Introducing Hyaluronic Acid into Supramolecular Polymers and Hydrogels

[Abstract] The use of supramolecular polymers to construct functional biomaterials is gaining more attention due to the tunable dynamic behavior and fibrous structures of supramolecular polymers, which resemble those found in natural systems, such as the extracellular matrix. Nevertheless, to obtain a biomaterial capable of mimicking native systems, complex biomolecules should be incorporated, as they allow one to achieve essential biological processes. In this study, supramolecular polymers based on water-soluble benzene-1,3,5-tricarboxamides (BTAs) were assembled in the presence of hyaluronic acid (HA) both in solution and hydrogel states. The coassembly of BTAs bearing tetra(ethylene glycol) at the periphery (BTA-OEG4) and HA at different ratios showed strong interactions between the two components that led to the formation of short fibers and heterogeneous hydrogels. BTAs were further covalently linked to HA (HA-BTA), resulting in a polymer that was unable to assemble into fibers or form hydrogels due to the high hydrophilicity of HA. However, coassembly of HA-BTA with BTA-OEG4 resulted in the formation of long fibers, similar to those formed by BTA-OEG4 alone, and hydrogels were produced with tunable stiffness ranging from 250 to 700 Pa, which is 10-fold higher than that of hydrogels assembled with only BTA-OEG4. Further coassembly of BTA-OEG4 fibers with other polysaccharides showed that except for dextran, all polysaccharides studied interacted with BTA-OEG4 fibers. The possibility of incorporating polysaccharides into BTA-based materials paves the way for the creation of dynamic complex biomaterials.The authors acknowledge the ICMS Animation Studio for providing the artwork. S.V.-A. and G.M. acknowledge the funding received by Gravitation Program “Materials Driven Regeneration,” funded by the Netherlands Organization for Scientific Research (024.003.013). J.M. acknowledges a Marie Skłodowska-Curie postdoctoral fellowship (794016) for financial support. G.M. acknowledges the funding received by the Swiss National Science Foundation (SNSF “Early PostDoc Mobility” P2EZP2-178435). R.C. acknowledges TA Instruments for providing the DHR-3 rheometer under the Young Distinguished Rheologist Award instrument grant. S.S. and E.W.M acknowledge the European Research Council (H2020-EU.1.1., SYNMAT project, ID 788618).Netherlands Organisation for Scientific Research; 024.003.013Swiss National Science Foundation; P2EZP2-17843

Chemical design of non-ionic polymer brushes as biointerfaces : poly(2-oxazine)s outperform both poly(2-oxazoline)s and PEG

The era of poly(ethylene glycol) (PEG) brushes as a universal panacea for preventing non-specific protein adsorption and providing lubrication to surfaces is coming to an end. In the functionalization of medical devices and implants, in addition to preventing non-specific protein adsorption and cell adhesion, polymer-brush formulations are often required to generate highly lubricious films. Poly(2-alkyl-2-oxazoline) (PAOXA) brushes meet these requirements, and depending on their side-group composition, they can form films that match, and in some cases surpass, the bioinert and lubricious properties of PEG analogues. Poly(2-methyl-2-oxazine) (PMOZI) provides an additional enhancement of brush hydration and main-chain flexibility, leading to complete bioinertness and a further reduction in friction. These data redefine the combination of structural parameters necessary to design polymer-brush-based biointerfaces, identifying a novel, superior polymer formulation

A long-term treatment with taurine prevents cardiac dysfunction in mdx mice

Taurine is an amino acid abundantly present in heart and skeletal muscle. Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to skeletal muscle wasting and heart failure. An altered taurine metabolism has been described in dystrophic animals and short-term taurine administration exerts promising amelioration of early muscular alterations in the mdx mouse model of DMD. To reinforce the therapeutic and nutraceutical taurine potential in DMD, we evaluated the effects of a long-term treatment on cardiac and skeletal muscle function of mdx mice in a later disease stage. Taurine was administered in drinking water (1 g/kg/day) to wt and mdx mice for 6 months, starting at 6 months of age. Ultrasonography evaluation of heart and hind limb was performed, in parallel with in vivo and ex vivo functional tests and biochemical, histological and gene expression analyses. 12-month-old mdx mice showed a significant worsening of left ventricular function parameters (shortening fraction, ejection fraction, stroke volume), which were significantly counteracted by the taurine treatment. In parallel, histologic signs of damage were reduced by taurine along with the expression of proinflammatory myocardial IL-6. Interestingly, no effects were observed on hind limb volume and percentage of vascularization or on in vivo and ex vivo muscle functional parameters, suggesting a tissue-specific action of taurine in relation to the disease phase. A trend toward increase in taurine was found in heart and quadriceps from treated animals, paralleled by a slight decrease in mdx mice plasma. Our study provides evidences that taurine can prevent late heart dysfunction in mdx mice, further corroborating the interest on this amino acid toward clinical trials

C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes

Poly(2-methyl-2-oxazoline) (PMOXA) is an alternative promising polymer to poly(ethylene glycol) (PEG) for design and engineering of macrophage-evading nanoparticles (NPs). Although PMOXA-engineered NPs have shown comparable pharmacokinetics and in vivo performance to PEGylated stealth NPs in the murine model, its interaction with elements of the human innate immune system has not been studied. From a translational angle, we studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived organically modified silica NPs (PMOXA-coated NPs) of approximately 100 nm in diameter with human complement system, blood leukocytes, and macrophages and compared their performance with PEGylated and uncoated NP counterparts. Through detailed immunological and proteomic profiling, we show that PMOXA-coated NPs extensively trigger complement activation in human sera exclusively through the classical pathway. Complement activation is initiated by the sensing molecule C1q, where C1q binds with high affinity (Kd = 11 \ub1 1 nM) to NP surfaces independent of immunoglobulin binding. C1q-mediated complement activation accelerates PMOXA opsonization with the third complement protein (C3) through the amplification loop of the alternative pathway. This promoted NP recognition by human blood leukocytes and monocyte-derived macrophages. The macrophage capture of PMOXA-coated NPs correlates with sera donor variability in complement activation and opsonization but not with other major corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps

Engineering inorganic and cartilage surfaces by topologically different poly(2-oxazolines)

Surface modification by polymer grafting has represented a revolution in material science, enabling the fabrication of stabilizers for colloids, biopassive coatings for sensors, drug delivery systems and model lubricants for technologically relevant applications. In this Thesis, I investigate the role of polymer topology in determining the interfacial physicochemical properties of surface-grafted assemblies, especially focusing on linear and cyclic polymer brushes. Cyclic polymers have been a scientific curiosity for decades, due to their intrinsic features, such as smaller hydrodynamic radius, higher thermal stability and unfavorable entanglement when compared to their linear analogues. In this work, cyclic polymers are applied for the first time as surface modifiers and the biopassive and lubricating properties of the derived films are studied. In particular, linear and cyclic poly(2-ethyl-2-oxazolines) (PEOXA) or poly(2-methyl-2-oxazolines) (PMOXA) are synthesized and coupled to specific functional moieties, which allow their anchoring to different surfaces. Cyclic and linear PEOXA are post-modified with catechols and chemisorbed on metal oxide surfaces, i.e. TiO2. The smaller hydrodynamic radius of cyclic polymers, combined with the absence of chain ends, determines the formation of denser films and provides enhanced steric stabilization to the surface when compared with linear polymers. Moreover, two opposite cyclic polymers-coated surfaces sliding against each other under load provide extremely low coefficient of friction, due to their highly unfavorable interdigitation. Cyclic and linear PMOXA are applied as side chains within graft-copolymers. The structure of these macromolecules resembles that of natural lubricants of articular joints and includes a poly(glutamic acid) (PGA) backbone, coupled to linear or cyclic PMOXA chains and to aldehyde-bearing segments (HBA). Since articular joint diseases, such as osteoarthritis (OA), are associated with a partial loss of natural lubricants and with a subsequent increase in friction, there is an emerging need for engineered friction-reducers for articular cartilage. PGA-PMOXA-HBA are designed to fulfill this need and to further stop or delay OA progression. Specifically, aldehyde groups spontaneously react with the degraded cartilage via Schiff-base formation and PMOXA chains form a biopassive and lubricious brush layer at the surface. Analogously to cyclic PEOXA on TiO2, graft-copolymers bearing cyclic PMOXA chains form denser films on degraded cartilage with respect to those having linear PMOXA. Furthermore, the replacement of linear PMOXA chains with cyclic ones results in enhanced biopassivity and in lubricating properties comparable to those of the healthy tissue

Nanostrutture inorganiche funzionali via miniemulsione: sintesi, caratterizzazione e funzionalizzazione

In this work a miniemulsion based approach was used for the synthesis of pure and doped copper sulphide nanostructures. Different sources of sulphide, like sodium sulphide, thioacetamide, thioacetic acid, thiourea and ammonium thioglycolate, were investigated to obtain pure and crystalline products. Complementary techniques (FT-IR, TEM, SEM, XRD, XPS and XAS) were used for a thorough characterization of the nanoproducts. For future bioimaging application, zinc oxide nanoparticles, synthesized via miniemulsion, were coated by a biocompatible polymeric ligand to enable them to be re-dispersed in acqueous media. The ligand chosen for this aim is a polymethyloxazoline (PMOXA) terminated with a nitrodopamine because this one is a good anchor for oxide surfaces. Functionalized nanoparticles were characterized by FT-IR and AFM and successfully re-despersed in water to form stable suspensions