Synthetic strategies for polysaccharide-protein conjugates, pH-responsive hydrogels, and amorphous solid dispersion (ASD) polymers were developed. Conjugating a polysaccharide to a protein drug via a covalent bond may improve its medical properties including solubility, stability, immunogenicity, circulation time, and targeting ability. Regioselectivity of conjugation is still challenging. We developed a strategy for regioselective conjugation of amino acid esters to polysaccharides, by employing 6-Br-polysaccharides in SN2 substitution reactions with amino acid esters. This work provides a good starting point for the regioselective conjugation of polysaccharides to proteins. Polysaccharides can also serve as hydrogel drug carriers. Most hydrogels employed in drug delivery work by incorporating the drug physically. We synthesized sustained and pH-responsive hydrogels using oxidized hydroxypropyl cellulose (Ox-HPC)/carboxymethyl chitosan (CMCS) crosslinked by imine bond. Phenylalanine as a model amine-containing drug was chemically bonded to the Ox-HPC hydrogel component and was observed to release faster at the pH of a tumor microenvironment. These hydrogels show promise as targeting cancer drug carriers. ASDs are polymeric systems to disperse poorly soluble drugs amorphously and enhance permeation from the gastrointestinal tract (GI tract) to the bloodstream. We synthesized potentially zwitterionic cellulose derivatives by reductive amination of Ox-HPC with ω-aminoalkanoic acids and obtained products with the degree of substitution (cation and anion) up to 1.6, which is difficult to attain using previous methods. The products showed manipulated amphiphilicity and excellent thermostability, exhibiting potential application in ASDs. We anticipate that these strategies will benefit future polysaccharide chemistry research and permit synthesis of a broad variety of more functional biomedical materials. / Doctor of Philosophy / Polysaccharides are long chains of individual sugars ("polymers"). Many natural-sourced polysaccharides are sustainable, biodegradable, and have low toxicity. Polysaccharide-based materials may improve the properties of current drugs, resulting in decreased cost, enhanced absorption efficiency, and continuous and/or targeted delivery. Protein drugs such as human insulin have a significant role in medicine. However, the residence time of a protein drug in the human body is short. To overcome this challenge, we designed a method to link polysaccharides to proteins at controlled reaction sites, and reported herein the first step of this route. The final polysaccharide-protein products will even have the ability to recognize and access target cells, like those of tumors. Tumor tissues are more acidic than normal tissue and can trigger faster release of drug from drug carriers. We developed polysaccharide-based hydrogels, which are gels that bind a great deal of water but won't dissolve in it, as acid-sensitive carriers. In addition, our hydrogels are also injectable, and can spontaneously repair themselves. These properties make our hydrogels promising as cancer targeting drug carriers. Most new drug candidates have poor water solubility and permeation through the gastrointestinal tract to reach the blood stream. Dispersing the insoluble drug into a properly designed polymer network can enhance dissolution, permeation, and absorption. We developed a new family of polymers designed for this purpose using two cheap starting materials. These polymers can interact with the drug, preventing it from forming crystals and simultaneously promoting slow drug release. Overall, we explored ways to modify polysaccharides to create harmless, effective medical materials. We aim to promote science and benefit human health via our research.

The research presented in this dissertation supports the overall goal of producing sensor functionalized neural microphysiological systems to enable deeper fundamental understandings of disease pathology and to provide drug screening and discovery platforms for improved clinical translation. Towards this goal, work addressing three broad objectives has been completed. The first objective was expanding the manufacturing process capabilities for hydrogels and tissues through augmentation of the 3D printing systems and developing novel modeling capabilities. The second objective was to expand the palette of available materials which exhibit the rheological properties required for 3D printing and the mechanical and biological properties required for neural tissue culture. The third objective was to develop sensing capabilities for both monitoring and control of the manufacturing process and to provide non-destructive assessment of microphysiological systems in real-time to quantify the dynamics of disease progression or response to treatment. The first objective of process improvement was addressed both through modification of the 3D printing system itself and through modeling of process physics. A new manifold was implemented which enabled on-the-fly mixing of bioprinting inks (bioinks) to produce smooth concentration gradients or discrete changes in concentration. Modeling capabilities to understand the transport occurring during both the processing and post-processing windows were developed to provide insight into the relationship between the programmed concentration distribution and its temporal evolution and stability. Vacuum-based pick-and-place capabilities for integration of prefabricated components for sensing and stimulation into the printed hydrogel constructs were developed. Models of the stress profiles, which relate to cell viability, within the printing nozzle during extrusion were produced using parameters extracted from rheological characterization of bioinks. The second objective was addressed through the development hydrogel bioinks which exhibited yield stresses without the use of rheological modifiers (fillers) to enable 3D printing of free-standing neural tissue constructs. A hybrid bioink was developed using the combination of a synthetic polaxamer with biomacromolecules present in native neural tissue. Functionalization of the biomacromolecules with catechol or methacrylate groups enabled two crosslinking mechanisms: chelation and UV exposure. Crosslinked gels exhibited moduli in the range of native neural tissue and enabled high viability culture of multiple neural cell types. The third objective was addressed through the characterization and implementation of physical and electronic sensors. The resonance of millimeter-scale dynamic-mode piezoelectric cantilevers submerged in polymer solutions was found to persist into the gel phase enabling viscoelastic sensing in hydrogels and monitoring of sol-gel transitions. Resonant frequency and quality factor of the cantilevers were related with the viscoelastic properties of hydrogels through both a first principles approach and empirical correlation. Electrode functionalized hollow fibers were implemented as impedimetric sensors to monitor bioink quality during 3D printing. Impedance spectra were collected during extrusion of cell-laden bioinks and the magnitude and phased angle of the impedance response correlated with quality measures such as cell viability, cell type, and stemness which were validated with traditional off-line assays. / Doctor of Philosophy / The research presented in this dissertation supports the overall goal of producing sensor functionalized neural microphysiological systems to enable deeper fundamental understandings of disease pathology and to provide drug screening and discovery platforms for improved clinical translation. Microphysiological systems are miniaturized tissue constructs which strive to mimic the complex conditions present in-vivo within an in-vitro platform. By producing these microphysiological systems with sensing functionality, new insight into the mechanistic progression of diseases and the response to new treatment options can be realized. Towards this goal, work addressing three broad objectives has been completed. The first objective was expanding the manufacturing process capabilities for hydrogels and tissues through augmentation of the 3D printing systems and developing novel modeling capabilities. The second objective was to expand the palette of available materials which exhibit both the properties required for 3D printing and the mechanical and biological properties required for neural tissue culture. The third objective was to develop sensing capabilities for both monitoring and control of the manufacturing process and to provide non-destructive assessment of microphysiological systems in real-time to quantify the dynamics of disease progression or response to treatment. Through these efforts higher quality microphysiological systems may be produced benefitting future researchers, medical professionals, and patients.

Cancer metastasis is the leading cause of death related to cancer diseases. Once the cancer cells depart the primary tumor site and enter the blood circulation, they spread through the body and will likely initiate a new tumor site. Therefore, understanding the cell migration and stopping the spread in the initial stage is the utmost of importance. In this dissertation, we have proposed a 3-D microenvironment that (partially) mimics the structures, complexity and circulation of human organs for cell migration studies. We have developed the tools to fabricate 3-D complex geometries in PDMS from our previously developed single-mask, single-etch technology in silicon. In this work, 3-D patterns are transferred from silicon structures to glass following anodic bonding and high temperature glass re-flow processes. Silicon is etched back thoroughly via wet etching and the glass is used as master device to create 3-D PDMS structures for use in dielectrophoresis cell sorting applications. Furthermore, this work has been modified to fabricate 3-D master devices in PDMS to create 3-D structures in collagen hydrogels to mimic native tissue structures. We have studied the interaction of endothelial cells with model geometries of blood vessels in collagen hydrogel at different concentrations to mimic the biomechanical properties of tissues varying from normal to tumor under the growth factor stimulation. Finally, we have designed and fabricated a silicon-based transmigration well with a 30um-thick membrane and 8um pores. This platform includes a deep microfluidic channel on the back-side sealed with a glass wafer. The migratory behavior of highly metastatic breast cancer cells, MDA-MB-231, is tested under different drug treatment conditions. This versatile platform will enable the application of more complex fluidic circulation profile, enhanced integration with other technologies, and running multiple assays simultaneously. / Ph. D.

Yes / Biological hydrogels have been increasingly sought after as wound dressings or scaffolds for regenerative medicine, owing to their inherent biofunctionality in biological environments. Especially in moist wound healing, the ideal material should absorb large amounts of wound exudate while remaining mechanically competent in situ. Despite their large hydration, however, current biological hydrogels still leave much to be desired in terms of mechanical properties in physiological conditions. To address this challenge, a multi-scale approach is presented for the synthetic design of cyto-compatible collagen hydrogels with tunable mechanical properties (from the nano- up to the macro-scale), uniquely high swelling ratios and retained (more than 70%) triple helical features. Type I collagen was covalently functionalized with three different monomers, i.e. 4-vinylbenzyl chloride, glycidyl methacrylate and methacrylic anhydride, respectively. Backbone rigidity, hydrogen-bonding capability and degree of functionalization (F: 16 ± 12–91 ± 7 mol%) of introduced moieties governed the structure–property relationships in resulting collagen networks, so that the swelling ratio (SR: 707 ± 51–1996 ± 182 wt%), bulk compressive modulus (Ec: 30 ± 7–168 ± 40 kPa) and atomic force microscopy elastic modulus (EAFM: 16 ± 2–387 ± 66 kPa) were readily adjusted. Because of their remarkably high swelling and mechanical properties, these tunable collagen hydrogels may be further exploited for the design of advanced dressings for chronic wound care.

Yes / The possibility of using differential pre‐heating prior to supramolecular gelation to control the balance between hydrogen‐bonding and aromatic stacking interactions in supramolecular gels and obtain consequent systematic regulation of structure and properties is demonstrated. Using a model aromatic peptide amphiphile, Fmoc‐tyrosyl‐leucine (Fmoc‐YL) and a combination of fluorescence, infrared, circular dichroism and NMR spectroscopy, it is shown that the balance of these interactions can be adjusted by temporary exposure to elevated temperatures in the range 313–365 K, followed by supramolecular locking in the gel state by cooling to room temperature. Distinct regimes can be identified regarding the balance between H‐bonding and aromatic stacking interactions, with a transition point at 333 K. Consequently, gels can be obtained with customizable properties, including supramolecular chirality and gel stiffness. The differential supramolecular structures also result in changes in proteolytic stability, highlighting the possibility of obtaining a range of supramolecular architectures from a single molecular structure by simply controlling the pre‐assembly temperature. / FP7 Ideas: European Research Council. Grant Number: 258775

Ortho-Fluorazobenzole stellen eine der interessantesten Familien von Azobenzolen dar, die mit sichtbarem Licht geschaltet werden können. Seit ihrer ersten Erwähnung durch unsere Gruppe im Jahr 2012 wurden sie aufgrund ihrer hervorragenden photo/elektrochemischen Eigenschaften intensiv auf molekularer Ebene, für biologische Anwendungen und in Volumenmaterialien untersucht. Typischerweise können ortho-fluorierte Azobenzole in beide Richtungen mit sichtbarem Licht und hohem Photoumsatz geschaltet werden. Außerdem weisen die Z-Isomere überlegene thermische Halbwertszeiten (bis zu 2 Jahre) auf. In dieser Arbeit werden zwei Projekte vorgestellt, die auf unseren kürzlich erworbenen Kenntnissen über fluorierte Azobenzole basieren. Zunächst wurde ein gemischtes Azobenzoldimer dargestellt, welches komplementäre Absorptionsprofile sowie die leichte elektrochemische Isomerisierung ausnutzt und dadurch dessen vier Schaltzustände orthogonal adressiert werden können. Dieses wurde bezüglich seiner Photoisomerisierung, thermischen Relaxation und seines elektrochemischen Schaltverhaltens untersucht. Anschließend haben wir ein 3D-Polymernetzwerk durch kovalente Vernetzung einer polyethylenglykol(PEG)-basierten Vorstufe mit einem fluorierten Azobenzol hergestellt, was zur Bildung eines photoempfindlichen Hydrogels führte. Als Folge davon konnten die mechanischen Eigenschaften des Gels durch Bestrahlung mit sichtbarem Licht und der dadurch ausgelösten Azobenzol-Isomerisierung reversibel beeinflusst werden. / Ortho-fluoroazobenzenes represent one of the most interesting family of visible-light-responsive azobenzenes. Since the first report by our group in 2012, they have been intensively studied at the molecular level, for biological applications, and in bulk materials, due to their outstanding photo/electrochemical properties. Typically, ortho-fluorinated azobenzenes can isomerize in both directions using visible light with high photo-conversions, and the Z-isomers exhibit superior thermal half-lives (up to 2 years). In this work, two projects based on our recently acquired knowledge of fluorinated azobenzenes are presented. First, exploiting complementary absorption profiles and ease of electrochemical isomerization, a mixed azobenzene dimer, whose four isomers can be orthogonally addressed was prepared. It was investigated from its photo-isomerization, thermal relaxation, and electrochemical isomerization aspects. Second, we prepared a photo-responsive hydrogel via covalently cross-linking a poly(ethylene glycol) (PEG)-based precursor with a fluorinated azobenzene forming a 3D polymer network. As a result, the gel’s mechanical properties could be tuned reversibly due to the azobenzenes’ isomerization triggered by visible light irradiation.

Il est difficile de réaliser une forte adhésion entre deux hydrogels par un procédé simple. Récemment, un nouveau concept a été proposé par Leibler et ses collaborateurs pour coller des hydrogels ou des tissus biologiques. Il consiste à utiliser des nanoparticules sur lesquels s'adsorbent les chaînes de polymère et qui jouent ainsi le rôle de connecteurs. L'objectif principal de la thèse est d'identifier et de contrôler les mécanismes à l'origine de l'adhésion de deux hydrogels par des nanoparticules. De nombreuses questions sont abordées : la nature des nanoparticules de silice (taille, charge, concentration, état de dispersion), l'influence de la structure de l'hydrogel et son état de gonflement, la répartition des nanoparticules sur les interfaces. Les expériences sont menées avec plusieurs catégories d'hydrogels: le Poly(N,N diméthyl-acrylamide) (PDMA), le Polyacrylamide (PAAm), des gels nanocomposites (PDMA renforcé par des nanoparticules de silice), ou encore des gels à double-réseaux. Nous mesurons les propriétés adhésives à l'aide de tests de joints de recouvrement, de pelage à 90°, et de pelage en Y, que nous avons mis au point. Nous avons utilisé des expériences d'ATR-FTIR, de microcopie confocale à fluorescence et de microscopie électronique à balayage pour mettre en évidence l'adsorption des chaînes polymères à la surface des hydrogels, évaluer la quantité de particules de silice à la surface du gel, et caractériser leur distribution. Les résultats nous permettent de proposer un mécanisme d'adhésion et de définir les conditions qui permettent de réaliser une adhésion optimale. / It is very challenging to achieve strong adhesion between two soft and wet materials like hydrogels. Recently Leibler and his collaborators invented a new concept to assemble hydrogels or biological tissues using nanoparticles. The principle relies on the adsorption of gel chains at the surface of nanoparticles, which act as connectors, and on the ability of the adsorbed gel chains to reorganize under stress. The main objective of this work is to identify and control the physical mechanisms fundamental to gel adhesion by silica nanoparticles. Many questions are investigated: the nature of the nanoparticles (size, surface chemistry, concentration, state of dispersion), the gel structure and its state of swelling, the distribution of the nanoparticles at the gel surface. Experiments are conducted using several types of gels: Poly(N,N dimethylacrylamide) (PDMA), Poly(acrylamide) (PAAm), nanocomposite gels (PDMA reinforces with silica nanoparticles), or double-network (DN) gels. We quantify the adhesive properties using lap-shear experiments, peeling tests at 90°, and Y-peeling tests that we developed. We use ATR-FTIR experiments, confocal microscopy and scanning electron microscopy to demonstrate the adsorption of polymers onto the silica nanoparticles and characterize their spatial repartition. The results allow us to propose a mechanism explaining the adhesion and to define conditions for optimal adhesion.

Le glioblastome (GBM) est une tumeur maligne du cerveau très agressive et actuellement incurable. Après le traitement standard, le GBM récidive toujours à cause de son caractère invasif et de sa résistance aux agents chimiothérapeutiques alkylants. Dans cette thèse, nous avons évalué la faisabilité, l'efficacité et la tolérance de l’hydrogel « nanocapsules lipidiques chargées en Lauroyl-gemcitabine » (GemC12-LNC) pour le traitement local du GBM. GemC12-LNC a été préparé par un procédé d'inversion de phase. Il est injectable, adapté à l'implantation cérébrale et capable de libérer de façon prolongée le médicament in vitro. Chez les souris saines, aucune inflammation, apoptose ou activation de la microglie n’a été observée après exposition à l'hydrogel, ce qui suggère que ce système est bien toléré. L'injection intra-tumorale de GemC12-LNC dans un modèle de GBM U87 sous-cutané et orthotopique a réduit de façon significative la croissance tumorale et a augmenté la survie médiane de l'animal par rapport aux contrôles, respectivement. De plus, en vue d’une meilleure relevance clinique, une technique de résection tumorale reproductible du GBM U87 et du gliosarcome 9L a été mise au point et l'hydrogel GemC12-LNC a réduit les récidives chez les souris et les rats, respectivement. En conclusion, l'efficacité et la tolérance de l’hydrogel GemC12-LNC ont été démontrées in vitro et in vivo. Cette formulation simple peut être injectée directement dans la cavité de résection du GBM, et combine les propriétés avantageuses des nanomédecines et des hydrogels. GemC12-LNC peut donc être considéré comme un système d'administration prometteur et innovant pour le traitement local du GBM. / Glioblastoma (GBM) is an aggressive malignant brain tumor characterized by rapid proliferation and propensity to infiltrate healthy brain tissue. Despite aggressive standard of care therapy GBM always recur, mainly because of its high invasiveness and chemoresistance to alkylating drugs. In this Thesis, we evaluate the feasibility, efficacy and safety of the nanomedicine hydrogel Lauroyl-gemcitabine lipid nanocapsule (GemC12-LNC) for the local treatment of GBM. GemC12-LNC was prepared by a phase-inversion technique process. It is injectable, adapted for brain implantation and able to sustainably release the drug in vitro. In healthy mice brain, no inflammation, apoptosis or microglia activation was observed after exposure to the hydrogel suggesting that this system is well tolerated and suitable for an application in the brain. Intratumoral injection of GemC12-LNC hydrogel in a U87subcutaneous and orthotopic GBM model significantly reduced tumor growth and increased the animal’s median survival compared to the controls, respectively. Moreover, to mimic the clinical setting, a reproducible tumor resection technique of U87 GBM and 9L gliosarcoma was developed and the GemC12-LNC hydrogel slowed down the formation of recurrences in mice and rats brain, respectively. In conclusion, the feasibility efficacy and safety of GemC12-LNC have been shown in vitro and in several preclinical in vivo models showing that this nanomedicine hydrogel is a promising and innovative delivery system for the local treatment of GBM. This gel can be directly injected in the GBM resection cavity, has a very simple formulation and combines the properties of nanomedicines and hydrogels.

Les nanoparticules de silice sont très largement étudiées pour les applications biomédicales. Elles permettent une facilité et une flexibilité de la synthèse des particules et une bio-toxicité limitée. Cette thèse a mené une grande diversité de résultats impliquant des nanomatériaux de silice. Premièrement, les propriétés physicochimiques et les propriétés de biodégradation de trois types de nanoparticules de silice structurées ont été étudiées dans un tampon, un milieu de culture et au contact de fibroblastes cutanés humains suggérant que les nanoparticules de silice doivent être principalement considérées comme dégradées par hydrolyse, et non biodégradé. Ensuite, des nanoparticules de silice multifonctionnelles constituées de nanoparticules de silice creuses et de nanoparticules de MnO2 ont été synthétisées. Ainsi le contrôle de la libération du médicament et la performance de l’imagerie de ces nanoplates ont été étudiées à partir de modèles 2D à 3D. Cette approche pourrait être utilisée pour une évaluation rapide de la bio-fonctionnalité des nanoparticules avant de mettre en place des expériences in vivo. En outre, un nouveau nanocomposite 3D à base de collagène utilisant des tiges de silice a été étudié et les relations entre la composition composite, la structure et les propriétés mécaniques, mettant en évidence le rôle clé des interactions collagène-silice. L'influence de ces paramètres sur l'adhésion et la prolifération des cellules fibroblastiques a également été étudiée. De plus, nous avons préparé et utilisé des nanobatonnêts de silice magnétiques pour contrôler l’orientation des particules dans le réseau de collagène grâce à un champ magnétique externe. Tous les résultats apportent de nouvelles connaissances sur la préparation et les propriétés des bionanocomposites et ouvrent la voie à des hydrogels multifonctionnels. / Silica nanoparticles, thanks to the great easy and adaptability of particle synthesis and limited biotoxicity, is very widely studied for biomedical applications. This thesis conducted a large diversity of investigations involving silica nanomaterials. Firstly, the physicochemical properties and biodegradation properties of three types of structured silica nanoparticles were studied in a buffer, a culture medium and in contact with human dermal fibroblasts that suggest that, under these conditions, the silica nanoparticles must be mainly considered as degraded by hydrolysis and not biodegraded. Then, multifunctional silica nanoparticles which are consist of hollow silica nanoparticles and MnO2 nanosheets were synthesized. And the control drug release and imaging performance of this nanoplatforms were studied from 2D to 3D models. This approach could be used for a rapid assessment of the biofunctionality of nanoparticles before setting up in vivo experiments. Furthermore, a new 3D collagen-based nanocomposites using silica rods were studied and the relationships between the composite composition, structure and mechanical properties, emphasizing the key role of collagen-silica interactions. The influence of these parameters on the adhesion and proliferation of fibroblast cells was also investigated. In addition, we prepared and used magnetic silica nanorods to control particle orientation within the collagen network thanks to an external magnetic field. All the results bring new insights on the preparation and properties of bionanocomposites and open the route to multifunctional hydrogels.

La première partie de cette thèse concerne la synthèse et les études structurales de 2:1-[α/aza]-oligomères linéaires et cycliques possédant des acides aminés hydrophobes et/ou basiques. Les études RMN et IRTF ont démontré que les oligomères adopteraient des conformations de type coude β en solution. Les calculs de dynamiques moléculaires des oligomères à base de résidus lysine ont révèlé l’importance du motif aza dans le repliement de ces oligomères indépendamment de l’impact de la chaîne latérale. Les études par DRX, IRTF et RMN ont révélé que les deux hexamère cycliques (L- ou D-Phe-azaPhe-Ala)2 homo- et hétérochiraux adoptent des conformations de type coude ß en solution et à l’état solide. Ils s’organisent en structures 3D très ordonnées, stabilisées par des ponts hydrogènes et des empilements π. La deuxième partie démontre l'auto-assemblage de quelques 2:1-[α/aza]-oligomères dans certains solvants pour former des gels supramoléculaires. Le cyclooligomère hétérochiral (D-Phe-azaPhe-Ala)2 peut former des organogels. La spectroscopie et rhéologie des organogels ont révélé de bonnes stabilités thermique et mécanique avec un comportement de type solide. La MEB/MET de l'aérogel a montré une structure fibreuse 3D. De plus, deux hydrogels Fmoc-D- ou L-Phe-azaPhe-Ala-OH ont été obtenus aux pH 7.0 et 10.0. Les spectres UV et de fluorescence ont révélé une stabilisation des hydrogels par interaction π entre les groupes aromatiques. Leur analyse par CD montre que les trimères s'auto-assemblent sous forme de feuillet β en accord avec les résultats ATR/IRTF. Ainsi, leurs études rhéologiques ont révélé un comportement de type solide. La MEB des xérogels a montré une structure fibreuse. La troisième partie propose deux applications; (i) les oligomères à base de résidus lysine ont révélé de bonnes performances pour la séparation CO2/N2 dans des membranes polymères Pebax®, et (ii) le cyclohexamère hétérochiral (D-Phe-azaPhe-Ala)2 convient pour la gélification sélective avec un bon pourcentage de récupération / The first part of this thesis reported the synthesis and structural studies of linear and cyclic 2:1-[α/aza]-oligomers possessing hydrophobic and/or basic amino acids (lysine). NMR and FTIR results demonstrated that the oligomers could adopt β-turn conformations in solution. Molecular dynamic calculations for oligomers based lysine residues reflected the important role of the aza-motif(s) in structuring the backbones regardless the chirality and nature of the amino acids. In the other hand, X-ray, FTIR, and NMR studies showed that homo- and heterochiral cyclo-(L- or D-Phe-azaPhe-Ala)2-hexamers adopt β-turn conformations in solution and solid states. Both molecules could organize into 3D highly ordered structures stabilized by hydrogen bonds and π-stacking. The second part reflected the propensity of some 2:1-[α/aza]-oligomers to self-assemble in some solvents to form supramolecular gels. Interestingly, the heterochiral cyclo-(D-Phe-azaPhe-Ala)2-hexamer could form organogels. The spectroscopic and rheological studies of the organogels revealed good thermal and mechanical stability with solid-like behavior. SEM and TEM images of the aerogel showed fibrous structure. Furthermore, two hydrogelators, Fmoc-D- or L-Phe-azaPhe-Ala-OH, have been developed and they could achieve hydrogels at pHs 7.0 and 10.0. UV and Flu studies demonstrated that the hydrogels are supported by π-stacking between the aromatic groups. CD analysis reflected that the two hydrogelators self-assemble into β-sheet like structure in consistent with ATR-FTIR results. Both hydrogels exhibited solid-like behavior through rheological studies and the SEM analysis of the xerogels revealed fibrous structure. The third part offered two applications; (i) oligomers based lysine residues reflected good performances in CO2/N2 separation when used as additives in polymeric Pebax® membrane, and (ii) the heterochiral cyclo-(D-Phe-azaPhe-Ala)2-hexamer is suitable for phase selective gelation with good recovery percentages