Tunable Crosslinked Cell‐Derived Extracellular Matrix Guides Cell Fate

Extracellular matrix (ECM), comprised of multiple cues (chemical, physiomechanical), provides a niche for cell attachment, migration, and differentiation. Given that different cells give rise to distinct physiological milieus, the role of such microenvironmental cues on various cells has been well‐studied. Particularly, the effect of various physiomechanical factors on stem cell lineage has been resolved into individual variables via ECM protein‐coated polymeric systems. Such platforms, while providing a reductionist approach as a means to remove any confounding factors, unfortunately fall short of capturing the full biophysical scope of the natural microenvironment. Herein, the use of a cell‐derived ECM platform is reported in which its crosslinking density is tunable; varying concentrations (0, 0.5, 1, 2% w/v) of genipin (GN), a naturally derived crosslinker with low toxicity, are used to form inter‐ and intrafibril crosslinks. ECM crosslinking produces GN concentration‐dependent changes in ECM stiffness (<0.1–9.4 kPa), roughness (96–280 nm), and chemical composition (100–60% amine content). The effect of the various crosslinked ECM profiles on human mesenchymal stem cell differentiation, vascular morphogenesis, and cardiomyogenesis are then evaluated. Taken together, this study demonstrates that tunable crosslinked cell‐derived ECM platform is capable of providing a comprehensive physiological platform, and envisions its use in future tissue engineering applications.

     

Ile‐Lys‐Val‐ala‐Val (IKVAV) peptide for neuronal tissue engineering

Despite the great advances in microsurgery, some neural injuries cannot be treated surgically. Stem cell therapy is a potential approach for treating neuroinjuries and neurodegenerative disease. Researchers have developed various bioactive scaffolds for tissue engineering, exhibiting enhanced cell viability, attachment, migration, neurite elongation, and neuronal differentiation, with the aim of developing functional tissue grafts that can be incorporated in vivo. Facilitating the appropriate interactions between the cells and extracellular matrix is crucial in scaffold design. Modification of scaffolds with biofunctional motifs such as growth factors, drugs, or peptides can improve this interaction. In this review, we focus on the laminin‐derived Ile‐Lys‐Val‐Ala‐Val peptide as a biofunctional epitope for neuronal tissue engineering. Inclusion of this bioactive peptide within a scaffold is known to enhance cell adhesion as well as neuronal differentiation in both 2‐dimensional and 3‐dimensional environments. The in vivo application of this peptide is also briefly described.     

来源于天然产物的基质金属蛋白酶(MMPs)抑制剂

基质金属蛋白酶（MMPs）参与一系列重大疾病的病理过程,基质金属蛋白酶抑制剂具有广阔的药用前景。本文概述了基质金属蛋白酶抑制剂的研究历史和最新的研究理念。重点回顾总结了天然产物中基质金属蛋白酶的活性抑制成分和对基质金属蛋白酶转录表达抑制的天然产物成分以及这些化合物的抗癌效果。     

Dual Enzyme‐Triggered In Situ Crosslinkable Gelatin Hydrogels for Artificial Cellular Microenvironments

Horseradish peroxidase (HRP) and hydrogen peroxide (H₂O₂)‐mediated crosslinking reaction has become an attractive method to create in situ forming hydrogels. While the crosslinking system has been widely utilized, there are certain issues require improvement to extend their biomedical applications, including creation of stiff hydrogels without compromising cytocompatibility due to initially high concentrations of H₂O₂. A gelatin‐based hydrogels formed through a dual enzyme‐mediated crosslinking reaction using HRP and glucose oxidase (GOx) as an H₂O₂‐generating enzyme to gradually supply a radical source in HRP‐mediated crosslinking reaction is reported. The physicochemical properties can be controlled by varying enzyme concentrations. Furthermore the hydrogel matrices provide 3D microenvironments for supporting the growth and spreading of human dermal fibroblasts with minimized cytotoxicity, despite the cells being encapsulated within stiff hydrogels. These hydrogels formed with HRP/GOx have great potential as artificial microenvironments for a wide range of biomedical applications.

     

Bioorthogonal Turn‐On Probe Based on Aggregation‐Induced Emission Characteristics for Cancer Cell Imaging and Ablation

Bioorthogonal turn‐on probes have been widely utilized in visualizing various biological processes. Most of the currently available bioorthogonal turn‐on probes are blue or green emissive fluorophores with azide or tetrazine as functional groups. Herein, we present an alternative strategy of designing bioorthogonal turn‐on probes based on red‐emissive fluorogens with aggregation‐induced emission characteristics (AIEgens). The probe is water soluble and non‐fluorescent due to the dissipation of energy through free molecular motion of the AIEgen, but the fluorescence is immediately turned on upon click reaction with azide‐functionalized glycans on cancer cell surface. The fluorescence turn‐on is ascribed to the restriction of molecular motion of AIEgen, which populates the radiative decay channel. Moreover, the AIEgen can generate reactive oxygen species (ROS) upon visible light (λ=400–700 nm) irradiation, demonstrating its dual role as an imaging and phototherapeutic agent.     

Visible Laser‐Induced In Situ Cell Detachment from Gold Nanoparticle‐Embedded Collagen Gel

Cell sorting is important for cell biology and regenerative medicine. A visible light‐responsive cell scaffold is produced using gold nanoparticles and collagen gel. Various kinds of cells are cultured on the visible light‐responsive cell scaffold, and the target cells are selectively detached by photoirradiation without any cytotoxicity. This is a new image‐guided cell sorting system.

     

New Strategy for Controlling Biodegradability of Biodegradable Polyesters by Enzyme‐Catalyzed Surface Grafting

A novel preparation method for the core‐shell type biodegradable polyesters or biodegradable materials grafted with biodegradable polyesters was developed by alkaline surface treatment of biodegradable polyester films and subsequent enzymatic polymerization of aliphatic lactones, one example of which is shown in this study, i.e., the preparation of poly(L ‐lactide) (PLLA) film grafted with poly(ε‐caprolactone). It is revealed that only alkaline surface treatment or the combination of alkaline surface treatment and enzyme‐catalyzed grafting, the former and the latter, respectively accelerating and delaying the enzymatic degradation of PLLA, will give PLLA materials having a wide variety of biodegradability. Also, the specificity of the enzyme used for hydrolysis could be used to confirm the grafted chain species.

     

Mass transfer from theophylline hydrogels of a‐PVA/H2O and a‐PVA/NaCl/H2O system on heating

Theophylline hydrogels of atactic‐poly(vinyl alcohol) (a‐PVA)/H₂O and a‐PVA/NaCl/H₂O systems were prepared followed by cyclic freezing (?30°C for 16 hr)–thawing (at room temperature for 8 hr) and one cycle gelation (at ?20°C for 24 hr) processes, respectively. In order to prepare xerogels (dried hydrogels) of these hydogel systems, an apparently first‐order mass transfer phenomenon of water as evaporation was observed for a‐PVA/H₂O hydrogel system, while heating at 60°C. The rate of evaporation decreased with increasing time in hyperbolic fashion. The total surface area (both lateral and two end surfaces of hydrogel matrix disc) decreased linearly for the first 90 min and thereafter had a tendency towards the steady‐state. The total mass flux showed time dependent linear reduction phenomenon, which is a characteristic physical behavior for these hydrogel systems on heat treatment. When NaCl was included in a‐PVA/H₂O system mass transfer of water followed fourth‐order polynomial. But in consideration of a comparative study, sustained mass transfer was found from the hydrogel matrices of a‐PVA/H₂O/NaCl system (gelation at ?20°C). Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of Folic Acid Functionalized PLLA‐b‐PPEGMA Nanoparticles for Cancer Cell Targeting

Poly(L ‐lactic acid)‐block‐poly(poly(ethylene glycol) monomethacrylate) (PLLA‐b‐PPEGMA) has been prepared by the ring‐opening polymerization of lactide with a double‐headed initiator, 2‐hydroxyethyl 2′‐methyl‐2′‐bromopropionate (HMBP), followed by atom transfer radical polymerization (ATRP) of poly(ethylene glycol) monomethacrylate (PEGMA). PLLA‐b‐PPEGMA nanoparticles with encapsulated Fe₃O₄ are prepared by a solvent evaporation/extraction technique, and then further functionalized with folic acid, a cancer targeting ligand. Our results show that such functionalized PLLA‐b‐PPEGMA nanoparticles have good potential as carriers for targeted drug delivery in cancer treatment.

     

Cross‐Linking and Degradation Properties of Plasma Enhanced Chemical Vapor Deposited Poly(2‐hydroxyethyl methacrylate)

Plasma Enhanced Chemical Vapor Deposition (PECVD) of poly‐2‐hydroxyethyl methacrylate (pHEMA) biocompatible, biodegradable polymer films were produced alone and cross‐linked with ethylene glycol diacrylate (EGDA). Degree of cross‐linking was controlled via manipulation of the EGDA flow rate, which influenced the amount of swelling and the extent of degradation of the films in an aqueous solution over time. Noncross‐linked pHEMA films swelled 10% more than cross‐linked films after 24 h of incubation in an aqueous environment. Increasing degree of film cross‐linking decreased degradation over time. Thus, PECVD pHEMA films with variable cross‐linking properties enable tuning of gel formation and degradation properties, making these films useful in a variety of biologically significant applications.

     

Hyaluronan/Collagen Hydrogels with Sulfated Hyaluronan for Improved Repair of Vascularized Tissue Tune the Binding of Proteins and Promote Endothelial Cell Growth

Innovative biomaterial‐based concepts are required to improve wound healing of damaged vascularized tissues especially in elderly multimorbid patients. To develop functional hydrogels as 3D cellular microenvironments and as carrier or scavenging systems, e.g., for mediator proteins or proinflammatory factors, collagen fibrils are embedded into a network of photo‐crosslinked acrylated hyaluronan (HA), chondroitin sulfate (CS), or sulfated HA (sHA). After lyophilization, the gels show a porous structure and an improved stability against degradation via hyaluronidase. Gels with CS and sHA bind significantly more lysozyme than HA/collagen gels and retard its release. The proliferation and metabolic activity of endothelial cells are significantly increased on sHA gels compared to CS‐ or only HA‐containing hydrogels. These findings highlight the potential of HA/collagen hydrogels with sulfated glycosaminoglycans to tune the protein binding and release behavior and to directly modulate cellular response. This can be easily translated into biomimetic biomaterials with defined properties to stimulate wound healing.     

Robust and Semi‐Interpenetrating Hydrogels from Poly(ethylene glycol) and Collagen for Elastomeric Tissue Scaffolds

Here we present an injectable PEG/collagen hydrogel system with robust networks for use as elastomeric tissue scaffolds. Covalently crosslinked PEG and physically crosslinked collagen form semi‐interpenetrating networks. The mechanical strength of the hydrogels depends predominantely on the PEG concentration but the incorporation of collagen into the PEG network enhances hydrogel viscoelasticity, elongation, and also cell adhesion properties. Experimental data show that this hydrogel system exhibits tunable mechanical properties that can be further developed. The hydrogels allow cell adhesion and proliferation in vitro. The results support the prospect of a robust and semi‐interpenetrating biomaterial for elastomeric tissue scaffolds applications.

     

Enhanced Visible‐Light‐Induced Photoelectrocatalytic Degradation of Methyl Orange by CdS Sensitized TiO2 Nanotube Arrays Electrode

In this work, CdS sensitized TiO₂ nanotube arrays (CdS/TiO₂NTs) electrode was synthesized with the CdS deposition on the highly ordered titanium dioxide nanotube arrays (TiO₂NTs) by sequential chemical bath deposition method (S‐CBD). The as‐prepared CdS/TiO₂NTs was characterized by field‐emission scanning electron microscopy (FE‐SEM) and X‐ray diffraction (XRD). The results indicated that the CdS nanoparticles were effectively deposited on the surface of TiO₂NTs. The amperometric I‐t curve on the CdS/TiO₂NTs electrode was also presented. It was found that the photocurrent density was enhanced significantly from 0.5 to 1.85 mA/cm² upon illumination with applied potential of 0.5 V at the central wavelength of 253.7 nm. The photoelectrocatalytic (PEC) activity of the CdS/TiO₂NTs electrode was investigated by degradation of methyl orange (MO) in aqueous solution. Compared with TiO₂NTs electrode, the degradation efficiencies of CdS/TiO₂NTs electrode increased from 78% to 99.2% under UV light in 2 h, and from 14% to 99.2% under visible light in 3 h, which was caused by effective separation of the electrons and holes due to the effect of CdS, hence inhibiting the recombination of electron/hole pairs of TiO₂NTs.     

Synergistic Effects of Beta Tri‐Calcium Phosphate and Porcine‐Derived Decellularized Bone Extracellular Matrix in 3D‐Printed Polycaprolactone Scaffold on Bone Regeneration

Bone‐derived extracellular matrix (ECM) is widely used in studies on bone regeneration because of its ability to provide a microenvironment of native bone tissue. However, a hydrogel, which is a main type of ECM application, is limited to use for bone graft substitutes due to relative lack of mechanical properties. The present study aims to fabricate a scaffold for guiding effective bone regeneration. A polycaprolactone (PCL)/beta‐tricalcium phosphate (β‐TCP)/bone decellularized extracellular matrix (dECM) scaffold capable of providing physical and physiological environment are fabricated using 3D printing technology and decoration method. PCL/β‐TCP/bone dECM scaffolds exhibit excellent cell seeding efficiency, proliferation, and early and late osteogenic differentiation capacity in vitro. In addition, outstanding results of bone regeneration are observed in PCL/β‐TCP/bone dECM scaffold group in the rabbit calvarial defect model in vivo. These results indicate that PCL/β‐TCP/bone dECM scaffolds have an outstanding potential as bone graft substitutes for effective bone regeneration.