Polymer Brushes on Nanoparticles for Controlling the Interaction with Protein-Rich Physiological Media.

The interaction of nanoparticles (NPs) with biological environments triggers the formation of a protein corona (PC), which significantly influences their behavior in vivo. This review explores the evolving understanding of PC formation, focusing on the opportunity for decreasing or suppressing protein-NP interactions by macromolecular engineering of NP shells. The functionalization of NPs with a dense, hydrated polymer brush shell is a powerful strategy for imparting stealth properties in order to elude recognition by the immune system. While poly(ethylene glycol) (PEG) has been extensively used for this purpose, concerns regarding its stability and immunogenicity have prompted the exploration of alternative polymers. The stealth properties of brush shells can be enhanced by tailoring functionalities and structural parameters, including the molar mass, grafting density, and polymer topology. Determining correlations between these parameters and biopassivity has enabled us to obtain polymer-grafted NPs with high colloidal stability and prolonged circulation time in biological media.

Oxygen Tolerance during Surface-Initiated Photo-ATRP: Tips and Tricks for Making Brushes under Environmental Conditions.

Achieving tolerance toward oxygen during surface-initiated reversible deactivation radical polymerization (SI-RDRP) holds the potential to translate the fabrication of polymer brush-coatings into upscalable and technologically relevant processes for functionalizing materials. While focusing on surface-initiated photoinduced atom transfer radical polymerization (SI-photoATRP), we demonstrate that a judicious tuning of the composition of reaction mixtures and the adjustment of the polymerization setup enable to maximize the compatibility of this grafting technique toward environmental conditions. Typically, the presence of O2 in the polymerization medium limits the attainable thickness of polymer brushes and causes the occurrence of "edge effects", i.e., areas at the substrates' edges where continuous oxygen diffusion from the surrounding environment inhibits brush growth. However, the concentrations of the Cu-based catalyst and "free" alkyl halide initiator in solution emerge as key parameters to achieve a more efficient consumption of oxygen and yield uniform and thick brushes, even for polymerization mixtures that are more exposed to air. Precise variation of reaction conditions thus allows us to identify those variables that become determinants for making the synthesis of brushes more tolerant toward oxygen, and consequently more practical and upscalable.

A one-pot approach to prepare stretchable and conductive regenerated silk fibroin/CNT films as multifunctional sensors.

Silk fibroin (SF)-based materials are characterized by their outstanding biocompatibility and biodegradability and are considered as the most promising candidates for next-generation flexible electronics. In order to generate such devices, SF can be mixed with carbon nanotubes (CNTs) which feature excellent mechanical, electrical, and thermal properties. However, obtaining regenerated SF with homogeneous dispersion of CNTs in a sustainable manner represents a challenging task, mainly due to the difficulty in overcoming van der Waals forces and strong π-π interactions that hold together the CNT structure. In this study, a one-pot strategy for fabricating SF/CNT films is proposed by designing SF as a modifier of CNTs through non-covalent interactions with the assistance of aqueous phosphoric acid solution. Glycerol (GL) was introduced, endowing the SF/GL/CNT composite film with excellent flexibility and stretchability. The sustainable strategy greatly simplifies the preparation process, avoiding dialysis of SF and the use of artificial dispersants. The as-fabricated SF/GL/CNT films showed an excellent mechanical strength of 1.20 MPa and high sensitivity with a gauge factor of up to 13.7 toward tensile deformation. The composite films had a sensitive monitoring capability for small strains with detection limits as low as 1% and can be assembled into versatile sensors to detect human movement. Simultaneously, the composite films showed a superb thermosensitive capacity (1.64% °C-1), which satisfied the requirement of real-time and continuous skin temperature monitoring. We anticipate that the presented one-pot strategy and the prepared composite films could open a new avenue for forthcoming technologies for electronic skins, personal health monitoring, and wearable electronics.

The Rational Design of Reducing Organophotoredox Catalysts Unlocks Proton-Coupled Electron-Transfer and Atom Transfer Radical Polymerization Mechanisms.

Photocatalysis has become a prominent tool in the arsenal of organic chemists to develop and (re)imagine transformations. However, only a handful of versatile organic photocatalysts (PCs) are available, hampering the discovery of new reactivities. Here, we report the design and complete physicochemical characterization of 9-aryl dihydroacridines (9ADA) and 12-aryl dihydrobenzoacridines (12ADBA) as strong reducing organic PCs. Punctual structural variations modulate their molecular orbital distributions and unlock locally or charge-transfer (CT) excited states. The PCs presenting a locally excited state showed better performances in photoredox defunctionalization processes (yields up to 92%), whereas the PCs featuring a CT excited state produced promising results in atom transfer radical polymerization under visible light (up to 1.21 D, and 98% I*). Unlike all the PC classes reported so far, 9ADA and 12ADBA feature a free NH group that enables a catalytic multisite proton-coupled electron transfer (MS-PCET) mechanism. This manifold allows the reduction of redox-inert substrates including aryl, alkyl halides, azides, phosphate and ammonium salts (Ered up to -2.83 vs SCE) under single-photon excitation. We anticipate that these new PCs will open new mechanistic manifolds in the field of photocatalysis by allowing access to previously inaccessible radical intermediates under one-photon excitation.

Oxygen Tolerance in Surface-Initiated Reversible Deactivation Radical Polymerizations: Are Polymer Brushes Turning into Technology?

Over the past three decades, the development of reversible deactivation radical polymerizations (RDRP), and advancements toward more user-friendly and accessible experimental setups have opened the door for nonexperts to design complex macromolecules with well-defined properties. External mediation, improved tolerance to oxygen, and increased reaction volumes for higher synthetic output are some of the many noteworthy technical improvements. The development of RDRPs in solution was paralleled by their application on solid substrates to synthesize surface-grafted "polymer brushes" via surface-initiated RDRP (SI-RDRP). This Viewpoint paper provides a current perspective on recent developments in SI-RDRP methods that are tolerant to oxygen, especially highlighting those that could potentially enable scaling up of the synthesis of brushes for the functionalization of technologically relevant materials.

Dispersity within Brushes Plays a Major Role in Determining Their Interfacial Properties: The Case of Oligoxazoline-Based Graft Polymers.

Many synthetic polymers used to form polymer-brush films feature a main backbone with functional, oligomeric side chains. While the structure of such graft polymers mimics biomacromolecules to an extent, it lacks the monodispersity and structural purity present in nature. Here we demonstrate that side-chain heterogeneity within graft polymers significantly influences hydration and the occurrence of hydrophobic interactions in the subsequently formed brushes and consequently impacts fundamental interfacial properties. This is demonstrated for the case of poly(methacrylate)s (PMAs) presenting oligomeric side chains of different length (n) and dispersity. A precise tuning of brush structure was achieved by first synthesizing oligo(2-ethyl-2-oxazoline) methacrylates (OEOXMAs) by cationic ring-opening polymerization (CROP), subsequently purifying them into discrete macromonomers with distinct values of n by column chromatography, and finally obtaining poly[oligo(2-ethyl-2-oxazoline) methacrylate]s (POEOXMAs) by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Assembly of POEOXMA on Au surfaces yielded graft polymer brushes with different side-chain dispersities and lengths, whose properties were thoroughly investigated by a combination of variable angle spectroscopic ellipsometry (VASE), quartz crystal microbalance with dissipation (QCMD), and atomic force microscopy (AFM) methods. Side-chain dispersity, or dispersity within brushes, leads to assemblies that are more hydrated, less adhesive, and more lubricious and biopassive compared to analogous films obtained from graft polymers characterized by a homogeneous structure.

The role of poly(2-alkyl-2-oxazoline)s in hydrogels and biofabrication.

Poly(2-alkyl-2-oxazoline)s (PAOXAs) have been rapidly emerging as starting materials in the design of tissue engineering supports and for the generation of platforms for cell cultures, especially in the form of hydrogels. Thanks to their biocompatibility, chemical versatility and robustness, PAOXAs now represent a valid alternative to poly(ethylene glycol)s (PEGs) and their derivatives in these applications, and in the formulation of bioinks for three-dimensional (3D) bioprinting. In this review, we summarize the recent literature where PAOXAs have been used as main components for hydrogels and biofabrication mixtures, especially highlighting how their easily tunable composition could be exploited to fabricate multifunctional biomaterials with an extremely broad spectrum of properties.

Topology and Molecular Architecture of Polyelectrolytes Determine Their pH-Responsiveness When Assembled on Surfaces.

Polymer composition and topology of surface-grafted polyacids determine the amplitude of their pH-induced swelling transition. The intrinsic steric constraints characterizing cyclic poly(2-carboxypropyl-2-oxazoline) (c-PCPOXA) and poly(2-carboxyethyl-2-oxazoline) (c-PCEOXA) forming brushes on Au surfaces induce an enhancement in repulsive interactions between charged polymer segments upon deprotonation, leading to an amplified expansion and a significant increment in swelling with respect to their linear analogues of similar molar mass. On the other hand, it is the composition of polyacid grafts that governs their hydration in both undissociated and ionized forms, determining the degree of swelling during their pH-induced transition.

Fabrication of Three-Dimensional Polymer-Brush Gradients within Elastomeric Supports by Cu0-Mediated Surface-Initiated ATRP.

Cu0-mediated surface-initiated ATRP (Cu0 SI-ATRP) emerges as a versatile, oxygen-tolerant process to functionalize three-dimensional (3D), microporous supports forming single and multiple polymer-brush gradients with a fully tunable composition. When polymerization mixtures are dispensed on a Cu0-coated plate, this acts as oxygen scavenger and source of active catalyst. In the presence of an ATRP initiator-bearing microporous elastomer placed in contact with the metallic plate, the reaction solution infiltrates by capillarity through the support, simultaneously triggering the controlled growth of polymer brushes. The polymer grafting process proceeds with kinetics that are determined by the progressive infiltration of the reaction solution within the microporous support and by the continuous diffusion of catalyst regenerated at the Cu0 surface. The combination of these effects enables the accessible generation of 3D polymer-brush gradients extending across the microporous scaffolds used as supports, finally providing materials with a continuous variation of interfacial composition and properties.

Hydrogels Generated from Cyclic Poly(2-Oxazoline)s Display Unique Swelling and Mechanical Properties.

Cyclic macromolecules do not feature chain ends and are characterized by a higher effective intramolecular repulsion between polymer segments, leading to a higher excluded-volume effect and greater hydration with respect to their linear counterparts. As a result of these unique properties, hydrogels composed of cross-linked cyclic polymers feature enhanced mechanical strength while simultaneously incorporating more solvent with respect to networks formed from their linear analogues with identical molar mass and chemical composition. The translation of topology effects by cyclic polymers into the properties of polymer networks provides hydrogels that ideally do not include defects, such as dangling chain ends, and display unprecedented physicochemical characteristics.

Biomaterials applications of cyclic polymers.

Cyclic polymers are an intriguing class of polymers due to their lack of chain ends. This unique architecture combined with steric constraints adorn cyclic polymers as well as nano-, micro- and macro-scale materials containing cyclic polymers with distinctive physicochemical properties which can have a profound effect on the performance of these materials in a wide range of applications. Within a biomedical context, biomaterials based on cyclic polymers have shown very distinct properties in terms of biodistribution, pharmacokinetics, drug/gene delivery efficiency and surface activity. This review summarizes the applications of cyclic polymers in the field of biomaterials and highlights their potential in the biomedical field as well as addressing future challenges in this area.

Polymer Topology Determines the Formation of Protein Corona on Core-Shell Nanoparticles.

Linear and cyclic poly(2-ethyl-2-oxazoline) (PEOXA) adsorbates provide excellent colloidal stability to superparamagnetic iron oxide nanoparticles (FexOy NPs) within protein-rich media. However, dense shells of linear PEOXA brushes cannot prevent weak but significant attractive interactions with human serum albumin. In contrast, their cyclic PEOXA counterparts quantitatively hinder protein adsorption, as demonstrated by a combination of dynamic light scattering and isothermal titration calorimetry. The cyclic PEOXA brushes generate NP shells that are denser and more compact than their linear counterparts, entirely preventing the formation of a protein corona as well as aggregation, even when the lower critical solution temperature of PEOXA in a physiological buffer is reached.

Functional Nanoassemblies of Cyclic Polymers Show Amplified Responsiveness and Enhanced Protein-Binding Ability.

The physicochemical properties of cyclic polymer adsorbates are significantly influenced by the steric and conformational constraints introduced during their cyclization. These translate into a marked difference in interfacial properties between cyclic polymers and their linear counterparts when they are grafted onto surfaces yielding nanoassemblies or polymer brushes. This difference is particularly clear in the case of cyclic polymer brushes that are designed to chemically interact with the surrounding environment, for instance, by associating with biological components present in the medium, or, alternatively, through a response to a chemical stimulus by a significant change in their properties. The intrinsic architecture characterizing cyclic poly(2-oxazoline)-based polyacid brushes leads to a broad variation in swelling and nanomechanical properties in response to pH change, in comparison with their linear analogues of identical composition and molecular weight. In addition, cyclic glycopolymer brushes derived from polyacids reveal an enhanced exposure of galactose units at the surface, due to their expanded topology, and thus display an increased lectin-binding ability with respect to their linear counterparts. This combination of amplified responsiveness and augmented protein-binding capacity renders cyclic brushes invaluable building blocks for the design of "smart" materials and functional biointerfaces.

Oxygen Tolerant and Cytocompatible Iron(0)-Mediated ATRP Enables the Controlled Growth of Polymer Brushes from Mammalian Cell Cultures.

The use of zerovalent iron (Fe0)-coated plates, which act both as a source of catalyst and as a reducing agent during surface-initiated atom transfer radical polymerization (SI-ATRP), enables the controlled growth of a wide range of polymer brushes under ambient conditions utilizing either organic or aqueous reaction media. Thanks to its cytocompatibility, Fe0 SI-ATRP can be applied within cell cultures, providing a tool that can broadly and dynamically modify the substrate's affinity toward cells, without influencing their viability. Upon systematically assessing the application of Fe-based catalytic systems in the controlled grafting of polymers, Fe0 SI-ATRP emerges as an extremely versatile technique that could be applied to tune the physicochemical properties of a cell's microenvironments on biomaterials or within tissue engineering constructs.

Versatile Surface Modification of Hydrogels by Surface-Initiated, Cu0-Mediated Controlled Radical Polymerization.

Surface-initiated controlled radical polymerization mediated by a Cu0 plate (SI-Cu0 CRP) emerges as a versatile and efficient method for the functionalization of the exposed surfaces of hydrogels with a wide variety of polymer brushes. When a Cu0 plate is placed in contact with initiator-bearing hydrogel surfaces in the presence of ligand and monomer and under ambient conditions, it rapidly consumes dissolved oxygen from the reaction mixture, further acting as a source of catalyst and leading to the rapid growth of hydrogel-bound polymer chains. Three types of functional surfaces have been prepared as examples of the wide range of potential materials that can be synthesized in this way, including a hydrogel with a protective, hydrophobic surface, a lubricious hydrogel, as well as a hydrogel with thermally switchable frictional properties.

Topological Polymer Chemistry Enters Materials Science: Expanding the Applicability of Cyclic Polymers.

Polymer-topology effects can alter technologically relevant properties when cyclic macromolecules are applied within diverse materials formulations. These include coatings, polymer networks, or nanostructures for delivering therapeutics. While substituting linear building blocks with cyclic analogues in commonly studied materials is itself of fundamental interest, an even more fascinating observation has been that the introduction of physical or chemical boundaries (e.g., a grafting surface or cross-links) can amplify the topology-related effects observed when employing cyclic polymer-based precursors for assembling multidimensional objects. Hence, the application of cyclic polymers has enabled the fabrication of coatings with enhanced biorepellency and superior lubricity, broadened the tuning potential for mechanical properties of polymer networks, increased the thermodynamic stability, and altered the capability of loading and releasing drugs within polymeric micelles.

Double-Network Hydrogels Including Enzymatically Crosslinked Poly-(2-alkyl-2-oxazoline)s for 3D Bioprinting of Cartilage-Engineering Constructs.

Double-network (DN) hydrogels are fabricated from poly(2-ethyl-2-oxazoline) (PEOXA)-peptide conjugates, which can be enzymatically crosslinked in the presence of Sortase A (SA), and physical networks of alginate (Alg), yielding matrices with improved mechanical properties with respect to the corresponding PEOXA and Alg single networks and excellent cell viability of encapsulated human auricular chondrocytes (hACs). The addition of a low content of cellulose nanofibrils (CNFs) within DN hydrogel formulations provides the rheological properties needed for extrusion-based three-dimensional (3D) printing, generating constructs with a good shape fidelity. In the presence of hACs, PEOXA-Alg-CNF prehydrogel mixtures can be bioprinted, finally generating 3D-structured DN hydrogel supports showing a cell viability of more than 90%. Expanding the application of poly(2-alkyl-2-oxazoline)-based formulations in the design of tissue-engineering constructs, this study further demonstrates how SA-mediated enzymatic crosslinking represents a suitable and fully orthogonal method to generate biocompatible hydrogels with fast kinetics.

Biocatalytic ATRP in solution and on surfaces.

The promiscuity of enzymes allows for their implementation as catalysts for non-native chemical transformations. Utilizing the redox activity of metalloenzymes under activator regenerated by electron transfer (ARGET) ATRP conditions, well-controlled and defined polymers can be generated. In this chapter, we review bioATRP in solution and on surfaces and provide experimental protocols for hemoglobin-catalyzed ATRP and for surface-initiated biocatalytic ATRP. This chapter highlights the polymerization of acrylate and acrylamide monomers and provides detailed experimental protocols for the characterization of the polymers and of the polymer brushes.

Bioinert and Lubricious Surfaces by Macromolecular Design.

The modification of a variety of biomaterials and medical devices often encompasses the generation of biopassive and lubricious layers on their exposed surfaces. This is valid when the synthetic supports are required to integrate within physiological media without altering their interfacial composition and when the minimization of shear stress prevents or reduces damage to the surrounding environment. In many of these cases, hydrophilic polymer brushes assembled from surface-interacting polymer adsorbates or directly grown by surface-initiated polymerizations (SIP) are chosen. Although growing efforts by polymer chemists have been focusing on varying the composition of polymer brushes in order to attain increasingly bioinert and lubricious surfaces, the precise modulation of polymer architecture has simultaneously enabled us to substantially broaden the tuning potential for the above-mentioned properties. This feature article concentrates on reviewing this latter strategy, comparatively analyzing how polymer brush parameters such as molecular weight and grafting density, the application of block copolymers, the introduction of branching and cross-links, or the variation of polymer topology beyond the simple, linear chains determine highly technologically relevant properties, such as biopassivity and lubrication.

Brushes, Graft Copolymers, or Bottlebrushes? The Effect of Polymer Architecture on the Nanotribological Properties of Grafted-from Assemblies.

Surface-grafted polyzwitterions (PZW) have gained a foothold in the design of synthetic materials that closely mimic the lubricious properties of articular joints in mammals. Besides their chemical composition, the architecture of PZW brushes strongly determines their morphological, nanomechanical, and nanotribological characteristics. This emerges while comparing the properties of linear poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) brushes with those displayed by graft copolymer and bottlebrush brushes, either featuring a low or a high content of PMPC side chains. Surface-initiated atom transfer radical polymerization (SI-ATRP) enabled the synthesis of different branched-brush architectures from multifunctional macroinitiators via multiple grafting steps, and allowed us to modulate their structure by tuning the polymerization conditions. At relatively low grafting densities (σ), long PMPC side segments extend at the interface of bottlebrush and graft copolymer brushes, providing both morphology and lubrication properties comparable to those shown by loosely grafted, linear PMPC brushes. When σ > 0.1 chains nm-2 the effect of the branched-brush architecture on the nanotribological properties of the films became evident. Linear PMPC brushes showed the lowest friction among the studied brush structures, with a coefficient of friction (µ) that reached 1 × 10-4, as measured by atomic force microscopy (AFM). Bottlebrush brushes showed comparatively higher friction, although the high content of hydrophilic PMPC side chains along their backbone substantially improved lubrication compared to that displayed by the more sparsely substituted graft copolymer brushes.