Anti-Fouling Surfaces for Extracorporeal Membrane Oxygenation by Surface Grafting of Hydrophilic Sulfoxide Polymers.

Non-thrombogenic surfaces for extracorporeal membrane oxygenation (ECMO) devices are important to increase their duration of usage and to enable long-term life support. However, the contact of blood with the hydrophobic synthetic ECMO membrane materials such as poly(4-methyl-1-pentene) (PMP) can activate the coagulation cascade, causing thrombosis and a series of consequent complications during ECMO operation. Targeting this problem, we proposed to graft highly hydrophilic sulfoxide polymer brushes onto the PMP surfaces via gamma ray irradiation-initiated polymerization to improve the hemocompatibility of the membrane. Through this chemical modification, the surface of the PMP film is altered from hydrophobic to hydrophilic. The extent of plasma protein adsorption and platelet adhesion, the prerequisite mediators of the coagulation cascade and thrombus formation, are drastically reduced compared with those of the unmodified PMP film. Therefore, the method provides a facile approach to modify PMP materials with excellent antifouling properties and improved hemocompatibility demanded by the applications in ECMO and other blood-contacting medical devices.

Low-Fouling Gold Nanorod Theranostic Agents Enabled by a Sulfoxide Polymer Coating.

Gold nanorods (GNRs) are widely used in various biomedical applications such as disease imaging and therapy due to their unique plasmonic properties. To improve their bioavailability, GNRs often need to be coated with hydrophilic polymers so as to impart stealth properties. Poly(ethylene glycol) (PEG) has been long used as such a coating material for GNRs. However, there is increasing acknowledgement that the amphiphilic nature of PEG facilitates its interaction with protein molecules, leading to immune recognition and consequent side effects. This has motivated the search for new classes of low-fouling polymers with high hydrophilicity as alternative low-fouling surface coating materials for GNRs. Herein, we report the synthesis, characterization, and application of GNRs coated with highly hydrophilic sulfoxide-containing polymers. We investigated the effect of the sulfoxide polymer coating on the cellular uptake and in vivo circulation time of the GNRs and compared these properties with pegylated GNR counterparts. The photothermal effect and photoacoustic imaging of these polymer-coated GNRs were also explored, and the results show that these GNRs are promising as nanotheranostic particles for the treatment of cancer.

Efficient Removal of Perfluorinated Chemicals from Contaminated Water Sources Using Magnetic Fluorinated Polymer Sorbents.

Efficient removal of per- and polyfluoroalkyl substances (PFAS) from contaminated waters is urgently needed to safeguard public and environmental health. In this work, novel magnetic fluorinated polymer sorbents were designed to allow efficient capture of PFAS and fast magnetic recovery of the sorbed material. The new sorbent has superior PFAS removal efficiency compared with the commercially available activated carbon and ion-exchange resins. The removal of the ammonium salt of hexafluoropropylene oxide dimer acid (GenX) reaches >99 % within 30 s, and the estimated sorption capacity was 219 mg g-1 based on the Langmuir model. Robust and efficient regeneration of the magnetic polymer sorbent was confirmed by the repeated sorption and desorption of GenX over four cycles. The sorption of multiple PFAS in two real contaminated water matrices at an environmentally relevant concentration (1 ppb) shows >95 % removal for the majority of PFAS tested in this study.

Emergence of Hexagonally Close-Packed Spheres in Linear Block Copolymer Melts.

The hexagonally close-packed (HCP) sphere phase is predicted to be stable across a narrow region of linear block copolymer phase space, but the small free energy difference separating it from face-centered cubic spheres usually results in phase coexistence. Here, we report the discovery of pure HCP spheres in linear block copolymer melts with A = poly(2,2,2-trifluoroethyl acrylate) ("F") and B = poly(2-dodecyl acrylate) ("2D") or poly(4-dodecyl acrylate) ("4D"). In 4DF diblocks and F4DF triblocks, the HCP phase emerges across a substantial range of A-block volume fractions (circa fA = 0.25-0.30), and in F4DF, it forms reversibly when subjected to various processing conditions which suggests an equilibrium state. The time scale associated with forming pure HCP upon quenching from a disordered liquid is intermediate to the ordering kinetics of the Frank-Kasper σ and A15 phases. However, unlike σ and A15, HCP nucleates directly from a supercooled liquid or soft solid without proceeding through an intermediate quasicrystal. Self-consistent field theory calculations indicate the stability of HCP is intimately tied to small amounts of molar mass dispersity (D); for example, an HCP-forming F4DF sample with fA = 0.27 has an experimentally measured D = 1.04. These insights challenge the conventional wisdom that pure HCP is difficult to access in linear block copolymer melts without the use of blending or other complex processing techniques.

Antifouling Surfaces Enabled by Surface Grafting of Highly Hydrophilic Sulfoxide Polymer Brushes.

Antifouling surfaces are important in a broad range of applications. An effective approach to antifouling surfaces is to covalently attach antifouling polymer brushes. This work reports the synthesis of a new class of antifouling polymer brushes based on highly hydrophilic sulfoxide polymers by surface-initiated photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) polymerization. The sulfoxide polymer brushes are able to effectively reduce nonspecific adsorption of proteins and cells, demonstrating remarkable antifouling properties. Given the outstanding antifouling behavior of the sulfoxide polymers and versatility of surface-initiated PET-RAFT technology, this work presents a useful and general approach to engineering various material surfaces with antifouling properties, for potential biomedical applications in areas such as tissue engineering, medical implants, and regenerative medicine.

Rapid Generation of Block Copolymer Libraries Using Automated Chromatographic Separation.

A versatile and scalable strategy is reported for the rapid generation of block copolymer libraries spanning a wide range of compositions starting from a single parent copolymer. This strategy employs automated and operationally simple chromatographic separation that is demonstrated to be applicable to a variety of block copolymer chemistries on multigram scales with excellent mass recovery. The corresponding phase diagrams exhibit increased compositional resolution compared to those traditionally constructed via multiple, individual block copolymer syntheses. Increased uniformity and lower dispersity of the chromatographic libraries lead to differences in the location of order-order transitions and observable morphologies, highlighting the influence of dispersity on the self-assembly of block copolymers. Significantly, this separation technique greatly simplifies the exploration of block copolymer phase space across a range of compositions, monomer pairs, and molecular weights (up to 50000 amu), producing materials with increased control and homogeneity when compared to conventional strategies.

Use of Microfluidics to Fabricate Bioerodable Lipid Hybrid Nanoparticles Containing Hydromorphone or Ketamine for the Relief of Intractable Pain.

PURPOSE: For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection. METHODS: A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot in vivo study was conducted in a rat model of peripheral neuropathic pain. RESULTS: The in vitro release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot in vivo study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 µg. Co-administration of ketamine-loaded NPs at 340 µg did not increase the duration of analgesia significantly. CONCLUSIONS: The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle in vivo study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.

Low-Fouling Fluoropolymers for Bioconjugation and In†Vivo Tracking.

The conjugation of hydrophilic low-fouling polymers to therapeutic molecules and particles is an effective approach to improving their aqueous stability, solubility, and pharmacokinetics. Recent concerns over the immunogenicity of poly(ethylene glycol) has highlighted the importance of identifying alternative low fouling polymers. Now, a new class of synthetic water-soluble homo-fluoropolymers are reported with a sulfoxide side-chain structure. The incorporation of fluorine enables direct imaging of the homopolymer by 19 F MRI, negating the need for additional synthetic steps to attach an imaging moiety. These self-reporting fluoropolymers show outstanding imaging sensitivity and remarkable hydrophilicity, and as such are a new class of low-fouling polymer for bioconjugation and in vivo tracking.

Integrating Fluorinated Polymer and Manganese-Layered Double Hydroxide Nanoparticles as pH-activated 19 F MRI Agents for Specific and Sensitive Detection of Breast Cancer.

19 F magnetic resonance imaging (19 F MRI) agents capable of being activated upon interactions with cancer triggers are attracting increasing attention, although challenges still remain for precise and specific detection of cancer tissues. In this study, a novel hybrid 19 F MRI agent for pH-sensitive detection of breast cancer tissues is reported, a composite system designed by conjugating a perfluoropolyether onto the surface of manganese-incorporated layered double hydroxide (Mn-LDH@PFPE) nanoparticles. The 19 F NMR/MRI signals from aqueous solutions of Mn-LDH@PFPE nanoparticles are quenched at pH 7.4, but "turned on" following a reduction in pH to below 6.5. This is due to partial dissolution of Mn2+ from the Mn-LDH nanoparticles and subsequent reduction in the effect of paramagnetic relaxation. Significantly, in vivo experiments reveal that an intense 19 F MR signal can be detected only in the breast tumor tissue after intravenous injection of Mn-LDH@PFPE nanoparticles due to such a specific activation. Thus pH-activated Mn-LDH@PFPE nanoparticles are a potential "smart" 19 F MRI agent for precise and specific detection of cancer diseases.

Fluorinated Glycopolymers as Reduction-responsive 19F MRI Agents for Targeted Imaging of Cancer.

Imaging agents that can be targeted to specific diseases and respond to the microenvironment of the diseased tissue are of considerable interest due to their potential in diagnosing and managing diseases. Here we report a new class of branched fluorinated glycopolymers as 19F MRI contrast agents that respond to a reductive environment, for targeted imaging of cancer. The fluorinated glycopolymers can be readily prepared by a one-pot RAFT polymerization of glucose- and fluorine-containing monomers in the presence of a disulfide-containing cross-linking monomer. The incorporation of glucose units along the polymer chain enables these fluorinated glycopolymers to effectively target cancer cells due to interactions with the overexpressed sugar transporters present on the cell surface. In addition, the polymers exhibit an enhanced 19F MRI signal in response to a reductive environment, one of the unique hallmarks of many cancer cells, demonstrating their potential as promising candidates for targeted imaging of cancer.

Importance of Thermally Induced Aggregation on 19F Magnetic Resonance Imaging of Perfluoropolyether-Based Comb-Shaped Poly(2-oxazoline)s.

An understanding of thermally induced aggregation and consequent 19F magnetic resonance imaging (MRI) performance is essential for improved design of thermoresponsive 19F MRI contrast agents. Herein we describe a series of novel thermoresponsive perfluoropolyether (PFPE)-based comb-shaped poly(2-oxazoline)s (POxs) with different side-chain structures (2-methyl- (MeOx), 2-ethyl- (EtOx), and 2-( n-propyl)-2-oxazoline (nPrOx)). The comb polymers were prepared through reversible addition-fragmentation chain transfer (RAFT) polymerization of the respective oligo(2-oxazoline)acrylates using a perfluoropolyether macro-RAFT agent. The fluoropolyether chain end drives aggregation of the polymers, with small aggregates forming at 300 K for both poly(OMeOx5A)9-PFPE and poly(OEtOx4A)9-PFPE. The aggregates decrease in size and display increases in 19F MRI intensity with temperature, and at 350 K the MeOx polymers are in the form of unimers in solution, similar to the oligoethylene glycol (OEG)-based PFPE polymer. Above the TCP of poly(OEtOx4A)9-PFPE, the polymer forms large aggregates, and the 19F MR imaging performance is degraded. Likewise, poly(OnPrOx4A)-PFPE is above the LCST at all temperatures studied (300-350 K), and so weak imaging intensity is obtained. This report of novel thermoresponsive POx-based PFPE polymers highlights the importance of understanding self-association of polymers in solution and provides important insights for the development of "smart" thermoresponsive 19F MRI contrast agents.

Bioconjugation and Fluorescence Labeling of Iron Oxide Nanoparticles Grafted with Bromomaleimide-Terminal Polymers.

Iron oxide nanoparticles have been widely applied in biomedical applications for their unique physical properties. Despite the relatively mature synthetic approaches for iron oxide nanoparticles, surface modification strategies for obtaining particles with satisfactory biofunctionality are still urgently needed to meet the challenge of nanomedicine. Herein, we report a surface modification and biofunctionalization strategy for iron oxide-based magnetic nanoparticles based on a dibromomaleimide (DBM)-terminated polymer with brushed polyethylene glycol (PEG) chains. PEG acrylate and phosphonate monomers, serving as antibiofouling and surface anchoring compartments for iron oxide nanoparticles, were incorporated utilizing a novel DBM containing reversible addition-fragmentation chain transfer (RAFT) agent. The particles prepared through this new surface architecture possessed high colloidal stability in a physiological buffer and the capacity of covalent conjugation with biomolecules for targeting. Cell tracking of the molecular probes was achieved concomitantly by exploiting DBM conjugation-induced fluorescence of the nanoparticles.

Hydrogels with Lotus Leaf Topography: Investigating Surface Properties and Cell Adhesion.

The interactions of cells with the surface of materials is known to be influenced by a range of factors that include chemistry and roughness; however, it is often difficult to probe these factors individually without also changing the others. Here we investigate the role of roughness on cell adhesion while maintaining the same underlying chemistry. This was achieved by using a polymerization in mold technique to prepare poly(hydroxymethyl methacrylate) hydrogels with either a flat topography or a topography that replicated the microscale features of lotus leaves. These materials were then assessed for cell adhesion, and atomic force microscopy and contact angle analysis were then used to probe the physical reasons for the differing behavior in relation to cell adhesion.

Polymerization-Induced Self-Assembly (PISA) - Control over the Morphology of 19F-Containing Polymeric Nano-objects for Cell Uptake and Tracking.

Fluorine-containing polymeric materials are receiving increasing attention as imaging probes in fluorine-19 magnetic resonance imaging (19F MRI), for example to enable quantitative in vivo detection of cells. Here we describe the one-pot polymerization synthesis of 19F-containing functional poly(oligo(ethylene glycol) methyl ether methacrylate-co-2,2,2-trifluoroethyl acrylate-b-poly(styrene-co-3-vinylbenzaldehyde) (poly(OEGA-co-TFEA)-b-poly(St-co-VBA)) copolymers as a new class of fluorinated MRI agent. A range of nanoparticle morphologies, including spheres, worm-like particles, and vesicles were formed as a consequence of polymerization-induced self-assembly (PISA). It was found that the extent of cell uptake strongly depends on the morphology of the nano-objects, with preferable uptake for worm-like particles compared to spherical nanoparticles and vesicles. All the nano-objects have a single resonance in the 19F NMR spectrum with relatively short MRI relaxation times, which were independent of the morphology of the nano-objects. These results confirm that these polymeric nano-objects of varied morphologies are promising as 19F MRI imaging agents for use in tracking of cells and selective MRI.

Segmented Highly Branched Copolymers: Rationally Designed Macromolecules for Improved and Tunable (19)F MRI.

Highly branched polymers are a promising platform for the design of next-generation contrast agents for (19)F magnetic resonance imaging (MRI). A series of segmented highly branched polymers (SHBPs) consisting of fluoro- and PEG-based monomers were synthesized by self-condensing vinyl copolymerization (SCVP) using the reversible addition-fragmentation chain transfer (RAFT) technique. SHBPs having different compositions and degrees of branching were obtained by varying the monomer type and feed ratio of monomer to chain transfer agent (CTA). The chemical structures and physical properties of the branched polymers were thoroughly characterized in detail by NMR, SEC and DSC. The systematic variation in structural parameters allowed the relationships between molecular structure, sequence distribution, and imaging performance to be examined. The (19)F NMR properties were strongly affected by the sequence distribution of the fluorinated monomers, the type of polymer backbone and the degree of branching. As a result, SHBPs consisting of statistical copolymeric segments of acrylate units were identified as excellent candidates for imaging due to a single (19)F signal, long T2 relaxation times, and high fluorine contents. The SHBPs could be all imaged or selectively imaged by taking advantage of the differences in relaxation times, demonstrating tunable and selective imaging performance through tailoring the structure and composition of the SHBPs.

Evaluation of Polymeric Nanomedicines Targeted to PSMA: Effect of Ligand on Targeting Efficiency.

Targeted nanomedicines offer a strategy for greatly enhancing accumulation of a therapeutic within a specific tissue in animals. In this study, we report on the comparative targeting efficiency toward prostate-specific membrane antigen (PSMA) of a number of different ligands that are covalently attached by the same chemistry to a polymeric nanocarrier. The targeting ligands included a small molecule (glutamate urea), a peptide ligand, and a monoclonal antibody (J591). A hyperbranched polymer (HBP) was utilized as the nanocarrier and contained a fluorophore for tracking/analysis, whereas the pendant functional chain-ends provided a handle for ligand conjugation. Targeting efficiency of each ligand was assessed in vitro using flow cytometry and confocal microscopy to compare degree of binding and internalization of the HBPs by human prostate cancer (PCa) cell lines with different PSMA expression status (PC3-PIP (PSMA+) and PC3-FLU (PSMA-). The peptide ligand was further investigated in vivo, in which BALB/c nude mice bearing subcutaneous PC3-PIP and PC3-FLU PCa tumors were injected intravenously with the HBP-peptide conjugate and assessed by fluorescence imaging. Enhanced accumulation in the tumor tissue of PC3-PIP compared to PC3-FLU highlighted the applicability of this system as a future imaging and therapeutic delivery vehicle.

Multimodal polymer nanoparticles with combined 19F magnetic resonance and optical detection for tunable, targeted, multimodal imaging in vivo.

Understanding the complex nature of diseased tissue in vivo requires development of more advanced nanomedicines, where synthesis of multifunctional polymers combines imaging multimodality with a biocompatible, tunable, and functional nanomaterial carrier. Here we describe the development of polymeric nanoparticles for multimodal imaging of disease states in vivo. The nanoparticle design utilizes the abundant functionality and tunable physicochemical properties of synthetically robust polymeric systems to facilitate targeted imaging of tumors in mice. For the first time, high-resolution (19)F/(1)H magnetic resonance imaging is combined with sensitive and versatile fluorescence imaging in a polymeric material for in vivo detection of tumors. We highlight how control over the chemistry during synthesis allows manipulation of nanoparticle size and function and can lead to very high targeting efficiency to B16 melanoma cells, both in vitro and in vivo. Importantly, the combination of imaging modalities within a polymeric nanoparticle provides information on the tumor mass across various size scales in vivo, from millimeters down to tens of micrometers.

Coordination complexes as molecular glue for immobilization of antibodies on cyclic olefin copolymer surfaces.

A novel metal-based chelating method has been used to provide an order of magnitude increase in immunoassay performance on cyclic olefin copolymer (COC) plastics compared with passive binding. COCs are hydrophobic, and without surface modification they are often unsuitable for applications where protein adhesion is desired. When interacting with the bare plastic, the majority of the bound proteins will be denatured and become nonfunctional. Many of the surface modification techniques reported to date require costly equipment setup or the use of harsh reaction conditions. Here, we have successfully demonstrated the use of a simple and quick metal chelation method to increase the sensitivity, activity, and efficiency of protein binding to COC surfaces. A detailed analysis of the COC surfaces after activation with the metal complexes is presented, and the immunoassay performance was studied using three different antibody pairs.

Synthesis and characterization of a POSS-PEG macromonomer and POSS-PEG-PLA hydrogels for periodontal applications.

A novel water-soluble macromonomer based on octavinyl silsesquioxane has been synthesized and contains vinyl-terminated PEG 400 in each of the eight arms to promote water solubility. The macromonomer was characterized by NMR and FTIR and its aqueous solution properties examined. In water it exhibits an LCST with a cloud point at 23 °C for a 10 wt % aqueous solution. It is surface active with a CMC of 1.5 × 10(-5) M in water and in 20:80 v/v acetone/water the CMC is 7.1 × 10(-5) M, and TEM images showed spherical 22 nm aggregates in aqueous solution above the CMC. The macromonomer was copolymerized in a 20:80 v/v acetone/water mixture with a vinyl-terminated, triblock copolymer of lactide-PEG-lactide to form a library of cross-linked hydrogels that were designed for use as scaffolds for alveolar bone repair. The cross-linked copolymer networks were shown to contain a range of nm-µm sized pores and their swelling properties in water and PBS at pH 7.4 were examined. At pH 7.4 the hydrogel networks undergo a slow hydrolysis with the release of principally PEG and lactic acid fragments. The hydrogels were shown to be noncytotoxic toward fibroblast cultures at pH 7.4, both initially (days 1-5) and after significant hydrolysis had taken place (days 23-28).

Mussel-inspired antimicrobial hydrogel with cellulose nanocrystals/tannic acid modified silver nanoparticles for enhanced calvarial bone regeneration.

Bacterial infection is a serious challenge in the treatment of open bone defects, and reliance on antibiotic therapy may contribute to the emergence of drug-resistant bacteria. To solve this problem, this study developed a mineralized hydrogel (PVA-Ag-PHA) with excellent antibacterial properties and osteogenic capabilities. Silver nanoparticles (CNC/TA@AgNPs) were greenly synthesized using natural macromolecular cellulose nanocrystals (CNC) and plant polyphenolic tannins (TA) as stabilizers and reducing agents respectively, and then introduced into polyvinyl alcohol (PVA) and polydopamine-modified hydroxyapatite (PDA@HAP) hydrogel. The experimental results indicate that the PVA-Ag-PHA hydrogel, benefiting from the excellent antibacterial properties of CNC/TA@AgNPs, can not only eliminate Staphylococcus aureus and Escherichia coli, but also maintain a sustained sterile environment. At the same time, the HAP modified by PDA is uniformly dispersed within the hydrogel, thus releasing and maintaining stable concentrations of Ca2+ and PO43- ions in the local environment. The porous structure of the hydrogel with excellent biocompatibility creates a suitable bioactive environment that facilitates cell adhesion and bone regeneration. The experimental results in the rat critical-sized calvarial defect model indicate that the PVA-Ag-PHA hydrogel can effectively accelerate the bone healing process. Thus, this mussel-inspired hydrogel with antibacterial properties provides a feasible solution for the repair of open bone defects, demonstrating the considerable potential for diverse applications in bone repair.