Plasmin-Cleavable Nanoparticles for On-Demand Release of Morphogens in Vascularized Osteogenesis.

The objective of this work was to engineer self-assembled nanoparticles (NPs) for on-demand release of bone morphogenetic protein-2 (BMP2) and vascular endothelial growth factor (VEGF) in response to enzymes secreted by the migrating human mesenchymal stem cells (hMSCs) and human endothelial colony forming cells (ECFCs) to induce osteogenesis and vasculogenesis. Gene expression profiling experiments revealed that hMSCs and ECFCs, encapsulated in osteogenic/vasculogenic hydrogels, expressed considerable levels of plasminogen, urokinase plasminogen activator and its receptor uPAR, and tissue plasminogen activator. Therefore, the plasmin-cleavable lysine-phenylalanine-lysine-threonine (KFKT) was used to generate enzymatically cleavable NPs. The acetyl-terminated, self-assembling peptide glycine-(phenylalanine)3GFFF-ac and the plasmin-cleavable GGKFKTGG were reacted with the cysteine-terminated CGGK(Fmoc/MTT) peptide through the MTT and Fmoc termini, respectively. The difunctional peptide was conjugated to polyethylene glycol diacrylate (PEGDA) with molecular weights (MW) ranging from 0.5 to 7.5 kDa, and the chain ends of the PEG-peptide conjugate were terminated with succinimide groups. After self-assembly in aqueous solution, BMP2 was grafted to the self-assembled, plasmin-cleavable PEG-based (PxSPCP) NPs for on-demand release. The NPs' stability in aqueous solution and that of the grafted BMP2 were strongly dependent on PEG MW. P2SPCP NPs showed high particle size stability, BMP2 grafting efficiency, grafted protein stability, and high extent of osteogenic differentiation of hMSCs. The localized and on-demand release of BMP2 from PxSPCP NPs coencapsulated with hMSCs in the linear polyethylene glycol-co-lactide acrylate patterned hydrogel with microchannels encapsulating hMSCs + ECFCs and VEGF-conjugated nanogels resulted in the highest extent of osteogenic and vasculogenic differentiation of the encapsulated cells compared to directly added BMP2/VEGF. The on-demand release of BMP2 from PxSPCP NPs not only enhances osteogenesis and vasculogenesis but also potentially reduces many undesired side effects of BMP2 therapy in bone regeneration.

Synthesis and Characterization of Photo-Cross-Linkable Keratin Hydrogels for Stem Cell Encapsulation.

The objective of this work was to synthesize an injectable and photopolymerizable hydrogel based on keratin extracted from poultry feather for encapsulation and delivery of stem cells in tissue regeneration. Since feather keratin is rich in cysteine residue, allylation of sulfhydryl groups was used for functionalization of keratin. Keratin was extracted from feather barbs by reducing the disulfide bonds in cysteine residues to sulfhydryl groups (-SH). Next, the free thiol groups were converted to dehydroalanine (Dha) by oxidative elimination using O-(2,4,6-trimethylbenzenesulfonyl) hydroxylamine. Then, the Dha moieties were converted to s-allyl cysteine by reaction with allyl mercaptan to produce keratin allyl thioether (KeratATE) biopolymer. Human mesenchymal stem cell (hMSCs) were suspended in the aqueous solution of KeratATE, injected into a mold, and photopolymerized to generate a KeratATE hydrogel encapsulating hMSCs. The freeze-dried photo-cross-linked KeratATE hydrogels had a porous, interconnected, honeycomb microstructure with pore sizes in the 20-60 µm range. The compressive modulus of the hydrogels ranged from 1 to 8 kPa depending on KeratATE concentration. KeratATE hydrogels had <5% mass loss in collagenase solution after 21 days of incubation, whereas the mass loss was 15% in trypsin solution. Degradation of KeratATE hydrogel was strongly dependent on trypsin concentration but independent of collagenase. hMSCs proliferated and adopted an elongated spindle-shape morphology after seeding on KeratATE hydrogel. KeratATE hydrogel supported differentiation of the encapsulated hMSCs to the osteogenic and chondrogenic lineages to the same extent as those hMSCs encapsulated in gelatin methacryloyl hydrogel. The results suggest that keratin allyl thioether hydrogel with controllable degradation is a viable matrix for encapsulation and delivery of stem cells in tissue regeneration.

Purification of high-quality RNA from synthetic polyethylene glycol-based hydrogels.

Polyethylene glycol (PEG)-based hydrogels, with variable stiffness, are widely used in tissue engineering to investigate substrate stiffness effects on cell properties. Transcriptome analysis is a critical method for understanding cell physiology. However, significant RNA degradation was observed during the process of isolating and purifying RNA from cells encapsulated in the PEG hydrogel, thereby precluding purification of high-quality RNA. Here, we describe a simple protocol that prevents RNA degradation and improves the quality and yield of RNA isolated from cells cultured in PEG hydrogels. This modification produces high-quality total RNA suitable for RNA sequencing and microarray analysis.

Effect of organic acids on calcium phosphate nucleation and osteogenic differentiation of human mesenchymal stem cells on peptide functionalized nanofibers.

Carboxylate-rich organic acids play an important role in controlling the growth of apatite crystals and the extent of mineralization in the natural bone. The objective of this work was to investigate the effect of organic acids on calcium phosphate (CaP) nucleation on nanofiber microsheets functionalized with a glutamic acid peptide and osteogenic differentiation of human mesenchymal stem cells (hMSCs) seeded on the CaP-nucleated microsheets. High molecular weight poly(dl-lactide) (DL-PLA) was mixed with low molecular weight L-PLA conjugated with Glu-Glu-Gly-Gly-Cys peptide, and the mixture was electrospun to generate aligned nanofiber microsheets. The nanofiber microsheets were incubated in a modified simulated body fluid (mSBF) supplemented with different organic acids for nucleation and growth of CaP crystals on the nanofibers. Organic acids included citric acid (CA), hydroxycitric acid (HCA), tartaric acid (TART), malic acid (MA), ascorbic acid (AsA), and salicylic acid (SalA). HCA microsheets had the highest CaP content at 240 ± 10% followed by TART and CA with 225 ± 8% and 225 ± 10%, respectively. The Ca/P ratio and percent crystallinity of the nucleated CaP in TART microsheets was closest to that of stoichiometric hydroxyapatite. The extent of CaP nucleation and growth on the nanofiber microsheets depended on the acidic strength and number of hydrogen-bonding hydroxyl groups of the organic acids. Compressive modulus and degradation of the CaP nucleated microsheets were related to percent crystallinity and CaP content. Osteogenic differentiation of hMSCs seeded on the microsheets and cultured in osteogenic medium increased only for those microsheets nucleated with CaP by incubation in CA or AsA-supplemented mSBF. Further, only CA microsheets stimulated bone nodule formation by the seeded hMSCs.

Morphogenic Peptides in Regeneration of Load Bearing Tissues.

Morphogenic proteins due to their short half-life require high doses of growth factors in regeneration of load bearing tissues which leads to undesirable side effects. These side effects include bone overgrowth, tumor formation and immune reaction. An alternative approach to reduce undesirable side effects of proteins in regenerative medicine is to use morphogenic peptides derived from the active domains of morphogenic proteins or soluble and insoluble components of the extracellular matrix of mineralized load bearing tissues to induce differentiation of progenitor cells, mineralization, maturation and bone formation. In that regard, many peptides with osteogenic activity have been discovered. These include peptides derived from bone morphogenic proteins (BMPs), those based on interaction with integrin and heparin-binding receptors, collagen derived peptides, peptides derived from other soluble ECM proteins such as bone sialoprotein and enamel matrix proteins, and those peptides derived from vasculoinductive and neuro-inductive proteins. Although these peptides show significant osteogenic activity in vitro and increase mineralization and bone formation in animal models, they are not widely used in clinical orthopedic applications as an alternative to morphogenic proteins. This is partly due to the limited availability of data on structure and function of morphogenic peptides in physiological medium, particularly in tissue engineered scaffolds. Due to their amphiphilic nature, peptides spontaneously self-assemble and aggregate into micellar structures in physiological medium. Aggregation alters the sequence of amino acids in morphogenic peptides that interact with cell surface receptors thus affecting osteogenic activity of the peptide. Aggregation and micelle formation can dramatically reduce the active concentration of morphogenic peptides with many-fold increase in peptide concentration in physiological medium. Other factors that affect bioactivity are the non-specific interaction of morphogenic peptides with lipid bilayer of the cell membrane, interaction of the peptide with cell surface receptors that do not specifically induce osteogenesis leading to less-than-optimal osteogenic activity of the peptide, and less-than-optimal interaction of the peptide with osteogenic receptors on the cell surface. Covalent attachment or physical interaction with the tissue engineered matrix can also alter the bioactivity of morphogenic peptides and lead to a lower extent of osteogenesis and bone formation. This chapter reviews advances in discovery of morphogenic peptide, their structural characterization, and challenges in using morphogenic peptides in clinical applications as growth factors in tissue engineered devices for regeneration of load bearing tissues.

Gelation characteristics, physico-mechanical properties and degradation kinetics of micellar hydrogels.

Due to their high water content and diffusivity of nutrients and biomolecules, hydrogels are very attractive as a matrix for growth factor immobilization and in situ delivery of cells to the site of regeneration in tissue engineering. The formation of micellar structures at the nanoscale in hydrogels alters the spatial distribution of the reactive groups and affects the rate and extent of crosslinking and mechanical properties of the hydrogel. Further, the degradation rate of a hydrogel is strongly affected by the proximity of water molecules to the hydrolytically degradable segments at the nanoscale. The objective of this review is to summarize the unique properties of micellar hydrogels with a focus on our previous work on star polyethylene glycol (PEG) macromonomers chain extended with short aliphatic hydroxy acid (HA) segments (SPEXA hydrogels). Micellar SPEXA hydrogels have faster gelation rates and higher compressive moduli compared to their non-micellar counterpart. Owing to their micellar structure, SPEXA hydrogels have a wide range of degradation rates from a few days to many months as opposed to non-degradable PEG gels while both gels possess similar water contents. Furthermore, the viability and differentiation of mesenchymal stem cells (MSCs) is enhanced when the cells are encapsulated in degradable micellar SPEXA gels compared with those cells encapsulated in non-micellar PEG gels.

Time Dependence of Material Properties of Polyethylene Glycol Hydrogels Chain Extended with Short Hydroxy Acid Segments.

The objective of this work was to investigate the effect of chemical composition and segment number (n) on gelation, stiffness, and degradation of hydroxy acid-chain-extended star polyethylene glycol acrylate (SPEXA) gels. The hydroxy acids included glycolide (G,), L-lactide (L), p-dioxanone (D) and -caprolactone (C). Chain-extension generated water soluble macromers with faster gelation rates, lower sol fractions, higher compressive moduli, and a wide-ranging degradation times when crosslinked into a hydrogel. SPEGA gels with the highest fraction of inter-molecular crosslinks had the most increase in compressive modulus with n whereas SPELA and SPECA had the lowest increase in modulus. SPEXA gels exhibited a wide range of degradation times from a few days for SPEGA to a few weeks for SPELA, a few months for SPEDA, and many months for SPECA. Marrow stromal cells and endothelial progenitor cells had the highest expression of vasculogenic markers when co-encapsulated in the faster degrading SPELA gel.

A Structure Independent Molecular Fragment Interfuse Model for Mesoscale Dissipative Particle Dynamics Simulation of Peptides.

There is a need to develop robust computational models for mesoscale simulation of the structure of peptides over large length scales toward the discovery of novel peptides for medical applications to address the issues of peptide aggregation, enzymatic degradation, and short half-life. The primary objective was to predict the structure and conformation of peptides whose native structures are not known. This work presents a new model for computation of interaction parameters between the beads in coarse-grained dissipative particle dynamics (DPD) simulation that is properly calibrated for amino acids, supports compressibility requirement of water molecules, and accounts for subtle differences in the structure of amino acids and the charge in the side chain of charged amino acids. This new model is referred to as Structure Independent Molecular Fragment Interfuse Model, abbreviated as SIMFIM, because it accounts for specific interactions between different beads, which represent molecular fragments of the amino acids, in calculating nonbonded interaction parameters in the absence of knowing the actual peptide structure. The electrostatic interactions are incorporated in this model by using a normal distribution of charges around the center of the beads to prevent the collapse of oppositely charged soft beads. The uniquely parameterized DPD force field in the SIMFIM model is optimized for a given peptide with respect to the degree of coarse-grained graining for simulating the peptide over long times and length scales. The SIMFIM model was tested in this work using four peptides, namely, TrpZip2, Rubrivinodin, Lihuanodin, and IC3-CB1/Gai peptides, whose structures were sourced from the Protein Data Bank. The SIMFIM model predicted radius of gyration (Rg) values for the peptides closer to the actual structures as compared to the conventional model, and there was less deviation between the predicted and actual structures of the peptides.

A fresh look at the male-specific region of the human Y chromosome.

The Chromosome-centric Human Proteome Project (C-HPP) aims to systematically map the entire human proteome with the intent to enhance our understanding of human biology at the cellular level. This project attempts simultaneously to establish a sound basis for the development of diagnostic, prognostic, therapeutic, and preventive medical applications. In Iran, current efforts focus on mapping the proteome of the human Y chromosome. The male-specific region of the Y chromosome (MSY) is unique in many aspects and comprises 95% of the chromosome's length. The MSY continually retains its haploid state and is full of repeated sequences. It is responsible for important biological roles such as sex determination and male fertility. Here, we present the most recent update of MSY protein-encoding genes and their association with various traits and diseases including sex determination and reversal, spermatogenesis and male infertility, cancers such as prostate cancers, sex-specific effects on the brain and behavior, and graft-versus-host disease. We also present information available from RNA sequencing, protein-protein interaction, post-translational modification of MSY protein-coding genes and their implications in biological systems. An overview of Human Y chromosome Proteome Project is presented and a systematic approach is suggested to ensure that at least one of each predicted protein-coding gene's major representative proteins will be characterized in the context of its major anatomical sites of expression, its abundance, and its functional relevance in a biological and/or medical context. There are many technical and biological issues that will need to be overcome in order to accomplish the full scale mapping.

Nanostructure formation and transition from surface to bulk degradation in polyethylene glycol gels chain-extended with short hydroxy acid segments.

Degradable, in situ gelling, inert hydrogels with tunable properties are very attractive as a matrix for cell encapsulation and delivery to the site of regeneration. Cell delivery is generally limited by the toxicity of gelation and degradation reactions. The objective of this work was to investigate by simulation and experimental measurement gelation kinetics and degradation rate of star acrylated polyethylene glycol (PEG) macromonomers chain-extended with short hydroxy acid (HA) segments (SPEXA) as a function of HA monomer type and number of HA repeat units. HA monomers included least hydrophobic glycolide (G), lactide (L), p-dioxanone (D), and most hydrophobic ε-caprolactone (C). Chain extension of PEG with short HA segments resulted in micelle formation for all HA types. There was a significant decrease in gelation time of SPEXA precursor solutions with HA chain-extension for all HA types due to micelle formation, consistent with the simulated increase in acrylate-acrylate (Ac-Ac) and Ac-initiator integration numbers. The hydrolysis rate of SPEXA hydrogels was strongly dependent on HA type and number of HA repeat units. SPEXA gels chain-extended with the least hydrophobic glycolide completely degraded within days, lactide within weeks, and p-dioxanone and ε-caprolactone degraded within months. The wide range of degradation rates observed for SPEXA gels can be explained by large differences in equilibrium water content of the micelles for different HA monomer types. A biphasic relationship between HA segment length and gel degradation rate was observed for all HA monomers, which was related to the transition from surface (controlled by HA segment length) to bulk (controlled by micelle equilibrium water content) hydrolysis within the micelle phase. To our knowledge, this is the first report on transition from surface to bulk degradation at the nanoscale in hydrogels.

Mammalian PER2 regulates AKT activation and DNA damage response.

PER2 is a key mammalian circadian clock protein. It also has a tumor suppressive function. Down regulation of PER2 in the cultured cancer cells accelerates cell proliferation, while overexpression of PER2 inhibits cell growth and induces apoptosis. The Per2 mutant mice have a cancer prone phenotype and an altered DNA damage response. Here we report that PER2 regulates AKT activity. Cells with down-regulated PER2 expression have prolonged high levels of AKT T308 phosphorylation after growth factor stimulation or DNA damage. PER2 down-regulation delays DNA damage induced Chk2 activation and overrides DNA damage induced apoptosis and cell cycle arrest.

Combined effect of osteopontin and BMP-2 derived peptides grafted to an adhesive hydrogel on osteogenic and vasculogenic differentiation of marrow stromal cells.

The objective of this work was to investigate the combined effect of grafting the peptide corresponding to amino acid residues 162-168 of osteopontin (OPD peptide) and the peptide corresponding to amino acid residues 73-92 of bone morphogenetic protein-2 (BMP peptide) to an RGD-conjugated inert hydrogel on osteogenic and vasculogenic differentiation of bone marrow stromal (BMS) cells. RGD-conjugated three-dimensional (3D) porous hydrogel scaffolds with well-defined cylindrical pore geometry were produced from sacrificial wax molds fabricated by fused deposition modeling rapid prototyping system. Propargyl acrylate and 4-pentenal were conjugated to the hydrogel for orthogonal grafting of BMP and OPD peptides by click reaction and oxime ligation, respectively. The OPD peptide was grafted by the reaction between aminooxy moiety of aminooxy-mPEG-OPD (mPEG = mini-poly(ethylene glycol)) and the aldehyde moiety in the hydrogel. The BMP peptide was grafted by the reaction between the azide moiety of Az-mPEG-BMP and the propargyl moiety in the hydrogel. The hydrogels seeded with BMS cells were characterized by biochemical, immunocytochemical, and mRNA analyses. Groups included RGD control hydrogel (RGD), RGD and BMP peptides without OPD (RGD+BMP), RGD and BMP peptides with mutant OPD (RGD+BMP+mOPD), and RGD and BMP peptides with OPD (RGD+BMP+OPD) grafted hydrogels. The extent of mineralization of RGD, RGD+BMP, RGD+BMP+mOPD, and RGD+BMP+OPD groups after 28 days was 650 ± 70, 990 ± 30, 850 ± 30, and 1150 ± 40 mg/(mg of DNA), respectively, indicating that the BMP and OPD peptides enhanced osteogenic differentiation of the BMS cells. The BMS cells seeded on RGD+BMP+OPD grafted hydrogels stained positive for vasculogenic markers α-SMA, PECAM-1, and VE-cadherin while the groups without OPD peptide (RGD+BMP and RGD+BMP+mOPD) stained only for α-SMA but not PECAM-1 or VE-cadherin. These results were consistent with the significantly higher PECAM-1 mRNA expression for RGD+BMP+OPD group after 21 and 28 days, compared to the groups without OPD. These findings suggest that the RGD+BMP+OPD peptides provide a favorable microenvironment for concurrent osteogenic and vasculogenic differentiation of progenitor marrow-derived cells.

Gelation characteristics and osteogenic differentiation of stromal cells in inert hydrolytically degradable micellar polyethylene glycol hydrogels.

The use of poly(ethylene glycol) (PEG) hydrogels in tissue engineering is limited by their persistence in the site of regeneration. In an attempt to produce inert hydrolytically degradable PEG-based hydrogels, star (SPELA) poly(ethylene glycol-co-lactide) acrylate macromonomers with short lactide segments (<15 lactides per macromonomer) were synthesized. The SPELA hydrogel was characterized with respect to gelation time, modulus, water content, sol fraction, degradation, and osteogenic differentiation of encapsulated marrow stromal cells (MSCs). The properties of SPELA hydrogel were compared with those of the linear poly(ethylene glycol-co-lactide) acrylate (LPELA). The SPELA hydrogel had higher modulus, lower water content, and lower sol fraction than the LPELA. The shear modulus of SPELA hydrogel was 2.2 times higher than LPELA, whereas the sol fraction of SPELA hydrogel was 5 times lower than LPELA. The degradation of SPELA hydrogel depended strongly on the number of lactide monomers per macromonomer (nL) and showed a biphasic behavior. For example, as nL increased from 0 to 3.4, 6.4, 11.6, and 14.8, mass loss increased from 7 to 37, 80, 100% and then deceased to 87%, respectively, after 6 weeks of incubation. The addition of 3.4 lactides per macromonomer (<10 wt % dry macromonomer or <2 wt % swollen hydrogel) increased mass loss to 50% after 6 weeks. Molecular dynamic simulations demonstrated that the biphasic degradation behavior was related to aggregation and micelle formation of lactide monomers in the macromonomer in aqueous solution. MSCs encapsulated in SPELA hydrogel expressed osteogenic markers Dlx5, Runx2, osteopontin, and osteocalcin and formed a mineralized matrix. The expression of osteogenic markers and extent of mineralization was significantly higher when MSCs were encapsulated in SPELA hydrogel with the addition of bone morphogenetic protein-2 (BMP2). Results demonstrate that hydrolytically degradable PEG-based hydrogels are potentially useful as a delivery matrix for stem cells in regenerative medicine.

Decellularized Articular Cartilage Microgels as Microcarriers for Expansion of Mesenchymal Stem Cells.

Conventional microcarriers used for expansion of human mesenchymal stem cells (hMSCs) require detachment and separation of the cells from the carrier prior to use in clinical applications for regeneration of articular cartilage, and the carrier can cause undesirable phenotypic changes in the expanded cells. This work describes a novel approach to expand hMSCs on biomimetic carriers based on adult or fetal decellularized bovine articular cartilage that supports tissue regeneration without the need to detach the expanded cells from the carrier. In this approach, the fetal or adult bovine articular cartilage was minced, decellularized, freeze-dried, ground, and sieved to produce articular cartilage microgels (CMGs) in a specified size range. Next, the hMSCs were expanded on CMGs in a bioreactor in basal medium to generate hMSC-loaded CMG microgels (CMG-MSCs). Then, the CMG-MSCs were suspended in sodium alginate, injected in a mold, crosslinked with calcium chloride, and incubated in chondrogenic medium as an injectable cellular construct for regeneration of articular cartilage. The expression of chondrogenic markers and compressive moduli of the injectable CMG-MSCs/alginate hydrogels incubated in chondrogenic medium were higher compared to the hMSCs directly encapsulated in alginate hydrogels.

Material Properties and Cell Compatibility of Photo-Crosslinked Sericin Urethane Methacryloyl Hydrogel.

There is a need to develop novel cytocompatible hydrogels for cell encapsulation and delivery in regenerative medicine. The objective of this work was to synthesize isocyanato ethyl methacryloyl-functionalized sericin and determine its material properties as a natural hydrogel for the encapsulation and delivery of human mesenchymal stem cells (MSCs) in regenerative medicine. Sericin extracted from silk cocoons was reacted with 2-isocyanatoethyl methacrylate (IEM) or methacrylic anhydride (MA) to produce sericin urethane methacryloyl (SerAte-UM) or sericin methacryloyl (SerAte-M, control) biopolymers, respectively. The hydrogels produced by photo-crosslinking of the biopolymers in an aqueous solution were characterized with respect to gelation kinetics, microstructure, compressive modulus, water content, degradation, permeability, and viability of encapsulated cells. The secondary structure of citric acid-extracted sericin was not affected by functionalization with IEM or MA. SerAte-UM hydrogel was slightly more hydrophilic than SerAte-M. The gelation time of SerAte-UM hydrogel decreased with an increasing degree of modification. The photo-polymerized SerAte-UM hydrogel had a highly porous, fibrous, honeycomb microstructure with an average pore size in the 40−50 µm range. The compressive modulus, swelling ratio, and permeability of SerAte-UM hydrogel depended on the degree of modification of sericin, and the mass loss after 21 days of incubation in aqueous solution was <25%. Both SerAte-UM and SerAte-M hydrogels supported viability and growth in encapsulated MSCs. The SerAte-UM hydrogel, with its higher hydrophilicity compared to SerAte-M, is promising as a matrix for encapsulation and delivery of stem cells in tissue engineering.

Editorial for Gels 6th Anniversary Special Issue.

This Special Issue celebrates many outstanding quality papers published in Gels over the past six years since its first issue was published in 2015 [...].

Antiviral Polymers: A Review.

Polymers, due to their high molecular weight, tunable architecture, functionality, and buffering effect for endosomal escape, possess unique properties as a carrier or prophylactic agent in preventing pandemic outbreak of new viruses. Polymers are used as a carrier to reduce the minimum required dose, bioavailability, and therapeutic effectiveness of antiviral agents. Polymers are also used as multifunctional nanomaterials to, directly or indirectly, inhibit viral infections. Multifunctional polymers can interact directly with envelope glycoproteins on the viral surface to block fusion and entry of the virus in the host cell. Polymers can indirectly mobilize the immune system by activating macrophages and natural killer cells against the invading virus. This review covers natural and synthetic polymers that possess antiviral activity, their mechanism of action, and the effect of material properties like chemical composition, molecular weight, functional groups, and charge density on antiviral activity. Natural polymers like carrageenan, chitosan, fucoidan, and phosphorothioate oligonucleotides, and synthetic polymers like dendrimers and sialylated polymers are reviewed. This review discusses the steps in the viral replication cycle from binding to cell surface receptors to viral-cell fusion, replication, assembly, and release of the virus from the host cell that antiviral polymers interfere with to block viral infections.

Nanoscale tissue engineering: spatial control over cell-materials interactions.

Cells interact with the surrounding environment by making tens to hundreds of thousands of nanoscale interactions with extracellular signals and features. The goal of nanoscale tissue engineering is to harness these interactions through nanoscale biomaterials engineering in order to study and direct cellular behavior. Here, we review two- and three-dimensional (2- and 3D) nanoscale tissue engineering technologies, and provide a holistic overview of the field. Techniques that can control the average spacing and clustering of cell adhesion ligands are well established and have been highly successful in describing cell adhesion and migration in 2D. Extension of these engineering tools to 3D biomaterials has created many new hydrogel and nanofiber scaffold technologies that are being used to design in vitro experiments with more physiologically relevant conditions. Researchers are beginning to study complex cell functions in 3D. However, there is a need for biomaterials systems that provide fine control over the nanoscale presentation of bioactive ligands in 3D. Additionally, there is a need for 2- and 3D techniques that can control the nanoscale presentation of multiple bioactive ligands and that can control the temporal changes in the cellular microenvironment.

Synthesis and Gelation Characteristics of Photo-Crosslinkable Star Poly(ethylene oxide-co-lactide-glycolide acrylate) Macromonomers.

Viability of encapsulated cells in situ crosslinkable macromonomers depends strongly on the minimum concentration of polymerization initiators and monomers required for gelation. Novel 4-arm poly(ethylene oxide-co-lactide-glycolide acrylate) (SPELGA) macromonomers were synthesized and characterized with respect to gelation, sol fraction, degradation, and swelling in aqueous solution. SPELGA macromonomers were crosslinked in the absence of N-vinyl-2-pyrrolidone (NVP) monomer to produce a hydrogel network with a shear modulus of 27±4 kPa. The shear modulus of the gels increased by 170-fold as the macromonomer concentration was increased from 10 to 25 wt%. Sol fraction ranged between 8-18%. Addition of only 0.4 mol% NVP to the polymerization mixture increased modulus by 2.2-fold from 27±4 (no NVP) to 60±10 kPa. The higher modulus was attributed to the dilution effect of polymer chains in the sol, by delaying the onset of diffusion-controlled reaction, and cross-propagation of the growing chains with network-bound SPELGA acrylates. Degradation of SPELGA gels depended on water content and density of hydrolytically degradable ester groups.

Functionalized carbon-based nanomaterials and quantum dots with antibacterial activity: a review.

INTRODUCTION: Emergence of antibiotic resistance in bacteria is a complicated issue, especially when treating infectious immunodeficiency related diseases. In recent years, when compared to bulk materials, nanomaterials (NMs) with specific antibacterial activities have played a novel role in treating bacterial infections. Among NMs, quantum dots (QDs), specifically carbon containing QDs including graphene oxide QD (GOQD), graphene QD (GQD), and carbon QD (CQD), have demonstrated bacteriostatic and bactericidal activities via photodynamic (PD) effects against antibiotic resistant bacteria under a certain wavelength of light. AREA COVERED: In this mini-review, recent advances and challenges related to antibacterial and biocompatibility activities of modified GQD, GOQD, CQD, and carbon nanotubes (CNTs) are discussed. EXPERT OPINION: Lower stability and biocompatibility of QDs at higher doses in physiological conditions are major disadvantages. In this regard, functionalization of these QDs can result in appropriate bactericidal, biocompatibility, and biodegradability properties. In the case of CNTs including single-wall carbon nanotube (SWCNTs) and multiwall carbon nanotube (MWCNTs), aspect ratio (AR) is a determinant factor for the antibacterial value. Moreover, MWCNTs show a lower antibacterial ability compared to SWCNTs, which can be improved by modifying their surface.