Fabrication of triple-crosslinked gelatin/alginate hydrogels for controlled release applications.

Hydrogels have been demonstrated as smart drug carriers to recognize the tumor microenvironment for cancer treatment, where the dynamic crosslinks in the hydrogel network contribute to the stimuli-responsive features but also result in poor stability and weak mechanical property of the hydrogels. Here, phenylboronic acid-grafted polyethyleneimine (PBA-PEI)-modified gelatin (PPG) was synthesized to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds, and then calcium ions (Ca2+) were added to introduce the third calcium-carboxylate crosslinking in the network to form the triple-crosslinked PPG/ADA-Ca2+ hydrogels. Given the three types of dynamic bonds in the network, PPG/ADA-Ca2+ hydrogels possessed a self-healing manner, stimuli-responsiveness, and better mechanical properties compared to single- or double-crosslinked hydrogels. The controlled release capability of PPG/ADA-Ca2+ hydrogels was also demonstrated, showing the encapsulated molecules can be rapidly released from the hydrogel network in the presence of hydrogen peroxide while the release rate can be slowed down at acidic pH. Furthermore, PPG/ADA-Ca2+ hydrogels presented selected cytotoxicity and drug delivery to cancer cells due to the regulated degradation by the cellular microenvironment. Taken together, PPG/ADA-Ca2+ hydrogels have been demonstrated as promising biomaterials with multiple desirable properties and dynamic features to perform controlled molecule release for biomedical applications.

Piperic acid derivative as a molecular modulator to accelerate the IAPP aggregation process and alter its antimicrobial activity.

Piperic acid derivatives were found to affect the islet amyloid polypeptide (IAPP) aggregation process. Structure-activity relationship studies revealed that PAD-13 was an efficient molecular modulator to accelerate IAPP fibril formation by promoting primary and secondary nucleation and reducing its antimicrobial activity.

Fabrication of versatile poly(xylitol sebacate)-co-poly(ethylene glycol) hydrogels through multifunctional crosslinkers and dynamic bonds for wound healing.

Poly(polyol sebacate) (PPS) polymer family has been recognized as promising biomaterials for biomedical applications with their characteristics of easy production, elasticity, biodegradation, and cytocompatibility. Poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) has been developed to fabricate PPS-based hydrogels; however, current PXS-co-PEG hydrogels presented limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. Here, we fabricate a new type of PXS-co-PEG hydrogels through the use of multifunctional crosslinkers as well as dynamic bonds. In our design, polyethyleneimine-polydopamine (PEI-PDA) macromers are utilized to crosslink aldehyde-functionalized PXS-co-PEG (APP) through imine bonds and hydrogen bonds. PEI-PDA/APP hydrogels present multiple functional properties (e.g., fluorescent, elastomeric, biodegradable, self-healing, bioadhesive, antioxidant, and antibacterial behaviors). These properties of PEI-PDA/APP hydrogels can be fine-tuned by changing the PDA grafting degrees in the PEI-PDA crosslinkers. Most importantly, PEI-PDA/APP hydrogels are considered promising wound dressings to promote tissue remodeling and prevent bacterial infection in vivo. Taken together, PEI-PDA/APP hydrogels have been demonstrated as versatile biomaterials to provide multiple tailorable properties and desirable functions to expand the utility of PPS-based hydrogels for advanced biomedical applications. STATEMENT OF SIGNIFICANCE: Various strategies have been developed to fabricate poly(polyol sebacate) (PPS)-based hydrogels. However, current PPS-based hydrogels present limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. This work describes that co-engineering crosslinkers and interfacial crosslinking is a promising approach to synthesizing a new type of poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) hydrogels as multifunctional hydrogels to expand the utility of PPS-based hydrogels for advanced biomedical applications. The fabricated hydrogels present multiple functional properties (e.g., fluorescent, biodegradable, elastomeric, self-healing, bioadhesive, antioxidative, and antibacterial), and these properties can be fine-tuned by the defined crosslinkers. The fabricated hydrogels are also used as promising wound dressing biomaterials to exhibit promoted tissue remodeling and prevent bacterial infection in vivo.

Hydrogel-Based Strategies for the Management of Osteomyelitis.

Osteomyelitis is a type of bone infection caused by bacteria, with Staphylococcus sepsis being responsible for most cases. Osteomyelitis treatment generally requires a multifaceted approach that may include intervention of surgery and administration of antibacterial agents, where several materials have been utilized as delivery vehicles for antibiotics and other antibacterial materials. Hydrogel has become a popular candidate for osteomyelitis treatment due to its biocompatibility, water-containing porous structure, and adaptable physicochemical properties. In this review, we discuss several hydrogel-based strategies for osteomyelitis treatment and categorized them based on the encapsulated cargos (i.e., antibiotics, silver nanoparticles, protein and bacteriophage, and reactive oxygen species (ROS) generator). Several representative examples of osteomyelitis treatment using hydrogels are described here, focusing on their design, preparation, properties, and outcomes. We also provide our perspectives on the remaining concerns regarding fabricating advanced hydrogels for osteomyelitis treatment. This review will be valuable to the hydrogel community and inspire researchers to develop next-generation hydrogels for specific and practical clinical applications in osteomyelitis.

Progress in the drug encapsulation of poly(lactic-co-glycolic acid) and folate-decorated poly(ethylene glycol)-poly(lactic-co-glycolic acid) conjugates for selective cancer treatment.

Poly(lactic-co-glycolic acid) (PLGA) is a US Food and Drug Administration (FDA)-approved polymer used in humans in the forms of resorbable sutures, drug carriers, and bone regeneration materials. Recently, PLGA-based conjugates have been extensively investigated for cancer, which is the second leading cause of death globally. This article presents an account of the literature on PLGA-based conjugates, focusing on their chemistries, biological activity, and functions as targeted drug carriers or sustained drug controllers for common cancers (e.g., breast, prostate, and lung cancers). The preparation and drug encapsulation of PLGA nanoparticles and folate-decorated poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) conjugates are discussed, along with several representative examples. Particularly, the reactions used for preparing drug-conjugated PLGA and FA-PEG-PLGA are emphasized, with the associated chemistries involved in the formation of structures and their biocompatibility with internal organs. This review provides a deeper understanding of the constituents and interactions of PLGA-conjugated materials to ensure successful conjugation in PLGA material design and the subsequent biomedical applications.

Poly(glycerol sebacate)-co-poly(ethylene glycol)/Gelatin Hybrid Hydrogels as Biocompatible Biomaterials for Cell Proliferation and Spreading.

Synthetic polymers have been widely employed to prepare hydrogels for biomedical applications, such as cell culture, drug delivery, and tissue engineering. However, the activity of cells cultured in the synthetic polymer-based hydrogels faces the challenges of limited cell proliferation and spreading compared to cells cultured in natural polymer-based hydrogels. To address this concern, a hybrid hydrogel strategy is demonstrated by incorporating thiolated gelatin (GS) into the norbornene-functionalized poly (glycerol sebacate)-co-polyethylene glycol (Nor_PGS-co-PEG, NPP) network to prepare highly biocompatible NPP/GS_UV hydrogels after the thiol-ene photo-crosslinking reaction. The GS introduces several desirable features (i.e., enhanced water content, enlarged pore size, increased mechanical property, and more cell adhesion sites) to the NPP/GS_UV hydrogels, facilitating the cell proliferation and spreading inside the network. Thus, the highly biocompatible NPP/GS_UV hydrogels are promising materials for cell encapsulation and tissue engineering applications. Taken together, the hybrid hydrogel strategy is demonstrated as a powerful approach to fabricate hydrogels with a highly friendly environment for cell culture, expanding the biomedical applications of hydrogels.

Formation of highly elastomeric and property-tailorable poly(glycerol sebacate)-co-poly(ethylene glycol) hydrogels through thiol-norbornene photochemistry.

Poly(glycerol sebacate) (PGS) is a synthetic biorubber that presents good biocompatibility, excellent elasticity and desirable mechanical properties for biomedical applications; however, the inherent hydrophobicity and traditional thermal curing of PGS restrict its use in the fabrication of hydrogels for advanced bioapplications. Here, we designed a new class of hydrophilic PGS-based copolymers that allow hydrogel formation through thiol-norbornene chemistry. Poly(glycerol sebacate)-co-polyethylene glycol (PGS-co-PEG) macromers were synthesized through a stepwise polycondensation reaction, and then the norbornene functional groups were introduced to the PGS-co-PEG structure to form norbornene-functionalized PGS-co-PEG (Nor_PGS-co-PEG). Nor_PGS-co-PEG macromers can be crosslinked using dithiols to prepare hydrogels in the presence of light and photoinitiators. The mechanical, swelling and degradation properties of Nor_PGS-co-PEG hydrogels can be controlled by altering the crosslinker amount. In particular, the elongation of Nor_PGS-co-PEG hydrogels can be modulated up to 950%. Nor_PGS-co-PEG can be processed using electrospinning and 3D printing techniques to generate microfibrous scaffolds and printed structures, respectively. In addition, the cytocompatibility of Nor_PGS-co-PEG was also demonstrated using in vitro cellular viability studies. These results indicate that Nor_PGS-co-PEG is a promising biomaterial with definable properties for scaffold manufacturing, presenting a great potential for biomedical applications.

Mechanically dynamic PDMS substrates to investigate changing cell environments.

Mechanics of the extracellular matrix (ECM) play a pivotal role in governing cell behavior, such as cell spreading and differentiation. ECM mechanics have been recapitulated primarily in elastic hydrogels, including with dynamic properties to mimic complex behaviors (e.g., fibrosis); however, these dynamic hydrogels fail to introduce the viscoelastic nature of many tissues. Here, we developed a two-step crosslinking strategy to first form (via platinum-catalyzed crosslinking) networks of polydimethylsiloxane (PDMS) and then to increase PDMS crosslinking (via thiol-ene click reaction) in a temporally-controlled manner. This photoinitiated reaction increased the compressive modulus of PDMS up to 10-fold within minutes and was conducted under cytocompatible conditions. With stiffening, cells displayed increased spreading, changing from ∼1300 to 1900 µm2 and from ∼2700 to 4600 µm2 for fibroblasts and mesenchymal stem cells, respectively. In addition, higher myofibroblast activation (from ∼2 to 20%) for cardiac fibroblasts was observed with increasing PDMS substrate stiffness. These results indicate a cellular response to changes in PDMS substrate mechanics, along with a demonstration of a mechanically dynamic and photoresponsive PDMS substrate platform to model the dynamic behavior of ECM.

Nanoparticle-dendrimer hybrid nanocapsules for therapeutic delivery.

BACKGROUND: Nanocapsules can efficiently encapsulate therapeutic cargo for anticancer drug delivery. However, the controlled release of the payload remains a challenge for effective drug delivery. MATERIALS & METHODS: We used dithiocarbamate-functionalized PAMAM dendrimer to cross-link the shell of arginine gold nanoparticles stabilized nanocapsule, and controlled the drug release from the nanocapsule. The ability of cross-linked nanocapsule to deliver hydrophobic paclitaxel to B16F10 cells was demonstrated both in vitro and in vivo. RESULTS: Cross-linked nanocapsule possesses tunable stability and modular permeability, and can deliver paclitaxel with improved anticancer efficiency compared with free drug both in vitro and in vivo. CONCLUSION: Dithiocarbamate chemistry provides a new tool to harness multifactorial colloidal self-assembly for controlled drug delivery for cancer therapy.

Rapid coating of surfaces with functionalized nanoparticles for regulation of cell behavior.

A robust monolayer of nanoparticles is formed via dip-coating of cell culture plates. These surfaces provide cell type-specific modulation of growth behavior without the uptake of nanoparticles.

Differentiation of cancer cell type and phenotype using quantum dot-gold nanoparticle sensor arrays.

We demonstrate rapid and efficient sensing of mammalian cell types and states using nanoparticle-based sensor arrays. These arrays are comprised of cationic quantum dots (QDs) and gold nanoparticles (AuNPs) that interact with cell surfaces to generate distinguishable fluorescence responses based on cell surface signatures. The use of QDs as the recognition elements as well as the signal transducers presents the potential for direct visualization of selective cell surface interactions. Notably, this sensor is unbiased, precluding the requirement of pre-knowledge of cell state biomarkers and thus providing a general approach for phenotypic profiling of cell states, with additional potential for imaging applications.

Determination of the intracellular stability of gold nanoparticle monolayers using mass spectrometry.

Monolayer stability of core-shell nanoparticles is a key determinant of their utility in biological studies such as imaging and drug delivery. Intracellular thiols (e.g., cysteine, cysteamine, and glutathione) can trigger the release of thiolate-bound monolayers from nanoparticles, a favorable outcome for controllable drug release applications but an unfavorable outcome for imaging agents. Here, we describe a method to quantify the monolayer release of gold nanoparticles (AuNPs) in living cells using parallel measurements by laser desorption/ionization (LDI) and inductively coupled plasma (ICP) mass spectrometry. This combination of methods is tested using AuNPs with structural features known to influence monolayer stability and on cells types with varying concentrations of glutathione. On the basis of our results, we predict that this approach should help efforts to engineer nanoparticle surface monolayers with tunable stability, providing stable platforms for imaging agents and controlled release of therapeutic monolayer payloads.

Stability of quantum dots in live cells.

Quantum dots are highly fluorescent and photostable, making them excellent tools for imaging. When using these quantum dots in cells and animals, however, intracellular biothiols (such as glutathione and cysteine) can degrade the quantum dot monolayer, compromising function. Here, we describe a label-free method to quantify the intracellular stability of monolayers on quantum dot surfaces that couples laser desorption/ionization mass spectrometry with inductively coupled plasma mass spectrometry. Using this new approach we have demonstrated that quantum dot monolayer stability is correlated with both quantum dot particle size and monolayer structure, with appropriate choice of both particle size and ligand structure required for intracellular stability.