Fluorenyl‐9‐methoxycarbonyl (Fmoc)‐diphenylalanine (Fmoc‐FF) and Fmoc‐arginine‐glycine‐aspartate (Fmoc‐RGD) peptides self‐assemble to form a 3D network of supramolecular hydrogel (Fmoc‐FF/Fmoc‐RGD), which provides a nanofibrous network that uniquely presents bioactive ligands at the fiber surface for cell attachment. In the present study, mesenchymal stem cells (MSCs) in Fmoc‐FF/Fmoc‐RGD hydrogel increase in proliferation and survival compared to those in Fmoc‐FF/Fmoc‐RGE hydrogel. Moreover, MSCs encapsulated in Fmoc‐FF/Fmoc‐RGD hydrogel and induced in each defined induction medium undergo in vitro osteogenic, adipogenic, and chondrogenic differentiation. For in vivo differentiation, MSCs encapsulated in hydrogel are induced in each defined medium for one week, followed by injection into gelatin sponges and transplantation into immunodeficient mice for four weeks. MSCs in Fmoc‐FF/Fmoc‐RGD hydrogel increase in differentiation into osteogenic, adipogenic, and chondrogenic differentiation, compared to those in Fmoc‐FF/Fmoc‐RGE hydrogel. This study concludes that nanofibers formed by the self‐assembly of Fmoc‐FF and Fmoc‐RGD are suitable for the attachment, proliferation, and multi‐differentiation of MSCs, and can be applied in musculoskeletal tissue engineering.
This study describes the development and cell culture application of nanometer thick photocrosslinkable thermoresponsive polymer films prepared by physical adsorption. Two thermoresponsive polymers, poly(N‐isopropylacrylamide (NIPAm)‐co‐acrylamidebenzophenone (AcBzPh)) and poly(NIPAm‐co‐AcBzPh‐co‐N‐tertbutylacrylamide) are investigated. Films are prepared both above and below the polymers' lower critical solution temperatures (LCSTs) and cross‐linked, to determine the effect, adsorption preparation temperature has on the resultant film. The films prepared at temperatures below the LCST are smoother, thinner, and more hydrophilic than those prepared above. Human pulmonary microvascular endothelial cell (HPMEC) adhesion and proliferation are superior on the films produced below the polymers LCST compared to those produced above. Cells sheets are detached by simply lowering the ambient temperature to below the LCST. Transmission electron, scanning electron, and light microscopies indicate that the detached HPMEC sheets maintain their integrity.
Carbon nanotube (CNT)‐hydrogel nanocomposites are beneficial for various biomedical applications, such as nerve regeneration, tissue engineering, sensing, or implant coatings. Still, there are impediments to developing nanocomposites, including attaining a homogeneous CNT‐polymer dispersion or patterning CNTs on hydrogels. While few approaches have been reported for patterning CNTs on polymeric substrates, these methods include high temperature, high vacuum or utilize a sacrificial layer and, hence, are incompatible with hydrogels as they lead to irreversible collapse in hydrogel structure. In this study, a novel two‐step method is designed to transfer CNTs onto hydrogels. First, dense CNTs are grown on quartz substrates. Subsequently, hydrogel solutions are deposited on the quartz‐grown CNTs. Upon gelation, the hydrogel with transferred CNTs is peeled from the quartz. Successful transfer is confirmed by scanning electron microscopy and indirectly by cell attachment. The efficient transfer is attributed to π‐interactions pregelation between the polymers in solution and the CNTs.
This article reports the behavior of embryonic neural stem cells on a hydrogel that combines cationic, non‐specific cell adhesion motifs with glycine‐arginine‐glycine‐aspartic acid‐serine‐phenylalanine (GRGDSF)‐peptides as specific cell adhesion moieties. Therefore, three hydrogels are prepared by free radical polymerization that contains either a GRGDSF‐peptide residue ( P1 ), amino ethylmethacrylate as a cationic residue ( P2 ), or a combination of both motifs ( P3 ). For each gel, cross linker concentrations of 8 mol% is used to have a comparable gel stiffness of 8–9 kPa. The cell experiments indicate a synergistic effect of the non‐specific, cationic residues, and the specific GRGDSF‐peptides on embryonic neural stem cell behavior that is especially pronounced in the cell adhesion experiments by more than doubling the number of cells after 72 h when comparing P3 with P2 and is less pronounced in the proliferation and differentiation experiments.
The development of chronic wounds has been frequently associated with alkaline pH values. The application of pH‐modulating wound dressings can, therefore, be a promising treatment option to promote normal wound healing. This study reports on the development and characterization of acidic hydrogel dressings based on interpenetrating poly(ethylene glycol) diacrylate/acrylic acid/alginate networks. The incorporation of ionizable carboxylic acid groups results in high liquid uptake up to 500%. The combination of two separate polymer networks significantly improves the tensile and compressive stability. In a 2D cell migration assay, the application of hydrogels (0% to 1.5% acrylic acid) results in complete “wound” closure; hydrogels with 0.25% acrylic acid significantly increase the cell migration velocity to 19.8 ± 1.9 µm h−1. The most promising formulation (hydrogels with 0.25% acrylic acid) is tested on 3D human skin constructs, increasing keratinocyte ingrowth into the wound by 164%.
In this contribution, amphiphilic star copolymers (H40‐star‐PCL‐a‐PEG) with an H40 hyperbranched polyester core and poly(ε‐caprolactone)‐a‐poly(ethylene glycol) copolymer arms linked with acetal groups are synthesized using ring‐opening polymerization and a copper (I)‐catalyzed alkyne‐azide cycloaddition click reaction. The acid‐cleavable acetal groups between the hydrophilic and hydrophobic segments of the arms endow the amphiphilic star copolymers with pH responsiveness. In aqueous solution, unimolecular micelles can be formed with good stability and a unique acid degradability, as is desirable for anticancer drug carriers. For the model drug of doxorubicin, the in vitro release behavior, intracellular release, and inhibition of proliferation of HeLa cells show that the acid‐cleavable unimolecular micelles with anticancer activity can be dissociated in an acidic environment and efficiently internalized by HeLa cells. Due to the acid‐cleavable and biodegradable nature, unimolecular micelles from amphiphilic star copolymers are promising for applications in intracellular drug delivery for cancer chemotherapy.
Integration of electrogenic microorganisms remains a challenge in biofuel cell technology. Here, synthetic biocomposites (“artificial biofilms”) are proposed. Bacteria (Shewanella oneidensis ) are embedded in a hydrogel matrix (poly(vinyl alcohol)) via wet‐ and electrospinning, creating fibers and nonwoven gauzes. The bacteria remain viable and metabolically active. The performance is compared to S. oneidensis suspension cultures and “natural” biofilms. While lower than with the suspension cultures, the power output from the fuel cells with the artificial biofilms is higher than with the natural one. Handling, reproducibility, and stability are also better. Artificial biofilms can therefore contribute to resolving fundamental issues of design, scale up, and monosepsis in biofuel cell technology.
Colorectal peritoneal carcinomatosis (CRPC) is a common systemic metastasis of intra‐abdominal cancers. Intraperitoneal chemotherapy against CRPC is at present the preferred treatment. The aim of this study is to develop a novel hydrogel drug delivery system through the combination of 5‐fluorouracil (5‐FU) loaded polymeric micelles and cisplatin (DDP) in biodegradable thermosensitive chitosan (CS) hydrogel. The prepared CS hydrogel drug is a free‐flowing solution at room temperature and forms a stationary gel at body temperature. Therefore, a CRPC mouse model is established to investigate the antitumor activity of CS hydrogel drug system. The results suggest that intraperitoneal administration of CS hydrogel drug can inhibit tumor growth and metastasis, and prolong survival time compared with other groups, thus improving the chemotherapeutic effect. Ki‐67 immunohistochemical analysis reveals that tumors in the CS hydrogel drug group has lower cell proliferation in contrast to other groups (P < 0.001). Furthermore, hematoxylin‐eosin staining of liver and lung tissue indicates that the CS hydrogel drug has also a certain inhibitory effect on colorectal cancer metastasis to the liver and lung. Hence, the work highlights the potential clinical applications of the CS hydrogel drug.
Herein, a kind of dual acid‐sensitive nanoparticles based on monomethoxy poly(ethylene glycol)‐imine‐β‐cyclodextrin is constructed by a facile phenylboronic acid‐cross‐linked way. The data of dynamic light scattering and transmission electron microscope reveal the cross‐linked nanoparticles have improved stability. The cross‐linked nanoparticles could easily self‐assemble and load the anticancer drug at neutral pH condition. However, when the drug‐loaded nanoparticles are delivered to extracellular tumor sites (pH ≈6.8), the surface of the nanoparticles would be amino positively charged and easily internalized by tumor cell due to the cleavage of the acid‐labile benzoic–imine. Subsequently, with the acidity in subcellular compartments significantly increasing (such as the endosome pH ≈5.3), the loaded drug would fast release from the endocytosis carriers due to the hydrolysis of boronate ester. These features suggest that these dual acid‐sensitive cross‐linked nanoparticles not only possess excellent biocompatibility but also can efficiently load and deliver anticancer drug into tumor cells to enhance the inhibition of cellular proliferation, outlining a favorable platform as drug carriers.
Stem cell transplantations for spinal cord injury (SCI) have been studied extensively for the past decade in order to replace the damaged tissue with human pluripotent stem cell (hPSC)‐derived neural cells. Transplanted cells may, however, benefit from supporting and guiding structures or scaffolds in order to remain viable and integrate into the host tissue. Biomaterials can be used as supporting scaffolds, as they mimic the characteristics of the natural cellular environment. In this study, hPSC‐derived neurons, astrocytes, and oligodendrocyte precursor cells (OPCs) are cultured on aligned poly(ε‐caprolactone) nanofiber platforms, which guide cell orientation to resemble that of spinal cord in vivo. All cell types are shown to efficiently spread over the nanofiber platform and orient according to the fiber alignment. Human neurons and astrocytes require extracellular matrix molecule coating for the nanofibers, but OPCs grow on nanofibers without additional treatment. Furthermore, the nanofiber platform is combined with a 3D hydrogel scaffold with controlled thickness, and nanofiber‐mediated orientation of hPSC‐derived neurons is also demonstrated in a 3D environment. In this work, clinically relevant materials and substrates for nanofibers, fiber coatings, and hydrogel scaffolds are used and combined with cells suitable for developing functional cell grafts for SCI repair.
Solution behavior of thermo‐responsive polymers and their complexes with biological macromolecules may be affected by environmental conditions, such as the concentration of macromolecular components, pH, ion concentration, etc. Therefore, a thermo‐responsive polymer and its complexes should be characterized in detail to observe their responses against possible environments under physiological conditions before biological applications. To briefly indicate this important issue, thermo‐responsive block copolymer of quaternized poly(4‐vinylpyridine) and poly(oligoethyleneglycol methyl ether methacrylate) as a potential nonviral vector has been synthesized. Polyelectrolyte complexes of this copolymer with the antisense oligonucleotide of c‐Myc oncogene are also thermo‐responsive but, have lower LCST (lower critical solution temperature) values compared to individual copolymer. LCST values of complexes decrease with molar ratio of macromolecular components and presence of salt. Dilution of solutions also affects solution behavior of complexes and causes a significant decrease in size and an increase in LCST, which indicates possible effects of severe dilutions in the blood stream.
Antimicrobial polymeric films that are both mechanically robust and function renewable would have broad technological implications for areas ranging from medical safety and bioengineering to foods industry; however, creating such materials has proven extremely challenging. Here, a novel strategy is reported to create high‐strength N‐halamine incorporated poly(vinyl alcohol‐co‐ethylene) films (HAF films) with renewable antimicrobial activity by combining melt radical graft polymerization and reactive extrusion technique. The approach allows here the intrinsically rechargeable N‐halamine moieties to be covalently incorporated into polymeric films with high biocidal activity and durability. The resulting HAF films exhibit integrated properties of robust mechanical strength, high transparency, rechargeable chlorination capability (>300 ppm), and long‐term durability, which can effectively offer 3–5 logs CFU reduction against typical pathogenic bacterium Escherichia coli within a short contact time of 1 h, even at high organism conditions. The successful synthesis of HAF films also provides a versatile platform for exploring the applications of antimicrobial N‐halamine moieties in a self‐supporting, structurally adaptive, and function renewable form.
Injectable hydrogels have been commonly used as drug‐delivery vehicles and tried in tissue engineering. Injectable self‐healing hydrogels have great advantage over traditional injectable hydrogels because they can be injected as a liquid and then rapidly form bulk gels in situ at the target site under physiological conditions. This study develops an injectable thermosensitive self‐healing hydrogel based on chain‐extended F127 (PEO90‐PPO65‐PEO90) multi‐block copolymer (m‐F127). The rapid sol–gel transition ability under body temperature allows it to be used as injectable hydrogel and the self‐healing property allows it to withstand repeated deformation and quickly recover its mechanical properties and structure through the dynamic covalent bonds. It is hoped that the novel strategy and the fascinating properties of the hydrogel as presented here will provide new opportunities with regard to the design and practical application of injectable self‐healing hydrogels.
There is increasing interest in the synthesis of low molecular weight heparin and heparan sulfate mimetic polymers because of their various potential biomedical applications. The functional activity of heparin and heparan sulfate is believed to arise from the presence of a number of functional groups, such as hydroxyl, carboxylate and sulfate groups. The design and synthesis of novel heparin‐mimetic polymers with a particular functionality poses a formidable challenge and requires carefully control of the selective conversion of functional groups on the polymer chain. Here, this study describes a simple and efficient synthetic protocol for the preparation of heparin‐mimetic linear polyglycidol copolymers based on the selective conversion of primary hydroxyl groups to carboxylic acids under ruthenium‐catalyzed selective dehydrogenation in basic aqueous solution. To achieve the anticoagulant activity of these polymers, primary hydroxyl groups are selectively converted to sulfate groups. The anticoagulant activity of the heparin mimics is studied by rotational thromboelastometry using EXTEM and INTEM assays. The environmentally benign process described herein provides an attractive route for the synthesis of heparin‐mimetic polymers with tailored functions such as anticoagulant activity.
New macromolecules such as dendrimers are increasingly needed to drive breakthroughs in diverse areas, for example, healthcare. Here, the authors report hybrid antimicrobial dendrimers synthesized by functionalizing organometallic dendrimers with quaternary ammonium groups or 2‐mercaptobenzothiazole. The functionalization tunes the glass transition temperature and antimicrobial activities of the dendrimers. Electron paramagnetic resonance spectroscopy reveals that the dendrimers form free radicals, which have significant implications for catalysis and biology. In vitro antimicrobial assays indicate that the dendrimers are potent antimicrobial agents with activity against multidrug‐resistant pathogens such as methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus faecium as well as other microorganisms. The functionalization increases the activity, especially in the quaternary ammonium group‐functionalized dendrimers. Importantly, the activities are selective because human epidermal keratinocytes cells and BJ fibroblast cells exposed to the dendrimers are viable after 24 h.
A nanoassembled drug delivery system for anticancer treatment, formed by the host–guest interactions between paclitaxel (PTX) and β‐cyclodextrin (β‐CD) modified poly(acrylic acid) (PCDAA), is successfully prepared. After such design, the aqueous solubility of PTX is greatly increased from 0.34 to 36.02 μg mL?1, and the obtained PCDAA‐PTX nanoparticles (PCDAA‐PTX NPs) exhibit a sustained PTX release behavior in vitro. In vitro cytotoxicity finds that PCDAA‐PTX NPs can accumulate significantly in tumor cells and remain the pharmacological activity of PTX. The in vivo real‐time biodistribution of PCDAA‐PTX NPs is investigated using near‐infrared fluorescence imaging, indicating that the PCDAA‐PTX NPs can effectively target to the tumor site by the enhanced permeability and retention effect in H22 tumor‐bearing mice. Through in vivo antitumor examination, PCDAA‐PTX NPs exhibit superior efficacy in impeding the tumor growth compared to the commercially available Taxol®.
3D hydrogels better replicate in vivo conditions, and yield different results from 2D substrates. However, imaging interactions between cells and the hydrogel microenvironment is challenging because of light diffraction and poor focal depth. Here, cryosectioning and vibrating microtomy methods and fixation protocols are compared. Collagen I/III hydrogel sections (20–100 µm) are fixed with paraformaldehyde (2%–4%) and structurally evaluated. Cryosectioning damaged hydrogels, and vibrating microtomy (100 µm, 2%) yielded the best preservation of microstructure and cell integrity. These results demonstrate a potential processing method that preserves hydrogel and cell integrity, permitting imaging of cell interactions with the microenvironment.
The phase behavior of a dendritic amphiphile containing a Newkome‐type dendron as the hydrophilic moiety and a cholesterol unit as the hydrophobic segment is investigated at the air–liquid interface. The amphiphile forms stable monomolecular films at the air–liquid interface on different subphases. Furthermore, the mineralization of calcium phosphate beneath the monolayer at different calcium and phosphate concentrations versus mineralization time shows that at low calcium and phosphate concentrations needles form, whereas flakes and spheres dominate at higher concentrations. Energy‐dispersive X‐ray spectroscopy, X‐ray photoelectron spectroscopy, and electron diffraction confirm the formation of calcium phosphate. High‐resolution transmission electron microscopy and electron diffraction confirm the predominant formation of octacalcium phosphate and hydroxyapatite. The data also indicate that the final products form via a complex multistep reaction, including an association step, where nano‐needles aggregate into larger flake‐like objects.
A novel rod‐containing block copolymer is constructed by supramacromolecular self‐assembly of α‐cyclodextrin and a triblock copolymer with methoxy polyethylene glycol as the flanking chains and the midterm block alternately connected by 2,2‐dimethylolbutyric acid and isophorone diisocyanate. The assembled rod‐containing block copolymer shows an exciting phenomenon of concentration‐ and pH‐dependent morphological switching of well‐defined nanostructures. In the solutions at pH 9.2, spherical micelles, rod‐like micelles, and hydrogel are observed successively with an increase of the concentration. Notably, the rod‐like micelles are composed of spherical segments due to the combination of the crystalline cores of the spherical micelles. In addition, 1D nanostructures with different curvatures from linear rod‐like micelles (pH 9.2) to ring‐shaped micelles (pH 7.5) can be obtained by controlling the pH values of the assembled systems.
This article summarizes recent progress in the post‐functionalization of conjugated polymers by electrochemical methods. These electrochemical polymer reactions typically proceed via electrochemical doping of a conjugated polymer film, followed by chemical transformation. Examples include the quantitative oxidative fluorination of polyfluorenes and oxidative halogenation of polythiophenes, as well as the reductive hydrogenation of polyfluorenones. The degree of functionalization, otherwise known as the reaction ratio, can be controlled by varying the charge passed through the polymer, allowing the optoelectronic properties of the conjugated polymers to be tailored. Wireless bipolar electrodes with an in‐plane potential distribution are also useful with regard to the electrochemical doping and reaction of conjugated polymers and allow the synthesis of films exhibiting composition gradients. Such bipolar electrochemistry can induce multiple reaction sites during electrochemical polymer reactions.
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