Yuhan Lee

Catechol-Functionalized Chitosan/Pluronic Hydrogels for Tissue Adhesives and Hemostatic Materials

Bioinspired from adhesion behaviors of mussels, injectable and thermosensitive chitosan/Pluronic composite hydrogels were synthesized for tissue adhesives and hemostatic materials. Chitosan conjugated with multiple catechol groups in the backbone was cross-linked with terminally thiolated Pluronic F-127 triblock copolymer to produce temperature-sensitive and adhesive sol-gel transition hydrogels. A blend mixture of the catechol-conjugated chitosan and the thiolated Pluronic F-127 was a viscous solution state at room temperature but became a cross-linked gel state with instantaneous solidification at the body temperature and physiological pH. The adhesive chitosan/Pluronic injectable hydrogels with remnant catechol groups showed strong adhesiveness to soft tissues and mucous layers and also demonstrated superior hemostatic properties. These chitosan/Pluronic hydrogels are expected to be usefully exploited for injectable drug delivery depots, tissue engineering hydrogels, tissue adhesives, and antibleeding materials.

Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction

Hyaluronic acid (HA) hydrogels are widely pursued as tissue regenerative and drug delivery materials due to their excellent biocompatibility and biodegradability. Inspired by mussel adhesion, we report here a novel class of thermo-sensitive and injectable HA/Pluronic F127 composite tissue-adhesive hydrogels applicable for various biomedical applications. HA conjugated with dopamine (HA-DN) was mixed with thiol end-capped Pluronic F127 copolymer (Plu-SH) to produce a lightly cross-linked HA/Pluronic composite gel structure based on Michael-type catechol-thiol addition reaction. The HA/Pluronic hydrogels exhibited temperature-dependent sol–gel phase transition behaviors different from Pluronic hydrogels. Rheological studies showed that the sol–gel transitions were rapid and reversible in response to temperature. The HA/Pluronic hydrogels could be injected in vivo in a sol state at room temperature using a syringe, but immediately became a robust gel state at body temperature. The in situ formed hydrogels exhibited excellent tissue-adhesion properties with superior in vivo gel stability and are potentially useful for drug and cell delivery.

Bioinspired Synthesis and Characterization of Gadolinium-Labeled Magnetite Nanoparticles for Dual Contrast T1- and T2-Weighted Magnetic Resonance Imaging

Gadolinium-labeled magnetite nanoparticles (GMNPs) were synthesized via a bioinspired manner to use as dual contrast agents for T1- and T2-weighted magnetic resonance imaging. A mussel-derived adhesive moiety, 3,4-dihydroxy-l-phenylalanine (DOPA), was utilized as a robust anchor to form a mixed layer of poly(ethylene glycol) (PEG) chains and dopamine molecules on the surface of iron oxide nanoparticles. Gadolinium ions were subsequently complexed at the distal end of the dopamine molecules that were prefunctionalized with a chelating ligand for gadolinium. The resultant GMNPs exhibited high dispersion stability in aqueous solution. Crystal structure and superparamagnetic properties of magnetite nanocrystals were also maintained after the complexation of gadolinium. The potential of GMNPs as dual contrast agents for T1 and T2-weighted magnetic resonance imaging was demonstrated by conducting in vitro and in vivo imaging and relaxivity measurements.

Thermo-sensitive and biodegradable hydrogels based on stereocomplexed Pluronic multi-block copolymers for controlled protein delivery

Injectable sol-gel transition hydrogels based on thermo-sensitive polymers are of great interest as potential biomaterials for sustained delivery of therapeutic molecules. A novel temperature-sensitive and in-situ forming hydrogel system based on Pluronic F127 was developed and evaluated. A series of multi-block Pluronic copolymers linked by d-lactide and l-lactide oligomers with different spacer lengths were synthesized. A pair of multi-block copolymers having the corresponding enantiomeric d- or l-lactide oligomer spacer was blended to form stereocomplexed hydrogels. The resultant physically crosslinked Pluronic hydrogels exhibited significantly altered sol-gel phase transition behaviors with much lower critical gelation concentrations and temperatures, compared to the uncomplexed multi-block or Pluronic homopolymer hydrogels. The stereocomplexed hydrogels also had far increased mechanical strength with high resistance to rapid dissolution in aqueous medium. When human growth hormone (hGH) was incorporated in the strereocomplexed multi-block Pluronic copolymers, hGH was released out in a sustained and zero-order fashion for 13 days by a diffusion/erosion coupled mechanism.

High‐Strength Carbon Nanotube Fibers Fabricated by Infiltration and Curing of Mussel‐Inspired Catecholamine Polymer

Carbon nanotubes (CNTs) have received extensive attention due to their extraordinary properties in electronic conduction, [ 1 ] heat transfer, [ 2 ] and mechanical strength. [ 3 ] Materials with unparallel performance, such as super-strong, lightweight e-textiles, can be fabricated from CNTs, suggesting a future revolution in materials science. Thus, the emerging CNT technology will largely depend on the development of effective spinning and post-spinning processes to realize such unprecedented materials. Two widely implemented strategies for fabricating CNT fi bers are in-solution [ 4–7 ] and solid-state spinning techniques. The in-solution spinning of CNTs can produce continuous CNT fi bers; however, homogeneous dispersion of CNTs in the solvent is necessary for proper spinning. Moreover, the properties of the CNT fi bers strongly depend on the methods of CNT dispersion. An alternative strategy is solid-state spinning, [ 8–17 ] which allows avoidance of CNT dispersion in solvents and for various post-spinning processes to be applied with ease. Twisting, [ 10–16 ] densifi cation, [ 9 , 18 ] and infi ltration [ 8 , 19,20 ] are examples of post-spinning processes, and the main purpose of the spinning and post-spinning processes is to enhance the mechanical properties of CNT fi bers. Despite the effort that has been made, however, fabrication of strong CNT fi bers remains a great challenge.

Synthesis, characterization, antitumor activity of pluronic mimicking copolymer micelles conjugated with doxorubicin via acid-cleavable linkage.

Pluronic mimicking poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer having multiple hydroxyl groups in the PPO middle segment (core-functionalized Pluronic: CF-PLU) was synthesized for conjugation of doxorubicin (DOX). DOX was conjugated on the multiple hydroxyl groups of CF-PLU via an acid-labile hydrazone linkage (CF-PLU-DOX). In aqueous solution, CF-PLU-DOX copolymers self-assembled to form a core/shell-type micelle structure consisting of a hydrophobic DOX-conjugated PPO core and a hydrophilic PEO shell layer. The conjugated DOX from CF-PLU-DOX micelles was released out more rapidly at pH 5 than pH 7.4, indicating that the hydrazone linkage was cleaved under acidic condition. CF-PLU-DOX micelles exhibited greatly enhanced cytotoxicity for MCF-7 human breast cancer cells compared to naked DOX, while CF-PLU copolymer itself showed extremely low cytotoxicity. Flow cytometry analysis revealed that the extent of cellular uptake for CF-PLU-DOX micelles was greater than free DOX. Confocal image analysis also showed that CF-PLU-DOX micelles had a quite different intracellular distribution profile from free DOX. CF-PLU-DOX micelles were mainly distributed in the cytoplasm, endosomal/lysosomal vesicles, and nucleus, while free DOX was localized mainly within the nucleus, suggesting that CF-PLU-DOX micellar formulation might be advantageously used for overcoming the multidrug resistance (MDR) effect, which gradually develops in many tumor cells during repeated drug administration.

A Blood-Resistant Surgical Glue for Minimally Invasive Repair of Vessels and Heart Defects

A light-activated, biodegradable adhesive seals cardiovascular defects in the presence of blood flow and could be useful during minimally invasive surgery. Light-Activated Adhesive Seals Tissues An easy way to repair vessels or attach devices to tissues would be welcomed by surgeons. An adhesive, for instance, can reconnect tissue and interface prosthetics, but currently available materials have limitations such as low strength, high toxicity, and most do not function well in wet environments. In response, Lang and colleagues developed a new biomaterial glue that is biocompatible, biodegradable, and easily manipulated. This material, called poly(glycerol sebacate acrylate) (PGSA), when combined with a photoinitiator, creates a solution that the authors called HLAA: hydrophobic light-activated adhesive. The HLAA is a thick gel that can be slathered on a tissue and then cross-linked within seconds by ultraviolet light, which is a unique feature that avoids stitches. The resulting bond is water-tight yet flexible and stays intact in the face of high pressure and flowing blood. The authors first tested their material in rats, showing that the HLAA could be used to attach a polymer patch to the heart and that the HLAA alone could seal up defects in the heart wall, performing as well as sutures. Lang et al. then moved into pigs, whose hearts beat at similar rates to humans (by contrast, rats have much higher heart rates). Lang et al. showed that the light-activated adhesive could attach a patch to the interventricular septum of a pig’s beating heart and that this patch remained in place even under higher than normal heart rates (induced by adrenaline). Additionally, the HLAA alone was able to immediately close up defects in the pig carotid artery without any bleeding complications. The light-responsive adhesive performed well in several different in vivo scenarios, suggesting its broad applicability in the clinic, at least for cardiovascular surgeries and defects. As an added bonus, components of PGSA—namely, glycerol and sebacic acid—exist in the body and are readily metabolized. It is expected that this material could be translated soon to use in people. Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.

Controlled synthesis of PEI-coated gold nanoparticles using reductive catechol chemistry for siRNA delivery

Development of nano-sized gene delivery vehicles for small interfering RNA (siRNA) delivery is of great importance for their clinical applications such as cancer therapy. Herein, we demonstrate the controlled synthesis of polyethyleneimine (PEI)-coated gold nanoparticles (AuNPs) using catechol-conjugated PEI (PEI-C) for siRNA delivery. Since the conjugated catechol groups are reductive and moderately hydrophobic, PEI-C formed spherical multi-cored micelles in aqueous solution and served as reductive templates for the growth and synthesis of spherical AuNPs with tunable sizes and surface charges. PEI-C was stably anchored on the surface of growing crystal gold seeds with crosslinking, resulting in robust cationic AuNPs. The fabricated PEI-coated AuNPs formed stable complexes with siRNA, and the complexes showed an excellent gene silencing effect in cancer cells. Size and surface charge values of the synthesized AuNPs had a great influence on intracellular uptake and unpacking of siRNA, and the resultant gene silencing efficiency. The PEI-coated AuNPs exhibited an extremely low cytotoxicity due to the reduced density of primary amine groups and the absence of uncomplexed PEI fraction in aqueous solution.

Facile synthetic route for surface-functionalized magnetic nanoparticles: cell labeling and magnetic resonance imaging studies.

Currently available methods to stably disperse iron oxide nanoparticles (IONPs) in aqueous solution need to be improved due to potential aggregation, reduction of superparamagnetism, and the use of toxic reagents. Herein, we present a facile strategy for aqueous transfer and dispersion of organic-synthesized IONPs using only polyethylene glycol (PEG), a biocompatible polymer. A library of PEG derivatives was screened, and it was determined that amine-functionalized six-armed PEG, 6(PEG-NH(2)), was the most effective dispersion agent. The 6(PEG-NH(2))-modified IONPs (IONP-6PEG) were stable after extensive washing, exhibited high superparamagnetism, and could be used as a platform material for secondary surface functionalization with bioactive polymers. IONP-6PEG biofunctionalized with hyaluronic acid (IONP-6PEG-HA) was shown to specifically label mesenchymal stem cells and demonstrate MR contrast potential with high r(2) relaxivity (442.7 s(-1)mM(-1)) compared to the commercially available Feridex (182.1 s(-1)mM(-1)).

Enzyme-mediated cross-linking of Pluronic copolymer micelles for injectable and in situ forming hydrogels

A new class of injectable and erodible hydrogels exhibiting highly robust gel strength at body temperature was fabricated by enzyme-mediated cross-linking between Pluronic copolymer micelles. Tyramine-conjugated Pluronic F-127 tri-block copolymers at two terminal ends of polyethylene oxide (PEO) side chains were synthesized and utilized to form self-assembled micelles in aqueous solution. Tyrosinase was employed to convert tyramine-conjugated micelles to highly reactive catechol conjugated micelles that could further cross-link individual Pluronic copolymer micelles to form a highly stable gel structure. The enzyme cross-linked Pluronic hydrogels showed far lower critical gelation concentration, concomitantly showing enhanced gel strength compared to unmodified Pluronic copolymer hydrogels, suitable for sustained delivery of bioactive agents. Rheological studies demonstrated that the enzyme cross-linked hydrogels exhibited a fast and reversible sol-gel transition in response to temperature while maintaining sufficient mechanical strength at the gel state. In situ formed hydrogels were eroded gradually, releasing FITC-labeled dextran in an erosion-controlled manner. Moreover, they showed tissue-adhesive properties due to the presence of unreacted catechol groups in the gel structure. Enzyme cross-linked Pluronic hydrogels could be potentially used for delivery applications of drugs and cells.