Multiresponsive Supramolecular Hydrogels Based On Phenylalanine Derivative With Controllable Chirality And Cell Adhesion

Manipulating cell adhesion response to external stimuli for simulating the complex function of living systems in vitro is of high interest both in medical basic research and for biotechnological applications. This motivation has led to the development of new biocompatible approaches to tailor cellular microenvironments. However, with few exceptions, it still remains a big challenge to regulate cell adhesion in three-dimensional(3D) environments, especially, to develop smart 3D scaffolds for resembling the living systems as a response to the applied stimuli. Supramolecular hydrogels assembled from amino acid derivative have been extensively studied as smart 3D scaffolds due to their excellent abilities to simulate the natural extracellular matrix(ECM) and respond to various external stimuli.Herein, we describe the use of the two enantiomers of a 1,4-benzenedicarboxamide phenylalanine derivative(DPH, LPH) as supramolecular gelators to investigate the influence of the chirality of nanofibers on cell adhesion and proliferation in three dimensions. To tuning the chirality of the nanofibers, it usually require the participation of chiral guests or asymmetric factors to influence the conformation of chiral assemblies. A left important challenge is how to tune the helical conformation(right-handed, P, or left-handed, M) of nanostructures by achiral guest molecules. Fortunately, the helical inversion of nanofibrous structures assembled from supramolecular hydrogel is successfully achieved by using achiral bis(pyridinyl) derivatives. To date, constructing an efficient hydrogel system exhibiting multiresponsive properties still poses a challenge. A multiresponsive hydrogel system coassembled from C2-derived Lphenylalanine derivative gelator(LPF2) and azobenzene(Azo) derivative is constructed to install gel-based supramolecular logic gates and to control cell encapsulation and release in three dimensional environments. The contents and results of thesis are as follows: 1. Control of three-dimensional cell adhesion by the chirality of nanofibers in hydrogels1) Supramolecular hydrogels based on two enantiomers of 1,4-benzenedicarboxamide phenylalanine derivative are achieved.2) Helical nanofibers of the supramolecular hydrogel are confirmed by SEM, TEM, and AFM. And the distinct difference between the chirality of supramolecular hydrogel and the chirality of gelators is demonstrated by CD measurement. Moreover, it is found that the supramolecular chirality of hydrogels can be controlled by external stimuli such as temperature and assembly time.3) We describe the use of two enantiomers of a 1,4-benzenedicarbox amide phenylalanine derivative as supramolecular gelators to investigate the influence of the chirality of nanofibers on cell adhesion and proliferation in three dimensions. It was found that left-handed helical nanofibers can increase cell adhesion and proliferation, whereas right-handed nanofibers have the opposite effect. The effect is ascribed to the mediation of the stereospecific interaction between chiral nanofibers and fibronectin. The results stress the crucial role of the chirality of nanofibers on cell-adhesion behavior in 3D environments. 2. Tuning the supramolecular chirality of co-assembled hydrogels by achiral bis(pyridinyl) derivative1) A supramolecular hydrogel system with chiral nanofibrous structures is co-assembled from phenylalanine based amphiphile and achiral bis(pyridinyl) derivative.2) It is found that the chirality of supramolecular hydrogels and the handedness of helical nanofibers can be inverted by exchanging the achiral bis(pyridinyl) derivatives during the co-assembly process. This finding provides a deeper understanding of the helical inversion in supramolecular chiral co-assembly, and exemplifies a feasible shortcut to the helical inversion by rational design of chiral nanostructures from basic molecular structures to supramolecular systems.3) To gain insight into the co-assembly mechanism of the hydrogels, colourless cocrystals of LPF2-L1 is prepared from tetrahydrofuran-p-xylene solution. It is confirmed that the framework of cocrystals was mainly stabilized through the intermolecular hydrogen bonds between amide/pyridine moieties and carbonyl groups. 3. Installing logic gates to multiresponsive supramolecular hydrogel co-assembled from phenylalanine amphiphile and azobenzene derivative1) Supramolecular hydrogel co-assembled from phenylalanine based amphiphile(LPF2) and bis(pyridinyl) derivative(AP) is constructed.2) A set of techniques including microscopic, spectroscopic and rheological measurements confirm that the hydrogel is formed through intermolecular hydrogen bonds between amide/pyridine moieties and carbonyl groups.3) The co-assembled hydrogel exhibits macroscopic gel-sol transition in response to four distinct input stimuli: temperature, acid,base and light. On the basis of its mutiple-stimulus responsiveness, installing gel-based supramolecular logic-gates(OR and XOR) is achieved. It may promote the possibility to develop smart soft materials, such as gels that can be used as tools releasing a drug quantitatively by rationally design and fine control the external stimuli. 4. Multiresponsive hydrogel co-assembled from phenylalanine and azobenzene derivatives as 3D scaffolds for photoguiding cell adhesion and release1) A multiresponsive hydrogel system co-assembled from C2-derived gelator(LPF2) and azobenzene(Azo) derivative(PPI) is constructed, which can respond to temperature, pH, host-guest interaction, and photoirradiation.2) The mechanism of co-assembled hydrogel is confirmed by a set of techniques including circular dichroism, Fourier transform infrared spectroscopy, 1H NMR, and X-ray powder diffraction.3) UV light is used to induce the gel-sol transition and release cells entrapped in the hydrogel into aqueous solution in a noncontact mode. It may promote the design of advanced multistimuli-functional scaffolds for the controlled delivery of various therapeutic biological agents and bioseparation.