Zwitterionic Porous Conjugated Polymers as a Versatile Platform for Antibiofouling Implantable Bioelectronics.
ABSTRACT: Here, we describe the design, synthesis, and evaluation of two kinds of multifunctional zwitterionic linear poly(carboxybetaine thiophene) (PCBTh) and porous poly(carboxybetaine thiophene-co-9,9'-bifluoreneylidene) (PCBTh-coBF) polymers, which can be facilely synthesized using Yamamoto and Suzuki polycondensation, respectively. The integrations of zwitterionic polymer-based biomaterials that consist of conjugated polymer backbones, multifunctional zwitterionic side chains, and distorted units are designed and studied to address a key challenge of conjugated polymers in biomedical applications: biofouling phenomena that eventually lead to the failure and reduced lifetime of bioelectronics in the body. The introduction of a twisting unit into the polymer backbone allows us to tune the porosity, morphology, optical properties, and efficiency of antibiofouling features of resulting polymers. The PCBTh-coBF coated surface exhibits good conductivity, stability, hydrophilicity, and antibiofouling properties against protein adsorption, cell growth, and bacteria attachment, which may be useful for chronic in vivo bioelectronics applications by minimizing the foreign body response.
Project description:An integrated zwitterionic conjugated polymer-based biomaterial platform was designed and studied to address some of the key challenges of conjugated polymers in biomedical applications. This biomaterial platform consists of conjugated polymer backbones and multifunctional zwitterionic side chains. Zwitterionic materials gain electrical conductivity and interesting optical properties through conjugated polymer backbones, and non-biocompatible conjugated polymers obtain excellent antifouling properties, enhanced electrical conductivity, functional groups of bioconjugation and response to environmental stimuli via multifunctional zwitterionic side chains. This platform can potentially be adapted to a wide range of applications (e.g. bioelectronics, tissue engineering and biofuel cell), which require high performance conducting materials with excellent antifouling/biocompatibility at biointerfaces.
Project description:Many proteins suffer from suboptimal pharmacokinetics (PK) that limit their utility as drugs. The efficient synthesis of polymer conjugates of protein drugs with tunable PK to optimize their in vivo efficacy is hence critical. We report here the first study of the in vivo behavior of a site-specific conjugate of a zwitterionic polymer and a protein. To synthesize the conjugate, we first installed an initiator for atom-transfer radical polymerization (ATRP) at the N?terminus of myoglobin (Mb-N-Br). Subsequently, in situ ATRP was carried out in aqueous buffer to grow an amine-functionalized polymer from Mb-N-Br. The cationic polymer was further derivatized to two zwitterionic polymers by treating the amine groups of the cationic polymer with iodoacetic acid to obtain poly(carboxybetaine methacrylate) with a one-carbon spacer (PCBMA; C1 ), and sequentially with 3-iodopropionic acid and iodoacetic acid to obtain PCBMA(mix) with a mixture of C1 and C2 spacers. The Mb-N-PCBMA polymer conjugates had a longer in vivo plasma half-life than a PEG-like comb polymer conjugate of similar molecular weights (MW). The structure of the zwitterion plays a role in controlling the in vivo behavior of the conjugate, as the PCBMA conjugate with a C1 spacer had significantly longer plasma circulation than the conjugate with a mixture of C1 and C2 spacers.
Project description:Covalent bonding of graphene oxide quantum dots (GOQDs) onto amino modified polyvinylidene fluoride (PVDF) membrane has generated a new type of nano-carbon functionalized membrane with significantly enhanced antibacterial and antibiofouling properties. A continuous filtration test using E. coli containing feedwater shows that the relative flux drop over GOQDs modified PVDF is 23%, which is significantly lower than those over pristine PVDF (86%) and GO-sheet modified PVDF (62%) after 10?h of filtration. The presence of GOQD coating layer effectively inactivates E. coli and S. aureus cells, and prevents the biofilm formation on the membrane surface, producing excellent antimicrobial activity and potentially antibiofouling capability, more superior than those of previously reported two-dimensional GO sheets and one-dimensional CNTs modified membranes. The distinctive antimicrobial and antibiofouling performances could be attributed to the unique structure and uniform dispersion of GOQDs, enabling the exposure of a larger fraction of active edges and facilitating the formation of oxidation stress. Furthermore, GOQDs modified membrane possesses satisfying long-term stability and durability due to the strong covalent interaction between PVDF and GOQDs. This study opens up a new synthetic avenue in the fabrication of efficient surface-functionalized polymer membranes for potential waste water treatment and biomolecules separation.
Project description:Materials that resist nonspecific protein adsorption are needed for many applications. However, few are able to achieve ultralow fouling in complex biological milieu. Zwitterionic polymers emerge as a class of highly effective ultralow fouling materials due to their superhydrophilicity, outperforming other hydrophilic materials such as poly(ethylene glycol). Unfortunately, there are only three major classes of zwitterionic materials based on poly(phosphorylcholine), poly(sulfobetaine), and poly(carboxybetaine) currently available. Inspired by trimethylamine N-oxide (TMAO), a zwitterionic osmolyte and the most effective protein stabilizer, we here report TMAO-derived zwitterionic polymers (PTMAO) as a new class of ultralow fouling biomaterials. The nonfouling properties of PTMAO were demonstrated under highly challenging conditions. The mechanism accounting for the extraordinary hydration of PTMAO was elucidated by molecular dynamics simulations. The discovery of PTMAO polymers demonstrates the power of molecular understanding in the design of new biomimetic materials and provides the biomaterials community with another class of nonfouling zwitterionic materials.
Project description:Many proteins, especially those used as therapeutics, are unstable to storage and shipping temperatures, leading to increased costs in research and industry. Therefore, the design and synthesis of novel stabilizers is an important area of investigation. Herein we report new degradable polymers that stabilize proteins to environmental stressors such as refrigeration and elevated temperature. Specifically, polycaprolactones with different pendant groups were synthesized and surveyed for their ability to stabilize an important therapeutic protein to storage and shipping conditions. Ring-opening polymerization (ROP) of an allyl-substituted caprolactone monomer was carried out using the organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) to yield a well-defined, alkene-substituted degradable polymer, which was used as a common backbone to control for the degree of polymerization. Relevant side chains such as trehalose, lactose, glucose, carboxybetaine, and oligo(ethylene glycol) were installed via postpolymerization thiol-ene reactions. These degradable polymers were then employed as excipients for the stabilization of the therapeutic protein granulocyte colony-stimulating factor (G-CSF) against storage at 4 °C and shipping temperatures of 60 °C. The best stabilization was observed using the trehalose- and zwitterion- substituted polyesters. Both the trehalose- and carboxybetaine-substituted pCL were further investigated with regard to molecular weight dependence, and it was found that the molecular weight was minimally important for stabilization to refrigeration, but critical for G-CSF stabilization at elevated temperatures. Both high performing zwitterionic and trehalose polyesters were also degraded, and the polymers and degradation products were shown to be noncytotoxic. This work provides potential biocompatible polymers for stabilization of the important therapeutic G-CSF, as well as a general platform for the future discovery of new polymeric protein stabilizers.
Project description:Polymer-protein conjugation has been extensively explored toward a better protein drug with improved pharmacokinetics. However, a major problem with polymer-protein conjugation is that the polymers drastically reduce the bioactivity of the modified protein. There is no perfect solution to prevent the bioactivity loss, no matter the polymer is conjugated in a non-site specific way, or a more complex site-specific procedure. Here the authors report for the first time that when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through simple conventional coupling chemistry. The resulting PCB-insulin does not show a significant reduction of in vitro bioactivity. The obtained PCB-insulin shows two significant advantages as a novel pharmaceutical agent. First, its therapeutic performance is remarkable. For PCB-insulin, there is a 24% increase of in vivo pharmacological activity of lowering blood glucose compared with native insulin. Such uncommonly seen increase has rarely been reported and is expected to be due to both the improved pharmacokinetics and retained bioactivity of PCB-insulin. Second, the production is simple from manufacturing standpoints. Conjugation procedure involves only one-step coupling reaction without complex site-specific linkage technique. The synthesized PCB-insulin conjugates do not require chromatographic separation to purify and obtain particular isoforms.
Project description:Developing materials that reduce or eliminate fibrosis encapsulation of neural prosthetic implants could significantly enhance implant fidelity by improving the tissue/electrode array interface. Here, we report on the photografting and patterning of two zwitterionic materials, sulfobetaine methacrylate (SBMA) and carboxybetaine methacrylate (CBMA), for controlling the adhesion and directionality of cells relevant to neural prosthetics. CBMA and SBMA polymers were photopolymerized and grafted on glass surfaces then characterized by X-ray photoelectron spectroscopy, water contact angle, and protein adsorption. Micropatterned surfaces were fabricated with alternating zwitterionic and uncoated bands. Fibroblasts, cells prevalent in fibrotic tissue, almost exclusively migrate and grow on uncoated bands with little to no cells present on zwitterionic bands, especially for CBMA-coated surfaces. Astrocytes and Schwann cells showed similarly low levels of cell adhesion and morphology changes when cultured on zwitterionic surfaces. Additionally, Schwann cells and inner ear spiral ganglion neuron neurites aligned well to zwitterionic patterns.
Project description:Treatment with therapeutic proteins is an attractive approach to targeting a number of challenging diseases. Unfortunately, the native proteins themselves are often unstable in physiological conditions, reducing bioavailability and therefore increasing the dose that is required. Conjugation with poly(ethylene glycol) (PEG) is often used to increase stability, but this has a detrimental effect on bioactivity. Here, we introduce conjugation with zwitterionic polymers such as poly(carboxybetaine). We show that poly(carboxybetaine) conjugation improves stability in a manner similar to PEGylation, but that the new conjugates retain or even improve the binding affinity as a result of enhanced protein-substrate hydrophobic interactions. This chemistry opens a new avenue for the development of protein therapeutics by avoiding the need to compromise between stability and affinity.
Project description:This paper reports a multifunctional zwitterionic poly(sulfobetaine-3,4-ethylenedioxythiophene) (PSBEDOT), which could be facilely synthesized by electropolymerization in aqueous solution. The PSBEDOT surface exhibits excellent conductivity, stability and switchable antifouling/antimicrobial properties. It shows great promise for applications in organic bioelectronics. This new material may significantly increase the performance and service life, minimize the foreign body reaction, improve the biocompatibility and reduce the infection of bio-electronic devices.
Project description:Zwitterionic polymers are suitable for replacing poly(ethylene glycol) (PEG) polymers because of their better antifouling properties, but zwitterionic polymers have poor mechanical properties, strong water absorption, and their homopolymers should not be used directly. To solve these problems, a reversible-addition fragmentation chain transfer (RAFT) polymerization process was used to prepare copolymers comprised of zwitterionic side chains that were attached to an ITO glass substrate using spin-casting. The presence of 4-vinylpyridine (4VP) and zwitterion chains on these polymer-coated ITO surfaces was confirmed using 1H NMR, FTIR, and GPC analyses, with successful surface functionalization confirmed using water contact angle, X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) studies. Changes in water contact angles and C/O ratios (XPS) analysis demonstrated that the functionalization of these polymers with β-propiolactone resulted in hydrophilic mixed 4VP/zwitterionic polymers. Protein adsorption and cell attachment assays were used to optimize the ratio of the zwitterionic component to maximize the antifouling properties of the polymer brush surface. This work demonstrated that the antifouling surface coatings could be readily prepared using a "P4VP-modified" method, that is, the functionality of P4VP to modify the prepared zwitterionic polymer. We believe these materials are likely to be useful for the preparation of biomaterials for biosensing and diagnostic applications.