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Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with the ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, it is demonstrated that PGs are heavily expressed in lung adenocarcinoma (LUAD) patients in correlation with invasive phenotype and poor prognosis. A bioengineered human lung tumor model that recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density, and porosity, is developed. This model reveals that increased sulfation stimulates extensive proliferation, epithelial‐mesenchymal transition (EMT), and stemness in cancer cells. The focal adhesion kinase (FAK)‐phosphatidylinositol 3‐kinase (PI3K) signaling axis is identified as a mediator of sulfation‐induced molecular changes in cells upon activation of a distinct set of RTKs within tumor‐mimetic hydrogels. The study shows that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG‐rich patient tumors by employing integrative omics and network modeling approaches. [ABSTRACT FROM AUTHOR]

Shear forces are involved in many cellular processes and increase remarkably in the case of cardiovascular diseases in the human body. While various stimuli, such as temperature, pH, light, and electromagnetic fields, have been considered for on‐demand release, developing drug delivery systems that are responsive to physiological‐level shear stresses remains as a challenge. For this purpose, liposomes embedded in hydrogel matrices are promising as they can dynamically engage with their environment due to their soft and deformable structure. However, for optimal drug delivery systems, the interaction between liposomes and the surrounding hydrogel matrix, and their response to the shear should be unraveled. Herein, we used unilamellar 1,2‐Dimyristoyl‐sn‐glycero‐3phosphocholine (DMPC) liposomes as drug nanocarriers and polyethylene (glycol) diacrylate (PEGDA) hydrogels having different elasticities, from 1 to 180 Pa, as extracellular matrix (ECM)‐mimetic matrices to understand shear‐triggered liposome discharge from hydrogels. The presence of liposomes provides hydrogels with temperature‐controlled water uptake which is sensitive to membrane microviscosity. By systematically applying shear deformation from linear to nonlinear deformation regimes, the liposome release under transient and cyclic stimuli is modulated. Considering that shear force is commonly encountered in biofluid flow, these results will provide fundamental basis for rational design of shear‐controlled liposomal drug delivery systems. [ABSTRACT FROM AUTHOR]

Cell-based therapies hold significant advantages in comparison with the traditional drug-based or injection-based treatments. However, for long-term functional cellular implants, immune acceptance must be established. To accomplish the acceptance of the implanted cells, various biomaterial systems have been studied. Nanogels have shown great potential for modulation of cellular microenvironments, acting as a physical barrier between the immune system and the implant. However, internalization of nano-scale materials by implanted cells is not desirable and is yet to be overcome. In this study, we incorporated acrylate modified cholesterol-bearing pullulan (CHPOA) nanogels into poly (ethylene glycol) diacrylate (PEGDA) hydrogels through covalent crosslinking, where we used visible light-induced photopolymerization. We characterized morphology and swelling properties of CHPOA incorporated PEG composite hydrogels using FE-SEM and gravimetric analysis. Also, we investigated the biocompatibility properties of composite hydrogels in vivo, where we used both healthy and diabetic mice. We induced diabetes in mice using a low dose streptozotocin (STZ) injections and implanted composite hydrogels in both diabetic and healthy mice through subcutaneous route. Immune cell infiltration of the retrieved tissue was examined through histological analysis, where we observed minimum immune response levels of 0–2 rareness, according to ISO standard of biological evaluation of medical devices. Our observation suggests that the composite hydrogel developed here can be used to introduce nanostructured domains into bulk hydrogels and that this system has potential to be used as immunologically acceptable composite material in cellular therapy without internalization of nanoparticles. [ABSTRACT FROM AUTHOR]

One of the key challenges in engineering three-dimensional tissue constructs is the development of a mature microvascular network capable of supplying sufficient oxygen and nutrients to the tissue. Recent angiogenic therapeutic strategies have focused on vascularization of the constructed tissue, and its integration in vitro; these strategies typically combine regenerative cells, growth factors (GFs) with custom-designed biomaterials. However, the field needs to progress in the clinical translation of tissue engineering strategies. The article first presents a detailed description of the steps in neovascularization and the roles of extracellular matrix elements such as GFs in angiogenesis. It then delves into decellularization, cell, and GF-based strategies employed thus far for therapeutic angiogenesis, with a particularly detailed examination of different methods by which GFs are delivered in biomaterial scaffolds. Finally, interdisciplinary approaches involving advancement in biomaterials science and current state of technological development in fabrication techniques are critically evaluated, and a list of remaining challenges is presented that need to be solved for successful translation to the clinics. [ABSTRACT FROM AUTHOR]

Biohybrid microswimmers exploit the swimming and navigation of a motile microorganism to target and deliver cargo molecules in a wide range of biomedical applications. Medical biohybrid microswimmers suffer from low manufacturing yields, which would significantly limit their potential applications. In the present study, a biohybrid design strategy is reported, where a thin and soft uniform coating layer is noncovalently assembled around a motile microorganism. Chlamydomonas reinhardtii (a single‐cell green alga) is used in the design as a biological model microorganism along with polymer–nanoparticle matrix as the synthetic component, reaching a manufacturing efficiency of ≈90%. Natural biopolymer chitosan is used as a binder to efficiently coat the cell wall of the microalgae with nanoparticles. The soft surface coating does not impair the viability and phototactic ability of the microalgae, and allows further engineering to accommodate biomedical cargo molecules. Furthermore, by conjugating the nanoparticles embedded in the thin coating with chemotherapeutic doxorubicin by a photocleavable linker, on‐demand delivery of drugs to tumor cells is reported as a proof‐of‐concept biomedical demonstration. The high‐throughput strategy can pave the way for the next‐generation generation microrobotic swarms for future medical active cargo delivery tasks. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Corneal collagen cross‐linking (CXL) treatment is widely applied to halt the progression of ectatic diseases such as keratoconus. Unfortunately, the standard CXL procedure based on riboflavin and UV‐A light can only be applied to cornea thicker than 400 μm and results in frequent complications, such as corneal haze and endothelial damage [1]. This study investigates a new CXL procedure based on ruthenium, which is a water‐soluble photoinitiator and visible light (430 nm) in vivo. Methods: For the CXL procedure, tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+), an SPS solution was applied to the rat's cornea and exposed to blue light. After the crosslinking procedure, observations were made for corneal opacity, corneal neovascularization, limbal neovascularization and corneal epithelial damage. Furthermore, the corneas were isolated for histopathological examination, cell viability and SEM analysis, and the results were compared with the conventional riboflavin/UV‐A crosslinking approach. Results: Crosslinked corneas with ruthenium‐based CXL approach showed significantly improved scoring in corneal opacity, corneal neovascularization, limbal neovascularization and corneal wound healing as compared to the standard riboflavin and UVA‐based CXL procedure. Histopathological analysis and cell viability revealed ruthenium to be nontoxic and create more bonds between collagen fibrils when observed under scanning electron microscopy. Conclusions: In this in vivo study, the ruthenium and visible light‐based crosslinking approach proved to be non‐toxic and a faster alternative to the conventional riboflavin and UVA‐based CXL method. We foresee that ruthenium visible light‐based crosslinking treatment could potentially change the treatment modality in keratoconus patients in a clinical setting. Funding Information: This work is supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK) under GrantARDEB‐219S349. References: 1. Gulzar, A., et al., Ruthenium‐induced corneal collagen crosslinking under visible light. Acta Biomater, 2022. 147: p. 198–208. [ABSTRACT FROM AUTHOR]

Tailoring hydrogel properties by modifications of the crosslinker structure is a good method for the design of hydrogels with a wide range of properties. In this study, two novel carboxylic acid‐functionalized dimethacrylate crosslinkers (1a and 2a) are synthesized by the reaction of poly(ethylene glycol) or 2‐hydroxyethyl disulfide with tert‐butyl α‐bromomethacrylate followed by cleavage of tert‐butyl groups using trifluoroacetic acid. Their copolymerization reactivity with 2‐hydroxyethyl methacrylate (HEMA) investigated by photopolymerization studies performed on photo‐differential scanning calorimetry shows higher reactivity of 2a compared to 1a. These crosslinkers are then used at different ratios for fabrication of pH‐ and redox‐responsive poly(2‐hydroxyethyl methacrylate)‐based hydrogels. The swelling behavior of the hydrogels is found to be dependent on the structure of the crosslinker, degree of crosslinking, pH, and CaCl2 concentration. The redox‐responsive behavior is demonstrated by degradation of the hydrogel upon exposure to 1,4‐dithiothreitol. The dye Rhodamine 6G and the drug resorcinol are used as models to demonstrate the pH and redox dependent release of loaded compounds from the hydrogels. The electrostatic interactions between the carboxylate groups and the positively charged R6G are found to govern the release profile in DTT and counteract the diffusion of dye molecules and significant amount of release (79% in 120 hr) occurs only at highly acidic conditions. The degradation mediated release in DTT is observed better in case of resorcinol (around 88% in 5 hr). Overall, these hydrogels can be regarded as good candidates for several applications, such as matrices for controlled release, tissue repair, and regeneration. [ABSTRACT FROM AUTHOR]

Calcification of implanted biomaterials is highly undesirable and limits clinical applicability. Experiments were carried out to assess the calcification resistance of polyisobutylene (PIB), PIB‐based polyurethane (PIB‐PU), PIB‐PU reinforced with (CH3)3N+CH2CH2CH2NH2 I−‐modified montmorillonite (PIB‐PU/nc), PIB‐based polyurethane urea (PIB‐PUU), PIB‐PU containing S atoms (PIBS‐PU), PIBS‐PU reinforced with (CH3)3N+CH2CH2CH2NH2 I−‐modified montmorillonite (PIBS‐PU/nc), and poly(isobutylene‐b‐styrene‐b‐isobutylene) (SIBS), relative to that of a clinically widely implanted polydimethylsiloxane (PDMS)–based PU, Elast‐Eon (the "control"). Samples were incubated in simulated body fluid for 28 days at 37°C, and the extent of surface calcification was analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), energy‐dispersive X‐ray spectroscopy (EDX), X‐ray photoelectron spectroscopy (XPS), and Fourier‐transform‐infrared (FT‐IR) spectroscopy. Whereas the PDMS‐based PU showed extensive calcification, PIB and PIB‐PU containing 72.5% PIB, ie, a polyurethane whose surface is covered with PIB, were free of calcification. PIBS‐PU and PIB‐PUU, ie, polyurethanes that contain S or urea groups, respectively, were slightly calcified. The amine‐modified montmorillonite‐reinforcing agent reduced the extent of calcification. SIBS was found slightly calcified. Evidently, PIB and materials fully coated with PIB are calcification resistant. [ABSTRACT FROM AUTHOR]

ABSTRACT Phosphorus-containing acidic monomers are able to interact with the inorganic phase of mineralized tissues such as enamel, dentin, and bone. From this perspective, three phosphonic acid-containing acrylamide monomers with different lengths of alkyl chains were synthesized to be used for both self-etching dental adhesives and mineralized hydrogel scaffolds. Monomers were synthesized by the reaction of α-aminophosphonates (diethyl aminomethylphosphonate, diethyl 2-aminobutan-2-ylphosphonate, and diethyl 2-aminooctan-2-ylphosphonate) with acryloyl chloride followed by the hydrolysis of phosphonate groups by using trimethylsilyl bromide. The properties such as pH in the range of mild self-etching adhesives, hydrolytic stability, high rate of copolymerizations with 2-hydroxyethyl methacrylate (HEMA) and HEMA/glycerol dimethacrylate, giving high-molecular-weight polymers on thermal polymerization, and strong decalcification ability of hydroxyapatite make these monomers good candidates for self-etching adhesives, although no appreciable effect of the number and size of the α-substituents was observed. Hydrogel scaffolds containing phosphonic acid groups were fabricated, characterized, and mineralized. Altogether, the results suggest that these phosphonic acid-containing monomers have suitable properties to be used in fabrication of biomaterials for both dental and bone tissue engineering applications. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2755-2767 [ABSTRACT FROM AUTHOR]

During the last couple of decades considerable research efforts have been directed towards the synthesis and coating of iron oxide nanoparticles (IONPs) for biomedical applications. To address the current limitations, recent studies have focused on the design of new generation nanoparticle systems whose internalization and targeting capabilities have been improved through surface modifications. This review covers the most recent challenges and advances in the development of IONPs with enhanced quality, and biocompatibility for various applications in biotechnology and medicine. [ABSTRACT FROM AUTHOR]

Circadian clock is an internal time keeping system recurring 24 h daily rhythm in physiology and behavior of organisms. Circadian clock contains transcription and translation feedback loop involving CLOCK/NPAS2, BMAL1, Cry1/2, and Per1/2. In common, heterodimer of CLOCK/NPAS2 and BMAL1 binds to EBOX element in the promoter of Per and Cry genes in order to activate their transcription. CRY and PER making heterodimeric complexes enter the nucleus in order to inhibit their own BMAL1-CLOCK-activated transcription. The aim of this study was to investigate and quantify real-time binding affinities of clock proteins among each other on and off DNA modes using surface plasmon resonance. The pairwise interaction coefficients among clock proteins, as well as interaction of PER2, CRY2, and PER2 : CRY2 proteins with BMAL1 : CLOCK complex in the presence and absence of EBOX motif have been investigated via analysis of surface plasmon resonance data with pseudo first-order reaction kinetics approximation and via nonlinear regression curve fitting. The results indicated that CRY2 and PER2, BMAL1, and CLOCK proteins form complexes in vitro and that PER2, CRY2 and PER2 : CRY2 complex have similar affinities toward BMAL1 : CLOCK complex. CRY2 protein had the highest affinity toward EBOX complex, whereas PER2 and CRY2 : PER2 complexes displayed low affinity toward EBOX complex. The quantification of the interaction between clock proteins is critical to understand the operation mechanism of the biological clock and to address the behavioral and physiological disorders, and it will be useful for the design of new drugs toward clock-related diseases. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Transplantation of cells within poly(ethylene glycol) (PEG) hydrogel scaffolds as effective immunoisolation barriers is becoming increasingly important strategy for tissue engineering and regenerative medicine. In these applications, crosslink density of these membranes has significant effect on the control of diffusion of many biomolecules such as nutrients, cellular wastes, and hormones. When these networks are designed with crosslink density gradients, alterations in network structure may have an effect on biomolecule diffusivity. The goal of this work was to synthesize PEG hydrogels via surface initiated photopolymerization for use in applications involving physiological protein delivery and cell encapsulation. For this purpose, PEG hydrogels of differing crosslink density gradients were formed via surface initiated photopolymerization, and the diffusion of model proteins with various molecular weights were observed through these PEG hydrogel scaffolds with defined properties. Diffusion coefficients were on the order of 10−7−10−8 cm2/s and protein diffusion time scales varied from 5 min to 30 h. The results confirm that synthetic PEG hydrogels with crosslink density gradients are promising for controlled release of bioactive molecules and for covalent incorporation of ligands to support cell viability. [ABSTRACT FROM AUTHOR]

Polymer composites consisted of small hydrophilic pockets homogeneously dispersed in a hydrophobic polymer matrix are important in many applications where controlled release of the functional agent from the hydrophilic phase is needed. As an example, a release of biomolecules or drugs from therapeutic formulations or release of salt in anti-icing application can be mentioned. Here, we report a method for preparation of such a composite material consisted of small KCOOH salt pockets distributed in the styrene-butadiene-styrene (SBS) polymer matrix and demonstrate its effectiveness in anti-icing coatings. The mixtures of the aqueous KCOOH and SBS-cyclohexane solutions were firstly stabilized by adding silica nanoparticles to the emulsions and, even more, by gelation of the aqueous phase by agarose. The emulsions were observed in optical microscope to check its stability in time and characterized by rheological measurements. The dry composite materials were obtained via casting the emulsions onto the glass substrates and evaporations of the organic solvent. Composite polymer films were characterized by water contact angle (WCA) measurements. The release of KCOOH salt into water and the freezing delay experiments of water droplets on dry composite films demonstrated their anti-icing properties. It has been concluded that hydrophobic and thermoplastic SBS polymer allows incorporation of the hydrophilic pockets/phases through our technique that opens the possibility for controlled delivering of anti-icing agents from the composite. [ABSTRACT FROM AUTHOR]

This paper reports the previously unknown interactions between eight low molecular weight commercially available drugs (130-800 Da) and DNA repair protein photolyase using computational docking simulations and surface plasmon resonance (SPR) experiments. Theoretical dissociation constants, Kd, obtained from molecular docking simulations were compared with the values found from SPR experiments. Among the eight drugs analyzed, computational and experimental values showed similar binding affinities between selected drug and protein pairs. We found no significant differences in binding interactions between pure and commercial forms of the drug lornoxicam and DNA photolyase. Among the eight drugs studied, prednisone, desloratadine, and azelastine exhibited the highest binding affinity ( Kd = 1.65, 2.05, and 8.47 μM, respectively) toward DNA photolyase. Results obtained in this study are promising for use in the prediction of unknown interactions of common drugs with specific proteins such as human clock protein cryptochrome. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The cyclobutane pyrimidine dimer (CPD) and 6-4 lesion formations along with the specific breaks on strands are the most common type of DNA damage caused by Ultraviolet light (UV) irradiation. CPD photolyase I and II construct two subfamilies of flavoproteins, which have recognition and repair capabilities of CPD sites on both single stranded (ssDNA) and double stranded DNA (dsDNA) with the aid of blue light energy. The other types of flavoprotein family consist of cryptochromes (CRY) that act as photoreceptors in plants, or circadian rhythm regulators in animals. Recent findings showed that a specific type of Cryptochrome-Drosophila, Arabidopsis, Synechocystis, Human (CRY-DASH) has photorepair activity on ssDNA. In this work, real-time interactions between CRY-DASH and ss/dsDNA as well as the interactions between Vibrio cholerae photolyase (VcPHR) and ss/dsDNA were investigated using Surface Plasmon Resonance (SPR). The interactions were then characterized and compared in order to investigate the effect of different types of flavoprotein on UV damaged ss/dsDNA. SPR results confirm the specific binding of VcPHR and CRY-DASH with UV treated DNA. This study is the first instance to quantify the interactions of UV treated and untreated DNA with flavoproteins. [ABSTRACT FROM AUTHOR]

Background: Insulin-degrading enzyme (IDE) is an allosteric Zn+2 metalloprotease involved in the degradation of many peptides including amyloid-β, and insulin that play key roles in Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), respectively. Therefore, the use of therapeutic agents that regulate the activity of IDE would be a viable approach towards generating pharmaceutical treatments for these diseases. Crystal structure of IDE revealed that N-terminal has an exosite which is ∼30 Å away from the catalytic region and serves as a regulation site by orientation of the substrates of IDE to the catalytic site. It is possible to find small molecules that bind to the exosite of IDE and enhance its proteolytic activity towards different substrates. Methodology/Principal Findings: In this study, we applied structure based drug design method combined with experimental methods to discover four novel molecules that enhance the activity of human IDE. The novel compounds, designated as D3, D4, D6, and D10 enhanced IDE mediated proteolysis of substrate V, insulin and amyloid-β, while enhanced degradation profiles were obtained towards substrate V and insulin in the presence of D10 only. Conclusion/Significance: This paper describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro and in vivo activation of this important enzyme with small molecules is possible. [ABSTRACT FROM AUTHOR]

Purpose: Keratoconus is a progressive disease which results thinning of the cornea and increase in the forward curvature of the cornea until corneal rupture. The first choice in clinical management of keratoconus is Ultraviolet‐A(UV‐A) crosslinking procedure with riboflavin. This procedure is painful, prolonged and has many side effects on the patient. Eosin‐y is well known molecule and it has been used as crosslinker with visible light on hydrogels with various cells. Methods: Firstly, we have examined effects of sequential concentrations of eosin‐y on proliferation and apoptosis of human corneal epithelial cells (HCECs). We have used MTT cytotoxicity assay, Xcelligence real‐time cell analysis, Ki67 and Caspase‐3 immunofluorescence staining. After these tests, visible light (525 nm) induced crosslinking has performed with Eosin‐Y in fresh bovine corneas at selected doses. Corneas which applied eosin‐y or riboflavin, or saline are observed under scanning electron microscopy for topographic, cross‐sectional and elemental analysis. Their young moduli measured with hybrid rheometer. Lastly, resistance to osmotic stress and chemical digestion of the corneas compared with water swelling test and enzymatic digestion test, respectively. Results: We have demonstrated non‐toxic doses of eosin‐y with cytotoxicity and immunofluorescence experiments on HCECs. We determined LD50 concentration of eosin‐y for HCECs. After that, we have showed significant crosslinking with eosin‐y in fresh bovine corneas. Eosin‐y and visible light procedure has created faster and stronger corneal crosslinking reaction on bovine corneas compared to riboflavin and UV‐A procedure. Conclusions: We have observed, eosin‐y initiate faster and stronger crosslinking in corneal stroma at subtoxic doses than standard procedure. It could be new photo‐initiator agent for corneal crosslinking procedure in clinics. For next step, we will examine its toxicity on corneal stromal cells and corneal endothelial cells. [ABSTRACT FROM AUTHOR]