This study presents a custom‐made in situ gelling polymeric precursor for cell encapsulation. Composed of poly((2‐hydroxyethyl)methacrylate‐co‐(3‐aminopropyl)methacrylamide) (P(HEMA‐co‐APM) mother backbone and RGD‐mimicking poly(amidoamine) (PAA) moiteis, the comb‐like structured polymeric precursor is tailored to gather the advantages of the two families of synthetic polymers, i.e., the good mechanical integrity of PHEMA‐based polymers and the biocompatibility and biodegradability of PAAs. The role of P(HEMA‐co‐APM) in the regulation of the chemico‐physical properties of P(HEMA‐co‐APM)/PAA hydrogels is thoroughly investigated. On the basis of obtained results, namely the capability of maintaining vital NIH3T3 cell line in vitro for 2 d in a 3D cell culture, the in vivo biocompatibility in murine model for 16 d, and the ability of finely tuning mechanical properties and degradation kinetics, it can be assessed that P(HEMA‐co‐APM)/PAAs offer a cost‐effective valid alternative to the so far studied natural polymer‐based systems for cell encapsulation.
A series of novel pH‐sensitive gene delivery vectors (POEI 1, 2, and 3) are synthesized through Michael addition from low molecular weight PEI (LMW PEI) via acid‐labile ortho ester linkage with terminal acrylates (OEAc) by various feed molar ratios. The obtained POEI 1 and POEI 2 can efficiently condense plasmid DNA into nanoparticles with size range of 200–300 nm and zeta‐potentials of about +15 mV while protecting DNA from enzymatic digestion compared with POEI 3. Significantly, ortho ester groups of POEI main‐chains can make an instantaneous degradation‐response to acidic endosomal pH (≈5.0), resulting in accelerated disruption of polyplexes and intracellular DNA release. MTT assay reveals that all POEIs exhibit much lower cytotoxicity in different cells than branched PEI (25 KDa). As expected, POEI 1 and POEI 2 perform improved gene transfection in vitro, suggesting that such polycations might be promising gene vectors based on overcoming toxicity‐efficiency contradiction.
Poly(ethylene glycol)‐poly(lactide) (PEG‐PLA) block copolymers are processed to solvent cast films and solution electrospun meshes. The effect of polymer composition, architecture, and number of anchoring points for the plasticizer on swelling, degradation, and mechanical properties of these films and meshes is investigated as potential barrier device for the prevention of peritoneal adhesions. As a result, adequate properties are achieved for the massive films with a longer retention of the plasticizer PEG for star‐shaped block copolymers than for the linear triblock copolymers and consequently more endurable mechanical properties during degradation. For electrospun meshes fabricated using the same polymers, similar trends are observed, but with an earlier start of fragmentation and lower tensile strengths. To overcome the poor mechanical strengths and an occurring shrinkage during incubation, which may impair the coverage of the wound, further adaptions of the meshes and the fabrication process are necessary.
A series of pH‐triggered charge‐reversal polyurethane copolymers (PS‐PUs) containing methoxyl‐poly(ethylene glycol) (mPEG), carboxylic acid groups, and piperazine groups is presented in this work. The obtained PS‐PUs copolymers can form into stable micelles at pH 7.4, which response to a narrow pH change (5.5–7.5) and show a tunable pH‐triggered charge‐reversal property. Doxorubicin (DOX) is encapsulated into the PS‐PU micelles as a model drug. The drug release of DOX‐loaded PS‐PU micelles shows an obviously stepped‐up with reducing the pH. Meanwhile, it is found that the charge‐reversal property can improve the cellular uptake behavior and intracellular drug release in both HeLa cells and MCF‐7 cells. Additionally, the time‐dependent cytotoxicity of the DOX‐loaded PS‐PU micelles is confirmed by MTT assay. Attributed to the tunable charge‐reversal property through changing the molar ratio of piperazine/carboxyl, the PS‐PU micelles will be a potential candidate as an intelligent drug delivery system in future studies.
Electrospun poly‐l ‐lactic acid (PLLA) nanofiber mats carrying surface amine groups, previously introduced by nitrogen atmospheric pressure nonequilibrium plasma, are embedded into aqueous solutions of oligomeric acrylamide‐end capped AGMA1, a biocompatible polyamidoamine with arg‐gly‐asp (RGD)‐reminiscent repeating units. The resultant mixture is finally cured giving PLLA‐AGMA1 hydrogel composites that absorb large amounts of water and, in the swollen state, are translucent, soft, and pliable, yet as strong as the parent PLLA mat. They do not split apart from each other when swollen in water and remain highly flexible and resistant, since the hydrogel portion is covalently grafted onto the PLLA nanofibers via the addition reaction of the surface amine groups to a part of the terminal acrylic double bonds of AGMA1 oligomers. Preliminary tested as scaffolds, the composites prove capable of maintaining short‐term undifferentiated cultures of human pluripotent stem cells in feeder‐free conditions.
Three‐dimensional hydrogel supports for mesenchymal and neural stem cells (NSCs) are promising materials for tissue engineering applications such as spinal cord repair. This study involves the preparation and characterization of superporous scaffolds based on a copolymer of 2‐hydroxyethyl and 2‐aminoethyl methacrylate (HEMA and AEMA) crosslinked with ethylene dimethacrylate. Ammonium oxalate is chosen as a suitable porogen because it consists of needle‐like crystals, allowing their parallel arrangement in the polymerization mold. The amino group of AEMA is used to immobilize RGDS and SIKVAVS peptide sequences with an N‐γ‐maleimidobutyryloxy succinimide ester linker. The amount of the peptide on the scaffold is determined using 125I radiolabeled SIKVAVS. Both RGDS‐ and SIKVAVS‐modified poly(2‐hydroxyethyl methacrylate) scaffolds serve as supports for culturing human mesenchymal stem cells (MSCs) and human fetal NSCs. The RGDS sequence is found to be better for MSC and NSC proliferation and growth than SIKVAVS.
Biosensing is an important and rapidly developing field, with numerous potential applications in health care, food processing, and environmental control. Polymer–graphene nanocomposites aim to leverage the unique, attractive properties of graphene by combining them with those of a polymer matrix. Molecular imprinted polymers, in particular, offer the promise of artificial biorecognition elements. A variety of polymers, including intrinsically conducting polymers (polyaniline, polypyrrole), bio‐based polymers (chitosan, polycatechols), and polycationic polymers (poly(diallyldimethylammonium chloride), polyethyleneimine), have been utilized as matrices for graphene‐based nanofillers, yielding sensitive biosensors for various biomolecules, such as proteins, nucleic acids, and small molecules.
Bacteria reside within biofilms at the infection site, making them extremely difficult to eradicate with conventional wound care products. Bacteria use quorum sensing (QS) systems to regulate biofilm formation, and QS inhibitors (QSIs) have been proposed as promising antibiofilm agents. Despite this, few antimicrobial therapies that interfere with QS exist. Nontoxic hydroxypropyl‐β‐cyclodextrin‐functionalized cellulose gauzes releasing a burst of the antibiotic vancomycin and the QSI hamamelitannin are developed, followed by a sustained release of both. The gauzes affect QS and biofilm formation of Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of chronic wound infection and can be considered as candidates to be used to prevent wound infection as well as treat infected wounds.
This study reports a series of novel amino acid based dual‐responsive hydrogels. Prepared by a facile one‐pot 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC) coupling reaction, the solid content, structure, and mechanical behavior of hydrogels could be easily adjusted by changing the concentrations of the polymers and the crosslinkers. With pH‐responsive anionic pseudo‐peptides as backbones and disulfide‐containing l ‐cystine dimethyl ester as crosslinkers, these hydrogels are able to collapse and form relatively compact structure at an acidic pH, while swelled and partly dissociated at a neutral pH. Further addition of dithiothreitol (DTT) facilitated complete degradation of hydrogels. The high loading efficiency, rapid but complete triggered‐release, and good biocompatibility make these hydrogels promising candidates for oral delivery.
Gelatin nanoparticles can be tuned with respect to their drug loading efficiency, degradation rate, and release kinetics, which renders these drug carriers highly suitable for a wide variety of biomedical applications. The ease of functionalization has rendered gelatin an interesting candidate material to introduce specific motifs for selective targeting to specific organs, but gelatin nanoparticles have not yet been modified to increase their affinity to mineralized tissue. By means of conjugating bone‐targeting alendronate to biocompatible gelatin nanoparticles, a simple method is developed for the preparation of gelatin nanoparticles which exhibit strong affinity to mineralized surfaces. It has been shown that the degree of alendronate functionalization can be tuned by controlling the glutaraldehyde crosslinking density, the molar ratio between alendronate and glutaraldehyde, as well as the pH of the conjugation reaction. Moreover, it has been shown that the affinity of gelatin nanoparticles to calcium phosphate increases considerably upon functionalization with alendronate. In summary, gelatin nanoparticles have been developed, which exhibit great potential for use in bone‐specific drug delivery and regenerative medicine.
In order to construct unique polypeptide architectures, a novel telechelic‐type initiator with two leucine ethyl ester units is designed for chemoenzymatic polymerization. Glycine or alanine ethyl ester is chemoenzymatically polymerized using papain in the presence of the initiator, and the propagation occurs at each leucine ethyl ester unit to produce the telechelic polypeptide. The formation of the telechelic polypeptides is confirmed by 1H NMR and MALDI‐TOF mass spectroscopies. It is revealed by AFM observation that long nanofibrils are formed from the telechelic polyalanine, whereas a conventional linear polyalanine with a similar degree of polymerization shows granule‐like structures. The telechelic polyglycine and polyalanine show the crystalline structures of Polyglycine II and antiparallel β‐sheet, respectively. It is demonstrated that this method to synthesize telechelic‐type polypeptides potentially opens up a pathway to construct novel hierarchical structures by self‐assembly.
Pinosylvin is a natural stilbenoid known to exhibit antibacterial bioactivity against foodborne bacteria. In this work, pinosylvin is chemically incorporated into a poly(anhydride‐ester) (PAE) backbone via melt‐condensation polymerization, and characterized with respect to its physicochemical and thermal properties. In vitro release studies demonstrate that pinosylvin‐based PAEs hydrolytically degrade over 40 d to release pinosylvin. Pseudo‐first order kinetic experiments on model compounds, butyric anhydride and 3‐butylstilbene ester, indicate that the anhydride linkages hydrolyze first, followed by the ester bonds to ultimately release pinosylvin. An antibacterial assay shows that the released pinosylvin exhibit bioactivity, while in vitro cytocompatibility studies demonstrate that the polymer is noncytotoxic toward fibroblasts. These preliminary findings suggest that the pinosylvin‐based PAEs can serve as food preservatives in food packaging materials by safely providing antibacterial bioactivity over extended time periods.
A polyzwitterion is synthesized by regioselective functionalization of cellulose possessing a uniform charge distribution. The positively charged ammonium group is present at position 6, while the negative charge of carboxylate is located at positions 2 and 3 of the repeating unit. The molecular structure of the biopolymer derivative is proved by NMR spectroscopy. This cellulose‐based zwitterion is applied to several support materials by spin‐coating and characterized by means of atomic force microscope, contact angle measurements, ellipsometry, and X‐ray photoelectron spectroscopy. The coatings possess antimicrobial activity depending on the support materials (glass, titanium, tissue culture poly(styrene)) as revealed by confocal laser scanning microscopy and live/dead staining.
The aim of this study is to establish the safe and effective ocular delivery system of therapeutic small interfering RNA (siRNA) in corneal neovascularization therapy. The major hurdle present in siRNA‐based corneal neovascularization (CNV) therapy is severe cytotoxicity caused by repetitive drug treatment. A reducible branched polyethylenimine (rBPEI)‐based nanoparticle (NP) system is utilized as a new siRNA carrier as a hope for CNV therapy. The thiolated BPEI is readily self‐crosslinked in mild conditions to make high molecular weight rBPEI thus allowing the creation of stable siRNA/rBPEI nanoparticles (siRNA‐rBPEI‐NPs). In the therapeutic region, the rBPEI polymeric matrix is effectively degraded into nontoxic LMW BPEI inside the reductive cytosol causing the rapid release of the encapsulated siRNA into the cytosol to carry out its function. The fluorescent‐labeled siRNA‐rBPEI‐NPs can release siRNA into the entire corneal region after subconjuctival injection into the eye of Sprague Dawley rats thus confirming the proof of concept of this system.
Polymicrobial biofilm‐associated implant infections present a challenging clinical problem. Through modifications of lyophilized chitosan sponges, degradable drug delivery devices for antibiotic solution have been fabricated for prevention and treatment of contaminated musculoskeletal wounds. Elution of amikacin, vancomycin, or a combination of both follows a burst release pattern with vancomycin released above minimum inhibitory concentration for Staphylococcus aureus for 72 h and amikacin released above inhibitory concentrations for Pseudomonas aeruginosa for 3 h. Delivery of a vancomycin, amikacin, or a combination of both reduces biofilm formation on polytetrafluoroethylene catheters in an in vivo model of contamination. Release of dual antibiotics from sponges is more effective at preventing biofilm formation than single‐loaded chitosan sponges. Treatment of pre‐formed biofilm with high‐dose antibiotic release from chitosan sponges shows minimal reduction after 48 h. These results demonstrate infection‐preventive efficacy for antibiotic‐loaded sponges, as well as the need for modifications in the development of advanced materials to enhance treatment efficacy in removing established biofilm.
Thin polymer films that prevent the adhesion of bacteria are of interest as coatings for the development of infection‐resistant biomaterials. This study investigates the influence of grafting density and film thickness on the adhesion of Staphylococcus epidermidis to poly(poly(ethylene glycol)methacrylate) (PPEGMA) and poly(2‐hydroxyethyl methacrylate) (PHEMA) brushes prepared via surface‐initiated atom transfer radical polymerization (SI‐ATRP). These brushes are compared with poly(ethylene glycol) (PEG) brushes, which are obtained by grafting PEG onto an epoxide‐modified substrate. Except for very low grafting densities (ρ = 1%), crystal violet staining experiments show that the PHEMA and PPEGMA brushes are equally effective as the PEG‐modified surfaces in preventing S. epidermis adhesion and do not reveal any significant variations as a function of film thickness or grafting density. These results indicate that brushes generated by SI‐ATRP are an attractive alternative to grafted‐onto PEG films for the preparation of surface coatings that resist bacterial adhesion.
There is an actual need of advanced materials for the emerging field of bioelectronics. One commonly used material is the conducting polymer poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) due to its general use in organic electronics. However, depending on the application in bioelectronics, PEDOT:PSS is not fully biocompatible due to the high acidity of the residual sulfonate protons of PSS. In this paper, the synthesis and biocompatibility properties of new poly(3,4‐ethylenedioxythiophene):GlycosAminoGlycan (PEDOT:GAG) aqueous dispersions and its resulting films are shown. Thus, negatively charged GAGs as an alternative to PSS are presented. Three different commercially available GAGs, hyaluronic acid, heparin, and chondroitin sulfate are used. Indeed, PEDOT:GAGs dispersions are prepared through an oxidative chemical polymerization in water. Biocompatibility assays of the PEDOT:GAGs coatings are performed using SH‐SY5Y and CCF‐STTG1 cell lines and with ATP and Ca2+. Results show full biocompatibility and a pronounced anti‐inflammatory effect. This last characteristic becomes crucial if implanted in the body. These materials can be used for in vivo applications, as transistor or electrode for electrical recording and for all the possible situations when there is contact between electronic circuits and living tissues.
Furoxans, or 1,2,5‐oxadiazole‐N‐oxides, are a class of nitric oxide (NO)‐donating compounds that release NO in response to thiol‐containing molecules. In this study, polymeric micelles bearing furoxan moieties are prepared from an amphiphilic block copolymer consisting of a hydrophobic furoxan‐bearing block and a hydrophilic poly(N‐acryloylmorpholine) block. The block copolymer is prepared using a combination of the reversible addition–fragmentation chain transfer polymerization and the copper‐catalyzed Huisgen cycloaddition techniques. The block copolymers form spherical micelles with a diameter of 50 nm by self‐assembly in water. The micelles release NO in response to cysteine and show improved stability against hydrolytic decomposition. Furthermore, the micelles show a synergistic anti‐proliferative effect with ibuprofen in human colon cancer cells.
There is a need for new and smart formulations that will help overcome the limitations of organic dyes used in photodynamic (PDT) and photothermal (PTT) therapy and significantly accelerate their clinical translation. Therefore the aim of this work was to create a responsive nanogel scaffold as a smart vehicle for dye administration. We developed a methodology that enables the conjugation of organic dyes to thermoresponsive nanogels and yields biocompatible, nanometer‐sized products with low polydispersity. The potential of the dye‐nanogel conjugate as a photothermal and photodynamic agent has been demonstrated by an in vitro evaluation with a model human carcinoma cell line. Additionally, confocal cell images showed their cellular uptake profile and their potential for bioimaging and intracellular drug delivery. These conjugates are a promising scaffold as a theranostic agents and will enable further applications in combination with controlled drug release.
Here, postfunctionalization and bioapplication of a π‐conjugated polymer named 4‐[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl]aniline (DTP‐aryl‐NH2) are reported, which is successfully synthesized via electropolymerization onto the glassy carbon electrode. Folic acid (FA) is used to modify the amino functional polymer via N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride/N‐hydroxysuccinimide chemistry for the further steps. The selective adhesion of folate receptor positive cells on the surface is followed by the electrochemical methods. Cyclic voltammetry and electrochemical impedance spectroscopy have been used to characterize stepwise modification of the electroactive surface. After optimization studies such as scan rate during the polymer deposition, FA amount for the efficient surface targeting, incubation time with the cells etc., analytical characterization is carried out. The surface morphologies at each step are imaged by using fluorescence microscopy.
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