From natural to synthetic hydrogels: how much biochemical complexity is required for mechanotransduction?

The biochemical complexity of a material determines the biological response of cells triggered by a cell-material interaction. The degree in which this complexity influences basic cell-material interactions such as cell adhesion, spreading, and mechanotransduction is not entirely clear. To this end, we compared three different hydrogel systems, ranging from completely natural to synthetic, in their ability to induce mechanotransduction in kidney epithelial cells (HK-2).

Synthetic, multi-dynamic hydrogels by uniting stress-stiffening and supramolecular polymers.

Nature uses discrete molecular building blocks to form polymers that assemble into multicomponent, multi-dynamic networks, inside (cytoskeleton) and outside (extracellular matrix) the cell. Both the intra-fibrous molecular dynamics and interactions between fibers dictate (non)linear mechanics, such as stress stiffening and relaxation, and ultimately biological function. Current synthetic systems capture only one dynamic process.

Using a Supramolecular Monomer Formulation Approach to Engineer Modular, Dynamic Microgels, and Composite Macrogels.

Microgels show advantages over bulk hydrogels due to convenient control over microgel size and composition, and the ability to use microgels to modularly construct larger hierarchical scaffold hydrogel materials. Here, supramolecular chemistry is used to formulate supramolecular polymer, dynamic microgels solely held together by non-covalent interactions. Four-fold hydrogen bonding ureido-pyrimidinone (UPy) monomers with different functionalities are applied to precisely tune microgel properties in a modular way, via variations in monomer concentration, bifunctional crosslinker ratio, and the incorporation of supramolecular dyes and peptides.

Investigating the self-assembly of 2NapFF and ureido-pyrimidinone multicomponent systems for cell culture.

Low molecular weight gels are formed the self-assembly of small molecules into fibrous structures. In the case of hydrogels, these networks entrap large volumes of water, yielding soft materials. Such gels tend to have weak mechanical properties and a high permeability for cells, making them particularly appealing for regenerative medicine applications.

Mimicking the extracellular world: from natural to fully synthetic matrices utilizing supramolecular biomaterials.

The extracellular matrix (ECM) has evolved around complex covalent and non-covalent interactions to create impressive function-from cellular signaling to constant remodeling. A major challenge in the biomedical field is the design and control of synthetic ECMs for applications ranging from tissue engineering to neuromodulation to bioelectronics. As we move towards recreating the ECM's complexity in hydrogels, the field has taken several approaches to recapitulate the main important features of the native ECM ( mechanical, bioactive and dynamic properties).

Tuning Structural Organization via Molecular Design and Hierarchical Assembly to Develop Supramolecular Thermoresponsive Hydrogels.

The cellular microenvironment is composed of a dynamic hierarchical fibrillar architecture providing a variety of physical and bioactive signals to the surrounding cells. This dynamicity, although common in biology, is a challenge to control in synthetic matrices. Here, responsive synthetic supramolecular monomers were designed that are able to assemble into hierarchical fibrous structures, combining supramolecular fiber formation via hydrogen bonding interactions, with a temperature-responsive hydrophobic collapse, resulting in cross-linking and hydrogel formation.

Molecularly Engineered Supramolecular Thermoresponsive Hydrogels with Tunable Mechanical and Dynamic Properties.

Synthetic supramolecular polymers and hydrogels in water are emerging as promising biomaterials due to their modularity and intrinsic dynamics. Here, we introduce temperature sensitivity into the nonfunctionalized benzene-1,3,5-tricarboxamide () supramolecular system by incorporating a poly(-isopropylacrylamide)-functionalized ( moiety, enabling 3D cell encapsulation applications. The viscous and structural properties in the solution state as well as the mechanical and dynamic features in the gel state of mixtures were investigated and modulated.

Using Chemistry To Recreate the Complexity of the Extracellular Matrix: Guidelines for Supramolecular Hydrogel-Cell Interactions.

Hydrogels have emerged as a promising class of extracellular matrix (ECM)-mimicking materials in regenerative medicine. Here, we briefly describe current state-of-the-art of ECM-mimicking hydrogels, ranging from natural to hybrid to completely synthetic versions, giving the prelude to the importance of supramolecular interactions to make true ECM mimics. The potential of supramolecular interactions to create ECM mimics for cell culture is illustrated through a focus on two different supramolecular hydrogel systems, both developed in our laboratories.

The effect of charge and albumin on cellular uptake of supramolecular polymer nanostructures.

Intracellular delivery of functional biomolecules by using supramolecular polymer nanostructures has gained significant interest. Here, various charged supramolecular ureido-pyrimidinone (UPy)-aggregates were designed and formulated a simple "mix-and-match" method. The cellular internalization of these UPy-aggregates in the presence or absence of serum proteins by phagocytic and non-phagocytic cells, , THP-1 derived macrophages and immortalized human kidney cells (HK-2 cells), was systematically investigated.

Collagen type I mimicking peptide additives to functionalize synthetic supramolecular hydrogels.

Small bioactive peptide sequences derived from extracellular matrix proteins possess the ability to interact with cell receptors. As such, these peptide additives are excellent mimics to develop materials for 3D cell culture. Two types of supramolecular modified collagen type I mimicking peptide additives are presented; UPy-GFOGER (39 amino acids), with a novel superstructure, and the more simplistic UPy-DGEA (7 amino acids).

Merging Modular Molecular Design with High Throughput Screening of Cell Adhesion on Antimicrobial Supramolecular Biomaterials.

A polymer microarray based on the supramolecular ureido-pyrimidinone (UPy) moiety is fabricated to screen antimicrobial materials for their ability to support cell adhesion. UPy-functionalized additives, either cell-adhesive, antimicrobial or control peptides, are used, and investigated in different combinations at different concentrations, resulting in a library of 194 spots. These are characterized on composition and morphology to evaluate the microarray fabrication.

Off-the-Shelf Synthetic Biodegradable Grafts Transform In Situ into a Living Arteriovenous Fistula in a Large Animal Model.

Current vascular access options require frequent interventions. In situ tissue engineering (TE) may overcome these limitations by combining the initial success of synthetic grafts with long-term advantages of autologous vessels by using biodegradable grafts that transform into autologous vascular tissue at the site of implantation. Scaffolds (6 mm-Ø) made of supramolecular polycarbonate-bisurea (PC-BU), with a polycaprolactone (PCL) anti-kinking-coil, are implanted between the carotid artery and jugular vein in goats.

Balancing Scaffold Degradation and Neo-Tissue Formation in Tissue Engineered Vascular Grafts.

An essential aspect of cardiovascular tissue engineering (TE) is to ensure balance between scaffold degradation and neo-tissue formation. We evaluated the rate of degradation and neo-tissue formation of three electrospun supramolecular bisurea-based biodegradable scaffolds that differ in their soft-block backbone compositions only. Scaffolds were implanted as interposition grafts in the abdominal aorta in rats, and evaluated at different time points ( = 1, 6, 12, 24, and 40 weeks) on function, tissue formation, strength, and scaffold degradation.

Supramolecular polymers form tactoids through liquid-liquid phase separation.

Liquid-liquid phase separation (LLPS) of biopolymers has recently been shown to play a central role in the formation of membraneless organelles with a multitude of biological functions. The interplay between LLPS and macromolecular condensation is part of continuing studies. Synthetic supramolecular polymers are the non-covalent equivalent of macromolecules but they are not reported to undergo LLPS yet.

Employment outcomes of adolescent and young adult cancer survivors and their partners: A Dutch population-based study.

Background: The aim of this population-based registry study was to examine the impact of cancer on employment outcomes in adolescent and young adult (AYA) survivors and their partners and associated sociodemographic and clinical characteristics.

Methods: A total of 2456 AYA cancer patients, diagnosed in 2013 and aged 18 through 39 years old, were selected from the Netherlands Cancer Registry and linked to employment data from Statistics Netherlands, from which 1252 partners of AYAs could be identified. For both patients and their partners, a control group with same age, migration background, and sex was selected.

Artificial cells with viscoadaptive behavior based on hydrogel-loaded giant unilamellar vesicles.

Viscoadaptation is an essential process in natural cells, where supramolecular interactions between cytosolic components drive adaptation of the cellular mechanical features to regulate metabolic function. This important relationship between mechanical properties and function has until now been underexplored in artificial cell research. Here, we have created an artificial cell platform that exploits internal supramolecular interactions to display viscoadaptive behavior.

Bisurea-Based Supramolecular Polymers for Tunable Biomaterials.

Water-soluble supramolecular polymers show great potential to develop dynamic biomaterials with tailored properties. Here, we elucidate the morphology, stability and dynamicity of supramolecular polymers derived from bisurea-based monomers. An accessible synthetic approach from 2,4-toluene diisocyanate (TDI) as the starting material is developed.

An Offset Patterned Cross-β Structure in Assemblies of C -Symmetric Peptide Amphiphiles.

Developing peptide-based materials with controlled morphology is a critical theme of soft matter research. Herein, we report the formation of a novel, patterned cross-β structure formed by self-assembled C -symmetric peptide amphiphiles based on diphenylalanine and benzene-1,3,5-tricarboxamide (BTA). The cross-β motif is an abundant structural element in amyloid fibrils and aggregates of fibril-forming peptides, including diphenylalanine.

Evaluation of pliable bioresorbable, elastomeric aortic valve prostheses in sheep during 12 months post implantation.

Pliable microfibrous, bioresorbable elastomeric heart valve prostheses are investigated in search of sustainable heart valve replacement. These cell-free implants recruit cells and trigger tissue formation on the valves in situ. Our aim is to investigate the behaviour of these heart valve prostheses when exposed to the high-pressure circulation.

Evaluation of the Effect of an Intraperitoneal Cytostatic-Loaded Supramolecular Hydrogel on Intestinal Anastomotic Healing in an Animal Model.

The prognosis of colorectal cancer patients with peritoneal metastases is very poor. Intraperitoneal drug delivery systems, like supramolecular hydrogels, are being developed to improve local delivery and intraperitoneal residence time of a cytostatic such as mitomycin C (MMC). In this study, we evaluate the effect of intraperitoneal hydrogel administration on anastomotic healing.

Iron Oxide Nanoparticles with Supramolecular Ureido-Pyrimidinone Coating for Antimicrobial Peptide Delivery.

Antimicrobial peptides (AMPs) can kill bacteria by disrupting their cytoplasmic membrane, which reduces the tendency of antibacterial resistance compared to conventional antibiotics. Their possible toxicity to human cells, however, limits their applicability. The combination of magnetically controlled drug delivery and supramolecular engineering can help to reduce the dosage of AMPs, control the delivery, and improve their cytocompatibility.

CO-Driven Nebulization of pH-Sensitive Supramolecular Polymers for Intraperitoneal Hydrogel Formation and the Treatment of Peritoneal Metastasis.

Because peritoneal metastasis (PM) from ovarian cancer is characterized by non-specific symptoms, it is often diagnosed at advanced stages. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) can be considered a promising drug delivery method for unresectable PM. Currently, the efficacy of intraperitoneal (IP) drug delivery is limited by the off-label use of IV chemotherapeutic solutions, which are rapidly cleared from the IP cavity.

Development of a Fully Synthetic Corneal Stromal Construct via Supramolecular Hydrogel Engineering.

Recent advances in the field of ophthalmology show great potential in the design of bioengineered constructs to mimic the corneal stroma. Hydrogels based on synthetic supramolecular polymers, are attractive synthetic mimics of the natural highly hydrated corneal stroma. Here, a fully synthetic corneal stromal construct is developed via engineering of an injectable supramolecular hydrogel based on ureido-pyrimidinone (UPy) moieties.