A new type of bioreducible poly(amido amine) copolymer is synthesized by the Michael addition polymerization of cystamine bisacrylamide (CBA) with 4‐aminobutylguanidine (agmatine, AGM) and 4‐aminobutanol (ABOL). Since the positively charged guanidinium groups of AGM and the hydroxybutyl groups of ABOL in the side chains have shown to improve the overall transfection efficiency of poly(amido amine)s, it is hypothesized that poly(CBA‐ABOL/AGM) synthesized at the optimal ratio of both components would result in high transfection efficiency and minimal toxicity. In this study, a series of the poly(CBA‐ABOL/AGM) copolymers is synthesized as gene carriers. The polymers are characterized and luciferase transfection efficiencies of the polymers in various cell lines are investigated to select the ideal ratio between AGM and ABOL. The poly(CBA‐ABOL/AGM) containing 80% AGM and 20% ABOL has shown the best transfection efficiency with the lowest cytotoxicity, indicating that this polymer is very promising as a potent and nontoxic gene carrier.
Polyelectrolyte block copolymer micelles assembled thin film is switched in response to local photocatalytic reactions on titanium dioxide, resulting in a layer of variable height, stiffness in response to visible light irradiation. Preosteoblasts migrate toward stiffer side of the substrates.
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.
New antimicrobial materials will be more and more in the focus for hygienic and clinical disease control. Antimicrobial materials have to be distinguished in leaching and nonleaching materials. For many applications of antimicrobial materials on implants the use of nonleaching materials is essential. Therefore, the antimicrobial efficiency of leaching and nonleaching polymers has been investigated quantitatively in vitro in direct comparison on a highly relevant implant of central venous catheters (CVCs) using a well‐established called Certika test. This test is especially designed to test antimicrobial properties of leachable and nonleachable materials. This contribution demonstrates that newly developed nonleaching antimicrobial CVCs are equivalent to conventional leaching CVC systems in their antimicrobial performance against gram‐positive and gram‐negative bacteria, as well as Candida species. The use of new nonleaching antimicrobial polymers as shown here for CVCs represents a different mode of action with the aim to prevent infections also with antibiotic‐resistant strains and reduced side effects.
The use of light‐sensitive polymers for the release of therapeutics is an important approach allowing the timing and amount of the release to be controlled precisely. The use of light has been pioneered to control insulin release from a dermal photoactivated depot, or PAD. One of the main impediments to the use of light‐sensitive polymers in this context is the density of the materials: The large majority of the material is the carrier polymer, with the minority being the therapeutic. In this work, the feasibility of using insulin itself as a monomer in the polymerization process is demonstrated. Insulin modified with either one or two light cleavable azide groups is polymerized with a tridentate alkyne‐bridging monomer using a click reaction. The resulting material called a “macropolymer” is ≈85% insulin, is insoluble in aqueous solvent, and releases native, soluble insulin upon irradiation.
The aim of this study is to design a polymeric nanogel system with tailorable degradation behavior. To this end, hydroxyethyl methacrylate‐oligoglycolates‐derivatized poly(hydroxypropyl methacrylamide) (pHPMAm‐Gly‐HEMA) and hydroxyethyl methacrylamide‐oligoglycolates‐derivatized poly(hydroxyethyl methacrylamide) (pHEMAm‐Gly‐HEMAm) are synthesized and characterized. pHEMAm‐Gly‐HEMAm shows faster hydrolysis rates of both carbonate and glycolate esters than the same ester groups of pHPMAm‐Gly‐HEMA. pHEMAm‐Gly‐HEMAm nanogels have tailorable degradation kinetics from 24 h to more than 4 d by varying their crosslink densities. It is shown that the release of a loaded macromolecular model drug is controlled by degradation of nanogels. The nanogels show similar cytocompatibility as PLGA nanoparticles and are therefore considered to be attractive systems for drug delivery.
The enzymatic release of a model drug from a polymer carrier inside a tumor using multispectral optical imaging in vivo in nude mice bearing colorectal carcinomas HT‐29 and DLD‐1 is demonstrated. Much higher release rate in vivo from a linear (30 kDa) (N‐2‐hydroxypropyl)methacrylamide‐based polymer compared with a high molecular weight branched (170 kDa) polymer conjugate is observed, probably due to steric hindrance of the cleavable spacer of the latter polymer to proteolytic enzymes. There is no significant difference in the relative biodistribution of the two polymers, but the branched polymer circulates much longer. Both polymers are labeled with two different fluorophores. Dyomics‐676 as a drug model is attached to the polymer via an enzymatically cleavable Gly‐Phe‐Leu‐Gly spacer; Dyomics 782 is bound to the same polymer via a nondegradable amide bond, enabling the tracking of the polymer carrier after i.v. application to mice.
A hydrophobic/amino functionalized derivative of hyaluronic acid (HA‐EDA‐C18) has been processed by salt leaching technique as porous scaffold without need of chemical crosslinking. Aim of this work is to demonstrate the improved versatility of HA‐EDA‐C18 in terms of processing and biological functionalization. In particular, the chemical procedure to tether thiol bearing RGD peptide has been described. Moreover, the possibility to load and to control the release of slightly water soluble effectors has been demonstrated by using dexamethasone. First, the swelling and degradation profiles of the scaffolds have been investigated, then the evaluation of metabolic activity of bovine chondrocytes, the histological analysis, and microscope observations has been performed to evaluate cellular adhesion and proliferation as well as the production of collagen type II.
There is a growing interest in modern healthcare to develop systems able to fight antibiotic resistant bacteria. Antimicrobial cationic biodegradable polymers able to mimic antimicrobial peptides have shown to be effective against both Gram‐positive and Gram‐negative bacteria. In these systems, the hydrophilic–hydrophobic ratio and the cationic charge density play a pivotal role in defining the killing efficiency. Nevertheless, many of these antimicrobial polymers show relatively low selectivity as defined by the relative toxicity to mammalian cells or hemolysis relative to pathogens. In this study, a series of polycarbonates containing pendant quaternary ammoniums are used to understand the role of different counter‐anions including chloride, citrate, malonate, benzoate, acetate, lactate and trifluoroacetate, and the antibiotic penicillin on antimicrobial efficacy and selectivity. Interestingly, it is found that in spite of the strong antimicrobial activity of trifluoroacetate and benzoate anions, they prove to be much less hemolytic than chloride anion. It is believed that the proper selection of the anion could enhance the potential of antimicrobial polymers to fight against clinically relevant pathogenic infections, while concurrently mitigating harmful side effects.
Adhesion and proliferation of cells are often suppressed in rigid hydrogels as gel stiffness induces mechanical stress to embedded cells. Herein, the composite hydrogel systems to facilitate high cellular activities are described, while maintaining relatively high gel stiffness. This unusual property is obtained by harmonizing gelatin‐poly(ethylene glycol)‐tyramine (GPT, semisynthetic polymer) and gelatin‐hydroxyphenyl propionic acid conjugates (GH, natural polymer) into hydrogels. A minimum GH concentration of 50% is necessary for cells to be proliferative. GPT is utilized to improve biological stability (>1 week) and gelation time (<20 s) of the hydrogels. These results suggest that deficiency in cellular activity driven by gel stiffness could be overcome by finely tuning the material properties in the microenvironments.
Glycodendrimers based on aromatic cores have an amphiphilic character and have been reported to generate supramolecuar assemblies in water. A new group of glycodendrimers with an aromatic rod‐like core were recently described as potent antagonists of DC‐SIGN‐mediated viral infections. A full characterization of the aggregation properties of these materials is presented here. The results show that these compounds exist mostly as monomers in water solution, in dynamic equilibrium with small aggregates (dimers or trimers). Larger aggregates observed by dynamic light scattering and transmission Electron Microscopy for some of the dendrimers are found to be portions of materials not fully solubilized and can be removed either by optimizing the dissolution protocol or by centrifugation of the samples.
Cell‐free approaches to in situ tissue engineering require materials that are mechanically stable and are able to control cell‐adhesive behavior upon implantation. Here, the development of mechanically stable grafts with non‐cell adhesive properties via a mix‐and‐match approach using ureido‐pyrimidinone (UPy)‐modified supramolecular polymers is reported. Cell adhesion is prevented in vitro through mixing of end‐functionalized or chain‐extended UPy‐polycaprolactone (UPy‐PCL or CE‐UPy‐PCL, respectively) with end‐functionalized UPy‐poly(ethylene glycol) (UPy‐PEG) at a ratio of 90:10. Further characterization reveals intimate mixing behavior of UPy‐PCL with UPy‐PEG, but poor mechanical properties, whereas CE‐UPy‐PCL scaffolds are mechanically stable. As a proof‐of‐concept for the use of non‐cell adhesive supramolecular materials in vivo, electrospun vascular scaffolds are applied in an aortic interposition rat model, showing reduced cell infiltration in the presence of only 10% of UPy‐PEG. Together, these results provide the first steps toward advanced supramolecular biomaterials for in situ vascular tissue engineering with control over selective cell capturing.
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.
Using a well‐defined poly(2,2‐bis(hydroxymethyl)propanoic acid) dendrimer scaffold, a series of G1 to G3 dendrons is functionalized at the periphery with alkynes to enable “Click” functionalization via the copper‐catalyzed alkyne–azide cycloaddition (CuAAC). The resulting dendrons are further functionalized at the core with a dipicolylamine (DPA) moiety to enable radiolabeling with 99mTc for molecular imaging applications. Efficient CuAAC coupling is achieved using an azide‐functionalized triethylene glycol monomethyl ether (TEG‐N3). Removal of copper from the DPA ligand is successfully performed on G1 and G2 dendrimers prior to radiolabeling with 99mTc. Radiolabeling of the G3 dendrimer is accomplished via transmetallation of the [CuDPA]2+ ligand with 99mTc, further demonstrating the feasibility of the synthetic strategies in the preparation of dendritic imaging agents. Subsequent attachment of an acyloxymethyl ketone (AOMK) derivative for targeting of cathepsin B is also explored. Despite demonstrating the ability to ligate multiple AOMK ligands, the AOMK–dendrimer conjugates are not able to bind to cathepsin B, which may be attributed to steric hindrance at the dendrimer periphery.
A stable polymeric network that mimics the highly polyanionic extracellular cartilage matrix still remains a great challenge. The main aim of this study is to present the synthesis of dendritic polyglycerol sulfate (dPGS)‐based in situ forming hydrogels using strain promoted azide‐alkyne cycloaddition reactions. A real time rheological study has been used to characterize the hydrogel properties. The viability of encapsulated human chondrocytes in the different hydrogels are monitored using live‐dead staining. Furthermore, type I and II collagen gene have been analyzed. Hydrogels with elastic moduli ranging from 1 to 5 kPa have been prepared by varying the dPGS amount. The chondrocyte viability in dPGS hydrogels is found to be higher than in pure PEG and alginate‐based hydrogels after 21 d. The higher cell viability in the dPGS engineered hydrogels can be explained by the fact that dPGS can interact with different proteins responsible for cell growth and proliferation.
Traditionally, conductive materials for electrodes are based on high modulus metals or alloys. Development of bioelectrodes that mimic the mechanical properties of the soft, low modulus tissues in which they are implanted is a rapidly expanding field of research. Many polymers exist that more closely match tissue mechanics than metals; however, the majority do not conduct charge. Integrating conductive properties via incorporation of metals and other conductors into nonconductive polymers is a successful approach to producing polymers that can be used in electrical interfacing devices. When combining conductive materials with nonconductive polymer matrices, there is often a tradeoff between the electrical and mechanical properties. This review analyzes the advantages and disadvantages of approaches involving coating or layer formation, composite formation via dispersion of conductive inclusions through polymer matrices, and in situ growth of a conductive network within polymers.
To enhance drug cellular uptake, a biodegradable terpolymer is synthesized using taurine, N,N‐Bis (acryloyl) cystamine, and dodecylamine as raw materials by Michael addition terpolymerization. The terpolymer is transformed to zwitterionic nanoparticles (NPs) through self‐assembly. The surface charge of the NPs is convertible from negative at pH 7.4 to positive at pH 6.5, which endows the NPs’ excellent nonfouling feature in bloodstream and effective uptake in tumor cells. The NPs display varied morphologies from solid micelles to polymersomes and nanorods depending on molar ratios of the structural units involved. The NPs can be biodegraded in l ‐glutathione (GSH) solution due to the split of disulfide bonds in main chains of the terpolymers. The NPs demonstrate good pH/reducing responsiveness in drug delivery and can be potentially used as anticancer drug vehicles for enhancement of cellular uptake of anticancer drug.
Development of artificial tissues providing the proper geometrical, mechanical, and environmental cues for cells is highly coveted in the field of tissue engineering. Recently, microfabrication strategies in combination with other chemistries have been utilized to capture the architectural complexity of intricate organs, such as the liver, in in vitro platforms. Here it is shown that a biofunctionalized poly (ethylene glycol) (PEG) hydrogel scaffold, fabricated using a sphere‐template, facilitates hepatic sheet formation that follows the microscale patterns of the scaffold surface. The design takes advantage of the excellent diffusion properties of porous, uniform 3D hydrogel platforms, and the enhanced‐cell–extracellular matrix interaction with the display of conjugated collagen type I, which in turn elicits favorable Huh‐7.5 response. Collectively, the experimental findings and corresponding simulations demonstrate the importance of biofunctionalized porous scaffolds and indicate that the microscaffold shows promise in liver tissue engineering applications and provides distinct advantages over current cell sheet and hepatocyte spheroid technologies.
A visible light and pH responsive anticancer drug delivery system based on polymer‐coated mesoporous silica nanoparticles (MSNs) has been developed. Perylene‐functionalized poly(dimethylaminoethyl methacrylates) sensitive to visible light and pH are electrostatically attached on the surface of MSNs to seal the nanopores. Stimulation of visible light and acid can unseal the nanopores to induce controlled drug release from the MSNs. More interestingly, the release can be enhanced under the combined stimulation of the dual‐stimuli. The synergistic effect of visible light and acid stimulation on the efficient release of anticancer drugs from the nanohybrids endows the system with great potential for cancer therapy.
Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased production of ROS may disrupt cellular homeostasis, giving rise to oxidative stress and a series of diseases. Utilizing these cell‐generated species as triggers for selective tuning polymer structures and properties represents a promising methodology for disease diagnosis and treatment. Recently, significant progress has been made in fabricating biomaterials including nanoparticles and macroscopic networks to interact with this dynamic physiological condition. These ROS‐responsive platforms have shown potential in a range of biomedical applications, such as cancer targeted drug delivery systems, cell therapy platforms for inflammation related disease, and so on.
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