Photo-click hydrogels prepared from functionalized cyclodextrin and poly(ethylene glycol) for drug delivery and in situ cell encapsulation

Polymers or hydrogels containing modified cyclodextrin (CD) are highly useful in drug delivery applications, as CD is a cytocompatible amphiphilic molecule that can complex with a variety of hydrophobic drugs. Here, we designed modular photoclick thiol-ene hydrogels from derivatives of βCD and poly(ethylene glycol) (PEG), including βCD-allylether (βCD-AE), βCD-thiol (βCD-SH), PEG-thiol (PEGSH), and PEG-norbornene (PEGNB). Two types of CD-PEG hybrid hydrogels were prepared using radical-mediated thiol-ene photoclick reactions. Specifically, thiol-allylether hydrogels were formed by reacting multiarm PEGSH and βCD-AE, and thiol-norbornene hydrogels were formed by cross-linking βCD-SH and multiarm PEGNB. We characterized the properties of these two types of thiol-ene hydrogels, including gelation kinetics, gel fractions, hydrolytic stability, and cytocompatibility. Compared with thiol-allylether hydrogels, thiol-norbornene photoclick reaction formed hydrogels with faster gelation kinetics at equivalent macromer contents. Using curcumin, an anti-inflammatory and anticancer hydrophobic molecule, we demonstrated that CD-cross-linked PEG-based hydrogels, when compared with pure PEG-based hydrogels, afforded higher drug loading efficiency and prolonged delivery in vitro. Cytocompatibility of these CD-cross-linked hydrogels were evaluated by in situ encapsulation of radical sensitive pancreatic MIN6 β-cells. All formulations and cross-linking conditions tested were cytocompatible for cell encapsulation. Furthermore, hydrogels cross-linked by βCD-SH showed enhanced cell proliferation and insulin secretion as compared to gels cross-linked by either dithiothreitol (DTT) or βCD-AE, suggesting the profound impact of both macromer compositions and gelation chemistry on cell fate in chemically cross-linked hydrogels

Improving gelation efficiency and cytocompatibility of visible light polymerized thiol-norbornene hydrogels via addition of soluble tyrosine

Hydrogels immobilized with biomimetic peptides have been used widely for tissue engineering and drug delivery applications. Photopolymerization has been among the most commonly used techniques to fabricate peptide-immobilized hydrogels as it offers rapid and robust peptide immobilization within a crosslinked hydrogel network. Both chain-growth and step-growth photopolymerizations can be used to immobilize peptides within covalently crosslinked hydrogels. A previously developed visible light mediated step-growth thiol-norbornene gelation scheme has demonstrated efficient crosslinking of hydrogels composed of an inert poly(ethylene glycol)-norbornene (PEGNB) macromer and a small molecular weight bis-thiol linker, such as dithiothreitol (DTT). Compared with conventional visible light mediated chain-polymerizations where multiple initiator components are required, step-growth photopolymerized thiol-norbornene hydrogels are more cytocompatible for the in situ encapsulation of radical sensitive cells (e.g., pancreatic β-cells). This contribution explored visible light based crosslinking of various bis-cysteine containing peptides with macromer 8-arm PEGNB to form biomimetic hydrogels suitable for in situ cell encapsulation. It was found that the addition of soluble tyrosine during polymerization not only significantly accelerated gelation, but also improved the crosslinking efficiency of PEG-peptide hydrogels as evidenced by a decreased gel point and enhanced gel modulus. In addition, soluble tyrosine drastically enhanced the cytocompatibility of the resulting PEG-peptide hydrogels, as demonstrated by in situ encapsulation and culture of pancreatic MIN6 β-cells. This visible light based thiol-norbornene crosslinking mechanism provides an attractive gelation method for preparing cytocompatible PEG-peptide hydrogels for tissue engineering applications

Thiol-norbornene photo-click hydrogels for tissue engineering applications.

Thiol-norbornene (thiol-ene) photo-click hydrogels have emerged as a diverse material system for tissue engineering applications. These hydrogels are cross-linked through light mediated orthogonal reactions between multi-functional norbornene-modified macromers (e.g., poly(ethylene glycol), hyaluronic acid, gelatin) and sulfhydryl-containing linkers (e.g., dithiothreitol, PEG-dithiol, bis-cysteine peptides) using low concentration of photoinitiator. The gelation of thiol-norbornene hydrogels can be initiated by long-wave UV light or visible light without additional co-initiator or co-monomer. The cross-linking and degradation behaviors of thiol-norbornene hydrogels are controlled through material selections, whereas the biophysical and biochemical properties of the gels are easily and independently tuned owing to the orthogonal reactivity between norbornene and thiol moieties. Uniquely, the cross-linking of step-growth thiol-norbornene hydrogels is not oxygen-inhibited, therefore the gelation is much faster and highly cytocompatible compared with chain-growth polymerized hydrogels using similar gelation conditions. These hydrogels have been prepared as tunable substrates for 2D cell culture, as microgels or bulk gels for affinity-based or protease-sensitive drug delivery, and as scaffolds for 3D cell culture. Reports from different laboratories have demonstrated the broad utility of thiol-norbornene hydrogels in tissue engineering and regenerative medicine applications, including valvular and vascular tissue engineering, liver and pancreas-related tissue engineering, neural regeneration, musculoskeletal (bone and cartilage) tissue regeneration, stem cell culture and differentiation, as well as cancer cell biology. This article provides an up-to-date overview on thiol-norbornene hydrogel cross-linking and degradation mechanisms, tunable material properties, as well as the use of thiol-norbornene hydrogels in drug delivery and tissue engineering applications

Visible light-initiated interfacial thiol-norbornene photopolymerization for forming islet surface conformal coating

A cytocompatible visible light-mediated interfacial thiol-norbornene photopolymerization scheme was developed for creating hydrogel conformal coating on pancreatic islets. The step-growth thiol-norbornene reaction affords high consistency and tunability in gel coating thickness. Furthermore, isolated islets coated with thiol-norbornene gel maintained their viability and function in vitro

Modular and adaptable tumor niche prepared from visible light-initiated thiol-norbornene photopolymerization

Photopolymerized biomimetic hydrogels with adaptable properties have been widely used for cell and tissue engineering applications. As a widely adopted gel crosslinking method, photopolymerization provides experimenters on-demand and spatial-temporal controls in gelation kinetics. Long wavelength ultraviolet (UV) light initiated photopolymerization is among the most popular methods in the fabrication of cell-laden hydrogels owing to its rapid and relatively mild gelation conditions. The use of UV light, however, still causes concerns regarding its potential negative impacts on cells. Alternatively, visible light based photopolymerization can be used to crosslink cell-laden hydrogels. The majority of visible light based gelation schemes involve photoinitiator, co-initiator, and co-monomer. This multi-component initiation system creates added challenges for optimizing hydrogel formulations. Here, we report a co-initiator/co-monomer-free visible light initiated thiol-norbornene photopolymerization scheme to prepare modular biomimetic hydrogels suitable for in situ cell encapsulation. Eosin-Y was used as the sole initiator to initiate modular gelation between synthetic macromers (e.g., thiolated poly(vinyl alcohol) or poly(ethylene glycol)) and functionalized extracellular matrices (ECM), including norbornene-functionalized gelatin (GelNB) and/or thiolated hyaluronic acid (THA). These components are modularly crosslinked to afford bio-inert (i.e., purely synthetic), bioactive (i.e., using gelatin), and biomimetic (i.e., using gelatin and hyaluronic acid) hydrogels. The stiffness of the hydrogels can be easily tuned without affecting the contents of the bioactive components. Furthermore, the use of naturally-derived biomacromolecules (e.g., gelatin and HA) renders these hydrogels susceptible to enzyme-mediated degradation. In addition to demonstrating efficient and tunable visible light mediated gelation, we also utilized this biomimetic modular gelation system to formulate artificial tumor niche and to study the effects of cell density and gel modulus on the formation of pancreatic ductal adenocarcinoma (PDAC) spheroids.

Lading of the Late Bronze Age ship at Uluburun

The Uluburun shipwreck was discovered in 1982 when a Turkish sponge diver informed the Institute of Nautical Archaeology (INA) of his discovery of metal biscuits with ears. INA archaeologists recognized this as a description of oxhide ingots, a clear indication of a Late Bronze Age site. This find was of considerable interest as very little is known about seafaring, long distance trade, and ship construction during the Late Bronze Age, except for a glimpse provided by the Cape Gelidonya shipwreck excavated in 1960 by George Bass. The site at Uluburun revealed only a handful of disarticulated ship fragments; nevertheless, a meticulous study of these timbers and the distribution of the cargo and shipboard items on the seabed resulted in a hypothetical, but carefully guided, reconstruction of the ship and the lading of its cargo. The artifacts recovered from the Uluburun shipwreck are unlike those discovered on land in quality of preservation as well as the quantity found. Items pertinent to this study include 354 copper oxhide ingots (approximately 10 tons), 152 copper bun ingots (nearly 1 ton), 110 tin ingot fragments (approximately 1 ton), 175 glass ingots (approximately 0.3 tons), 150 Canaanite jars (approximately 2 tons if filled with water), 10 large storage jars (pithoi) (approximately 3.5 tons if filled with water), approximately 51 Canaanite pilgrim flasks, 24 stone anchors (3.3 tons), nearly 1 ton of ballast stones, and the hull remains itself. Two computer programs, Rhinoceros and PHASER, were used to visually model the artifacts and ship in three-dimensions and to systematically test various hull shapes and lading arrangements in a range of hydrostatic conditions. Tests showed that a hull measuring 15 x 5 x 2 m would be capable of carrying the estimated 20 tons of cargo and shipboard items recovered from the wreck at a draft of 1 m, with sufficient freeboard to allow six passengers to stand on one side of the vessel without compromising the stability of the ship.Institute of Nautical Archaeolog

Determining the physical conditions of extremely young Class 0 circumbinary disk around VLA1623A

We present detailed analysis of high-resolution C18O (2-1), SO (88-77), CO (3-2) and DCO+ (3-2) data obtained by the Atacama Large Millimeter/sub-millimeter Array (ALMA) towards a Class 0 Keplerian circumbinary disk around VLA1623A, which represents one of the most complete analysis towards a Class 0 source. From the dendrogram analysis, we identified several accretion flows feeding the circumbinary disk in a highly anisotropic manner. Stream-like SO emission around the circumbinary disk reveals the complicated shocks caused by the interactions between the disk, accretion flows and outflows. A wall-like structure is discovered south of VLA1623B. The discovery of two outflow cavity walls at the same position traveling at different velocities suggests the two outflows from both VLA1623A and VLA1623B overlays on top of each other in the plane of sky. Our detailed flat and flared disk modeling shows that Cycle 2 C18O J = 2-1 data is inconsistent with the combined binary mass of 0.2 Msun as suggested by early Cycle 0 studies. The combined binary mass for VLA1623A should be modified to 0.3 ~ 0.5 Msun.Comment: 26 pages, 20 figures, accepted by ApJ 2020.2.2

Visible light cured thiol-vinyl hydrogels with tunable degradation for 3D cell culture

We report here a synthetically simple yet highly tunable and diverse visible light mediated thiol- vinyl gelation system for fabricating cell-instructive hydrogels. Gelation was achieved via a mixed-mode step-and-chain-growth photopolymerization using functionalized 4-arm poly(ethylene glycol) as backbone macromer, eosin-Y as photosensitizer, and di-thiol containing molecule as dual purpose co-initiator/cross-linker. N-vinylpyrrolidone (NVP) was used to accelerate gelation kinetics and to adjust the stiffness of the hydrogels. Visible light (wavelength: 400–700nm) was used to initiate rapid gelation (gel points: ~20 seconds) that reached completion within a few minutes. The major differences between current thiol-vinyl gelation and prior visible light mediated photopolymerization are that: (1) the co-initiator triethanolamine (TEOA) used in the previous systems was replaced with multifunctional thiols and (2) mixed-mode polymerized gels contain less network heterogeneity. The gelation kinetics and gel properties at the same PEG macromer concentration could be tuned by changing the identity of vinyl groups and di-thiol cross-linkers, as well as concentration of cross-linker and NVP. Specifically, acrylate-modified PEG afforded the fastest gelation rate, followed by acrylamide and methacrylate-functionalized PEG. Increasing NVP concentration also accelerated gelation and led to a higher network cross- linking density. Further, increasing di-thiol peptide concentration in the gel formulation increased hydrogel swelling and decreased gel stiffness. Due to the formation of thiol-ether-ester bonds following thiol-acrylate reaction, the gels degraded hydrolytically following a pseudo first order degradation kinetics. Degradation rate was controlled by adjusting thiol or NVP content in the polymer precursor solution. The cytocompatibility and utility of this hydrogel system were evaluated using in situ encapsulation of human mesenchymal stem cells (hMSC). Encapsulated hMSCs remained alive (>90%) throughout the duration of the study and the cells were differentiated down osteogenic lineage with varying degrees by controlling the rate and mode of gel degradation

Poly[bis­(μ2-4,4′-bipyridine)­bis­(3-nitro­benzoato)nickel(II)]

The crystal structure of the title complex, [Ni(C7H4NO4)2(C10H8N2)2]n, exhibits a two-dimensional network, which is built up from slightly distorted NiN4O2 polyhedra (2 symmetry), bipyridine ligands, and carboxyl­ate anions. The NiII atoms are six-coordinated by two O atoms of two monodentate carboxyl­ate anions and four N atoms from bipyridine ligands and are connected into layers by the 4,4′-bipyridine ligands