polycrystalline assemblies with heparin, proving that the micelles remain intact during the hierarchical assembly process. C16-DAPMA proved to be the most charge-efficient heparin binder, also with the lowest critical aggregation concentration, with high stability when free and solution and when electrostatically interacting with heparin.
Two dibenzylidene-D-sorbitol (DBS) derivatives capable of forming hydrogels are then introduced: a pH-activated LMWG (DBS-COOH) and a thermally-activated LWMG (DBS- CONHNH2). The incorporation and release of heparin from the LMWGs hydrogels in the presence and absence of C16-DAPMA, and from hybrid hydrogels consisting of one of the LMWGs and a PG - agarose is reported. The rate of heparin release can be controlled through network density and composition, and control of the release surface area to volume ratio, while the presence of C16-DAPMA inhibits heparin release. Characterisation of this multi-component complexes (LMWG + Heparin + C16-DAPMA) showed the orthogonal self-assembly of each individual component within one single system. Cytocompatilibity of the multi-component hydrogels is reported. Heparin was then incorporated and released from three different hydrogels based on triamide cyclohexane derivatives. From these, a positively charged LMWG able to directly interact with heparin, resulted in the triggered release of heparin by hydrogel disruption through enzymatic cleavage.