Supramolecular antifouling additives for robust and efficient functionalization of elastomeric materials:molecular design matters

\u3cp\u3eThe ultimate functionality of elastomeric materials can be largely influenced by the molecular design of antifouling additives that interact through directed hydrogen bonding bisurea motifs. Herein, three additives, composed of matching bisurea groups and antifouling oligo(ethylene glycol) (OEG) functionalities, are judiciously designed. The first additive is composed of one bisurea and one OEG, the second additive of one bisurea and two OEGs, and the third additive of two bisurea and one OEG. On solution-cast films, non-cell adhesive properties are dependent on the amount of incorporated OEG irrespective of the bisurea design; however, on 3D electrospun scaffolds only the additive that consists of two bisurea moieties connected via an OEG functionality ensures proper non-cell adhesive properties. Interestingly, robust non-cell adhesive properties are maintained, both with repeated cell seeding and after partial enzymatic degradation of the scaffold. These results highlight the importance of additive design in supramolecular functionalization and show that translation from simple 2D solution-cast films to 3D electrospun scaffolds is not trivial with respect to additive presentation and functionality.\u3c/p\u3

A novel approach to tracer-kinetic modeling for (macromolecular) dynamic contrast-enhanced MRI

\u3cp\u3ePurpose To develop a novel tracer-kinetic modeling approach for multi-agent dynamic contrast-enhanced MRI (DCE-MRI) that facilitates separate estimation of parameters characterizing blood flow and microvascular permeability within one individual. Methods Monte Carlo simulations were performed to investigate the performance of the constrained multi-agent model. Subsequently, multi-agent DCE-MRI was performed on tumor-bearing mice (n = 5) on a 7T Bruker scanner on three measurement days, in which two dendrimer-based contrast agents having high and intermediate molecular weight, respectively, along with gadoterate meglumine, were sequentially injected within one imaging session. Multi-agent data were simultaneously fit with the gamma capillary transit time model. Blood flow, mean capillary transit time, and bolus arrival time were constrained to be identical between the boluses, while extraction fractions and washout rate constants were separately determined for each agent. Results Simulations showed that constrained multi-agent model regressions led to less uncertainty and bias in estimated tracer-kinetic parameters compared with single-bolus modeling. The approach was successfully applied in vivo, and significant differences in the extraction fraction and washout rate constant between the agents, dependent on their molecular weight, were consistently observed. Conclusion A novel multi-agent tracer-kinetic modeling approach that enforces self-consistency of model parameters and can robustly characterize tumor vascular status was demonstrated.\u3c/p\u3

Combinatorial functionalization with bisurea-peptides and antifouling bisurea additives of a supramolecular elastomeric biomaterial

\u3cp\u3eThe bioactive additive toolbox to functionalize supramolecular elastomeric materials expands rapidly. Here we have set an explorative step toward screening of complex combinatorial functionalization with antifouling and three peptide-containing additives in a bisurea-based supramolecular system. Thorough investigation of surface properties of thin films with contact angle measurements, X-ray photoelectron spectroscopy and atomic force microscopy, was correlated to cell-adhesion of endothelial and smooth muscle cells to apprehend their respective predictive values for functional biomaterial development. Peptides were presented at the surface alone, and in combinatorial functionalization with the oligo(ethylene glycol)-based non-cell adhesive additive. The bisurea-RGD additive was cell-adhesive in all conditions, whereas the endothelial cell-specific bisurea-REDV showed limited bioactive properties in all chemical nano-environments. Also, aspecific functionality was observed for a bisurea-SDF1α peptide. These results emphasize that special care should be taken in changing the chemical nano-environment with peptide functionalization.\u3c/p\u3

Efficient functionalization of additives at supramolecular material surfaces

Selective surface modification reactions can be performed on additives that are supramolecularly incorporated into supramolecular materials. Hereby, processing of the material, that regularly requires harsh processing conditions (i.e., the use of organic solvents and/or high temperatures), and functionalization can be decoupled. Moreover, high-resolution depth profiling by time-of-flight (ToF) secondary-ion mass spectrometry clearly shows distinct differences in surface and bulk material composition

Improved evaluation of antivascular cancer therapy using constrained tracer-kinetic modeling for multiagent dynamic contrast-enhanced MRI

\u3cp\u3eDynamic contrast–enhanced MRI (DCE-MRI) is a promising technique for assessing the response of tumor vasculature to antivascular therapies. Multiagent DCE-MRI employs a combination of low and high molecular weight contrast agents, which potentially improves the accuracy of estimation of tumor hemodynamic and vascular permeability parameters. In this study, we used multiagent DCE-MRI to assess changes in tumor hemodynamics and vascular permeability after vascular-disrupting therapy. Multiagent DCE-MRI (sequential injection of G5 dendrimer, G2 dendrimer, and Gd-DOTA) was performed in tumor-bearing mice before, 2 and 24 hours after treatment with vascular disrupting agent DMXAA or placebo. Constrained DCE-MRI gamma capillary transit time modeling was used to estimate flow F, blood volume fraction v\u3csub\u3eb\u3c/sub\u3e, mean capillary transit time t\u3csub\u3ec\u3c/sub\u3e, bolus arrival time t\u3csub\u3ed\u3c/sub\u3e, extracellular extravascular fraction v\u3csub\u3ee\u3c/sub\u3e, vascular heterogeneity index a\u3csup\u3e1\u3c/sup\u3e (all identical between agents) and extraction fraction E (reflective of permeability), and transfer constant K\u3csup\u3etrans\u3c/sup\u3e (both agent-specific) in perfused pixels. F, v\u3csub\u3eb\u3c/sub\u3e, and a\u3csup\u3e1\u3c/sup\u3e decreased at both time points after DMXAA, whereas t\u3csub\u3ec\u3c/sub\u3e increased. E (G2 and G5) showed an initial increase, after which, both parameters restored. K\u3csup\u3etrans\u3c/sup\u3e (G2 and Gd-DOTA) decreased at both time points after treatment. In the control, placebo-treated animals, only F, t\u3csub\u3ec\u3c/sub\u3e, and K\u3csup\u3etrans\u3c/sup\u3e Gd-DOTA showed significant changes. Histologic perfused tumor fraction was significantly lower in DMXAA-treated versus control animals. Our results show how multiagent tracer-kinetic modeling can accurately determine the effects of vascular-disrupting therapy by separating simultaneous changes in tumor hemodynamics and vascular permeability. Significance: These findings describe a new approach to measure separately the effects of antivascular therapy on tumor hemodynamics and vascular permeability, which could help more rapidly and accurately assess the efficacy of experimental therapy of this class.\u3c/p\u3

Supramolecular polymers in action

Abstract onl

Supramolecular surface functionalization via catechols for the improvement of cell-material interactions

\u3cp\u3eOptimization of cell-material interactions is crucial for the success of synthetic biomaterials in guiding tissue regeneration. To do so, catechol chemistry is often used to introduce adhesiveness into biomaterials. Here, a supramolecular approach based on ureido-pyrimidinone (UPy) modified polymers is combined with catechol chemistry in order to achieve improved cellular adhesion onto supramolecular biomaterials. UPy-modified hydrophobic polymers with non-cell adhesive properties are developed that can be bioactivated via a modular approach using UPy-modified catechols. It is shown that successful formulation of the UPy-catechol additive with the UPy-polymer results in surfaces that induce cardiomyocyte progenitor cell adhesion, cell spreading, and preservation of cardiac specific extracellular matrix production. Hence, by functionalizing supramolecular surfaces with catechol functionalities, an adhesive supramolecular biomaterial is developed that allows for the possibility to contribute to biomaterial-based regeneration.\u3c/p\u3

Molecular MR imaging of collagen in mouse atherosclerosis by using paramagnetic CNA35 micelles

Magnetic resonance imaging (MRI) is increasingly used in biomedicine to visualize plaques in the walls of major arteries in relation to atherosclerosis, the prime cause of myocardial infarction and ischemic stroke. The present study aims to explore the utility of contrast-enhanced MRI for improving the specificity of the MRI evaluation of atherosclerotic plaques with the use of a Gd-based paramagnetic contrast agent that is targeted to collagen. Collagen is a major component of the extracellular matrix and as such plays an important role in the stability of atherosclerotic plaques. Micelles were made with lipid containing 45 mol-% Gd for MRI detection and a low mol fraction of fluorescent lipid for fluorescence microscopic analysis. Collagen-targeted, functional micelles were prepared by conjugation of the CNA35 protein, while nonfunctional control micelles were conjugated with a mutated version of the protein. The micelles were characterized with respect to their magnetic, biochemical, and biophysical properties. Atherosclerotic plaques were induced in the right carotid artery of apo-E knock-out mice by surgical placement of a tapered polymeric cast. In vivo MRI was performed at 6.3 Tesla before and up to 24 h after intravenous injection of paramagnetic micelles (50 µmol Gd kg -1). MRI revealed the strongest signal enhancements by CNA35 micelles. At early time points after injection of CNA35 micelles, contrast enhancement was higher in the collagen-richer lesions compared to that in the collagen-poorer lesions. Confocal laser scanning microscopy confirmed co-localization of CNA35 micelles and collagen in the plaques. We have demonstrated molecular MR imaging of collagen in experimental atherosclerosis by using a CNA35-functionalized micellar contrast agent