Recent advances of injectable hydrogels for drug delivery and tissue engineering applications

Injectable hydrogel is a kind of in situ gelling system but has its specificity on the process procedure, which requires a better control of gelation kinetics. Hydrogels with injectability under mild condition are preferred in the field of biomedicine, especially for drug delivery and tissue engineering, because of the favorable carrier property in three-dimension, biocompatibility, low invasive and adaptable shape for administration. Despite the advantages, the development of injectable hydrogels may also face some challenges to meet the various clinical requirements. In this review, we provide a brief summary on the recent progresses on the design, synthesis and evaluation of injectable hydrogels towards biomedical applications.     

Microwave-assisted synthesis and click chemistry as simple and efficient strategy for RGD functionalized hydrogels

Click chemistry reactions have recently attracted significant attention for several applications in biomaterials science. In addition microwave irradiation of aqueous solutions containing appropriate combinations of polymers is gaining increasing interests in the synthesis of sterile hydrogels without using monomers, eliminating so the need for removal of unreacted species. The combination of these two approaches promises to be a simple and efficient strategy to produce RGD functionalized hydrogels with a high degree of functionalization and appropriate physico-chemical properties.     

Frontal photopolymerization synthesis of multilayer hydrogels with high mechanical strength

Multilayer hydrogels were prepared by frontal photopolymerization of acrylamide and 2-acrylamido-2-methylpropane sulfonic acid using hydrophilic reactive microgels (HRM) as crosslinkers instead of conventional crosslinkers. The hydrophilic microgels (HM) were prepared by inverse emulsion photopolymerization and then were chemical modified by N-methylolacrylamide (NMA) to obtain HRM with CC double bonds. The HM and HRM was characterized by dynamic light scattering measurements, SEM, TEM and FTIR, respectively. It was found that the resulting multilayer hydrogels showed high fracture strength and high tensile elongation along parallel direction. However their fracture strength and tensile elongation along perpendicular direction was very weak. The swollen multilayer hydrogels were about 1.0–2.0 mm in thickness, the maximal equilibrium swelling degree was only 30.45. The multilayer hydrogels were characterized by DSC, TEM and XRD, respectively. The swelling property and mechanical strength of some typical multilayer hydrogels were studied.     

Rheological properties of cross-linked hyaluronan-gelatin hydrogels for tissue engineering

Hydrogels that mimic the natural extracellular matrix (ECM) are used in three-dimensional cell culture, cell therapy, and tissue engineering. A semi-synthetic ECM based on cross-linked hyaluronana offers experimental control of both composition and gel stiffness. The mechanical properties of the ECM in part determine the ultimate cell phenotype. We now describe a rheological study of synthetic ECM hydrogels with storage shear moduli that span three orders of magnitude, from 11 to 3 500 Pa, a range important for engineering of soft tissues. The concentration of the chemically modified HA and the cross-linking density were the main determinants of gel stiffness. Increase in the ratio of thiol-modified gelatin reduced gel stiffness by diluting the effective concentration of the HA component.     

光盘用2P胶应用研究进展

对光盘用２Ｐ胶的应用研究进展情况进行了评述，其中光盘制备用光聚合浮雕成型２Ｐ胶的基本组成为各类多官能团丙烯酸酯类单体；光盘保护涂层用２Ｐ胶主要组分为环氧丙烯酸酯类预聚体。     

Porous membranes of PLLA-PCL blend for tissue engineering applications

Porous membranes of polycaprolactone-poly(l-lactic acid) blends were prepared by a freeze-extraction process. This procedure was able to disperse homogeneously both components despite their amorphous phases being immiscible (as proven by the fact that the glass transition temperature of PCL in the blend is independent of blend composition) and both polymers crystallize. Thus, the porous membrane consists of amorphous and crystalline phases of both components. DSC and AFM were used to characterize the microstructure of the blends, whereas SEM and gravimetric methods enabled the porosity (around 70%) and pore architecture to be determined. Compression stress-strain experiments show the characteristic behaviour of porous materials with a yield stress that rapidly drops when the PCL content increases - whereas the deformation plateau zone enlarges.     

Personalized hydrogels for individual health care: preparation,features, and applications in tissue engineering

Biomaterials-based tissue engineering scaffolds play an essential role as an independent therapy or with the combination of cellular or biological active constituents in tissue regeneration applications. However, synthetic grafts, xenografts, and allografts are recognized as foreign materials in human body, resulting in suboptimal clinical outcomes. Recently, autologous materials from a patient's body have drawn great attention in clinical treatment and tissue engineering. Moreover, the autologous scaffolds equipped with the advantages of tissue-like hydrogels have great potential to become a highly versatile tool as personalized hydrogels (PHs) for applications in 3D cell culture and tissue engineering. PHs may feature excellent biocompatibility, tailorable mechanical properties, regenerative capability, non-rejection of grafts/transplants on immunological responses, and customizable properties which could be suitable to meet the personal and clinical care. Here, we present a scoping review of recent progress of PHs with a focus on detailed preparation methods, material properties, and tissue engineering applications along with their challenges and opportunities. It is expected that PHs will circumvent the limitations of current tissue engineering therapies and will be used as next-generation scaffolds for tissue engineering and translational research.     

Injectable hydrogels for targeted delivering of therapeutic molecules for tissue engineering and disease treatment

Hydrogels are cross‐linked three‐dimensional polymeric networks that play a vital role in solving the pharmacological and clinical limitations of the existing systems due to their unique physical properties such as affinity for biological fluids, tunable porous nature, high water content, ease of preparation, flexibility, and biocompatibility. Hydrogel also mimics the living natural tissue, which opens several opportunities for its use in biomedical areas. Injectable hydrogel allows temporal control and exceptional spatial arrangements and can offset hitches with established hydrogel‐based drug delivery systems. Here, we review the recent development of injectable hydrogels and their significance in the delivery of therapeutics such as cells, genes, and drug molecules and how these innovatory systems can complement the current delivery systems.     

Combining photo-cleavable and hydrogen-abstracting groups in quinoxaline with thioether bond as hybrid photoinitiator

We synthesized four diphenylquinoxaline derivatives(SQs) with phenyl-thioether units, which combine photo-cleavable and hydrogen-abstracting groups in one molecule. The photochemistry and photopolymerization of SQs were investigated. SQs possess suitable UV-vis absorption in the range of 350-400 nm with high extinction coefficients. UV-vis and HPLC-MS spectra revealed that C–S bond in phenyl-thioether group of SQs can be broken by irradiation of UV-light. Photolysis and photopolymerization experiments showed that SQs can be used as photo-cleavable photointiators,their photoinitiating efficiency can be enhanced by hydrogen donor. As photo-cleavable photoinitiators,SQs could initiate hexamethylene diacrylate(HDDA) very efficiently with the double bond conversion(DBC) of 80%. In the presence of ethyl-4-(dimethylamino) benzoate(EDB) as coinitiator, photoinitiator systems initiated photopolymerization of commercial acrylate monomers with higher double bond conversion than 90%. These characteristics make SQs potential photoinitiators in photo-curing field.     

Biodegradable polymer matrix nanocomposites for tissue engineering: A review

Nanocomposites have emerged in the last two decades as an efficient strategy to upgrade the structural and functional properties of synthetic polymers. Aliphatic polyesters as polylactide (PLA), poly(glycolides) (PGA), poly(?-caprolactone) (PCL) have attracted wide attention for their biodegradability and biocompatibility in the human body. A logic consequence has been the introduction of organic and inorganic nanofillers into biodegradable polymers to produce nanocomposites based on hydroxyapatite, metal nanoparticles or carbon nanotructures, in order to prepare new biomaterials with enhanced properties. Consequently, the improvement of interfacial adhesion between the polymer and the nanostructures has become the key technique in the nanocomposite process. In this review, different results on the fabrication of nanocomposites based on biodegradable polymers for specific field of tissue engineering are presented. The combination of bioresorbable polymers and nanostructures open new perspectives in the self-assembly of nanomaterials for biomedical applications with tuneable mechanical, thermal and electrical properties.     

Surface modification and property analysis of biomedical polymers used for tissue engineering

The response of host organism in macroscopic, cellular and protein levels to biomaterials is, in most cases, closely associated with the materials’ surface properties. In tissue engineering, regenerative medicine and many other biomedical fields, surface engineering of the bio-inert synthetic polymers is often required to introduce bioactive species that can promote cell adhesion, proliferation, viability and enhanced ECM-secretion functions. Up to present, a large number of surface engineering techniques for improving biocompatibility have been well established, the work of which generally contains three main steps: (1) surface modification of the polymeric materials; (2) chemical and physical characterizations; and (3) biocompatibility assessment through cell culture. This review focuses on the principles and practices of surface engineering of biomedical polymers with regards to particular aspects depending on the authors’ research background and opinions. The review starts with an introduction of principles in designing polymeric biomaterial surfaces, followed by introduction of surface modification techniques to improve hydrophilicity, to introduce reactive functional groups and to immobilize functional protein molecules. The chemical and physical characterizations of the modified biomaterials are then discussed with emphasis on several important issues such as surface functional group density, functional layer thickness, protein surface density and bioactivity. Three most commonly used surface composition characterization techniques, i.e. ATR-FTIR, XPS, SIMS, are compared in terms of their penetration depth. Ellipsometry, CD, EPR, SPR and QCM's principles and applications in analyzing surface proteins are introduced. Finally discussed are frequently applied methods and their principles to evaluate biocompatibility of biomaterials via cell culture. In this section, current techniques and their developments to measure cell adhesion, proliferation, morphology, viability, migration and gene expression are reviewed.     

Photo-RAFT Polymerization for Hydrogel Synthesis through Barriers and Development of Light-Regulated Healable Hydrogels under NIR Irradiation

We report an aqueous and near-infrared (NIR) light mediated photoinduced reversible addition–fragmentation chain transfer (photo-RAFT) polymerization system catalyzed by tetrasulfonated zinc phthalocyanine (ZnPcS₄⁻) in the presence of peroxides. Taking advantage of its fast polymerization rates and high oxygen tolerance, this system is successfully applied for the preparation of hydrogels. Exploiting the enhanced penetration of NIR light, photoinduced gelation is effectively performed through non-transparent biological barriers. Notably, the RAFT agents embedded in these hydrogel networks can be reactivated on-demand, enabling the hydrogel healing under NIR light irradiation. In contrast to the minimal healing capability (<15 %) of hydrogels prepared by free radical polymerization (FRP), RAFT-mediated networks display more than 80 % recovery of tensile strength. Although healable polymer networks under UV and blue lights have already been established, this work is the first photochemistry system using NIR light, facilitating photoinduced healing of hydrogels through thick non-transparent barriers.     

Morphology and characterization of 3D micro-porous structured chitosan scaffolds for tissue engineering

This research studies the morphology and characterization of three-dimensional (3D) micro-porous structures produced from biodegradable chitosan for use as scaffolds for cells culture. The chitosan 3D micro-porous structures were produced by a simple liquid hardening method, which includes the processes of foaming by mechanical stirring without any chemical foaming agent added, and hardening by NaOH cross linking. The pore size and porosity were controlled with mechanical stirring strength. This study includes the morphology of chitosan scaffolds, the characterization of mechanical properties, water absorption properties and in vitro enzymatic degradation of the 3D micro-porous structures. The results show that chitosan 3D micro-porous structures were successfully produced. Better formation samples were obtained when chitosan concentration is at 1–3%, and concentration of NaOH is at 5%. Faster stirring rate would produce samples of smaller pore diameter, but when rotation speed reaches 4000 rpm and higher the changes in pore size is minimal. Water absorption would reduce along with the decrease of chitosan scaffolds’ pore diameter. From stress–strain analysis, chitosan scaffolds’ mechanical properties are improved when it has smaller pore diameter. From in vitro enzymatic degradation results, it shows that the disintegration rate of chitosan scaffolds would increase along with the processing time increase, but approaching equilibrium when the disintegration rate reaches about 20%.     

Novel poly(amido-amine)-based hydrogels as scaffolds for tissue engineering

Biodegradable and biocompatible amphoteric poly(amido-amine) (PAA)-based hydrogels, containing carboxyl groups along with amino groups in their repeating unit, were considered as scaffolds for tissue engineering applications. These hydrogels were obtained by co-polymerising 2,2-bisacrylamidoacetic acid with 2-methylpiperazine with or without the addition of different mono-acrylamides as modifiers, and in the presence of primary bis-amines as crosslinking agents. Hybrid PAA/albumin hydrogels were also prepared. The polymerisation reaction was a Michael-type polyaddition carried out in aqueous media. The PAA hydrogels were soft and swellable materials. Cytotoxicity tests were carried out by the direct contact method with fibroblast cell lines on the hydrogels both in their native state (that is, as free bases) and as salts with acids of different strength, namely hydrochloric, sulfuric, acetic and lactic acid. This was done in order to ascertain whether counterion-specific differences in cytotoxicity existed. It was found that all the amphoteric PAA hydrogels considered were cytobiocompatible both as free bases and salts. Selected hydrogels samples underwent degradation tests under controlled conditions simulating biological environments, i.e. Dulbecco medium at pH 7.4 and 37 degrees C. All samples degraded completely and dissolved within 10 d, with the exception of hybrid PAA/albumin hydrogels that did not dissolve even after eight months. The degradation products of all samples turned to be non-cytotoxic. All these results led us to conclude that PAA-based hydrogels have a definite potential as degradable matrices for biomedical applications.     

Resorbable polymer electrospun nanofibers: History,shapes and application for tissue engineering

Resorbable polymer electrospun nanofiber-based materials/devices have high surface-to-volume ratio and often have a porous structure with excellent pore interconnectivity,which are suitable for growth and development of different types of cells.Due to the huge advantages of both resorbable polymers and electrospun nano fibers,re sorbable polymer electrospun nanofibers(RPENs)have been widely applied in the field of tissue engineering.In this paper,we will mainly introduce RPENs for tissue engineering.Firstly,the electrospinning technique and electrospun nanofiber architectures are briefly introduced.Secondly,the application of RPENs in the field of tissue engineering is mainly reviewed.Finally,the advantages and disadvantages of RPENs for tissue engineering are discussed.This review will provide a comprehensive guide to apply resorbable polymer electrospun nanofibers for tissue engineering.     

Modified silicon carbide NPs reinforced nanocomposite hydrogels based on alginate-gelatin by with high mechanical properties for tissue engineering

Hydrogels are encouraging for different clinical purposes because of their high water absorption and mechanical relation to native tissues. Injectable hydrogels can modify the invasiveness of utilization, which decreases recovery and surgical costs. Principal designs applied to create injectable hydrogels incorporate in situ formation owing to chemical or/and physical crosslinking. Here, we report nontoxic, thermosensitive, injectable hydrogels composed of gelatin (GEL) and oxidized alginate (OA) reinforced by silicon carbide nanoparticles (SiC NPs) and crosslinked with N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The mechanical characteristics of the hydrogels were examined via rheological analysis. The outcomes reveal that extending the SiC NPs contents enhances the mechanical properties around five times. The cross-sectional microstructure of the scaffolds comprising 0.25, 1.0, and 1.5% SiC NPs was scrutinized by FESEM, verifying porous structure with interconnected pores. Because of the smaller pore sizes in the hydrogels, the swelling rate has reduced at the higher content of SiC, which diminishes the water uptake. Additionally, the biodegradation study unveils that the hydrogels with SiC are more long-lasting than the hydrogel without SiC. By adding SiC NPs, a decrease is observed in the biodegradation and swelling ratio. The scaffold with a higher SiC NPs content (1.5%) manifested better cell attachment and was less cytotoxic than hydrogel without SiC. OA/GEL composites embedded SiC NPs have manifested excellent physical properties for tissue engineering in comparison with hydrogel without nanoparticles.     

A novel method to prepare microporous and nanofibrous hydrogel scaffolds as neural tissue engineering

A new method to prepare poly (vinyl alcohol) hydrogels by nebulization method.is introduced. A blend of Poly (vinyl alcohol) (PVA), sodium gum malate (SGM) and cellulose nanofibers (CNFs) originated from Catha Edulis was prepared and tested as neural tissue substitutes. Glutaraldehyde (GLA) was used as a crosslinker. Presence of SGM and CNFs in the formulation improved the nebulization process of PVA solution as well as mechanical properties of the fabricated hydrogels. The tensile strength of neat PVA films attains 46.7 MPa, while the tensile strength was 94.23 MPa for crosslinked-PVA. The tensile strength was found to increase with the increase in the CNFs content in the PVA compared with PVA/SGM. These soft tissues were characterized by using FTIR, SEM, and DSC. Scanning electron microscopy (SEM) results showed that PVA/SGM/CNFs blends has a diameter about 50 ± 8µm. The hydrogels were tested also for antimicrobial activities against pathogenic bacteria like Candida albicans (fungus), Bacillus subtilis (G + Ve), Staphylococcus aureus (G + Ve), Proteus vulgaris (G ? Ve) and Erwinia carotovora (G ? Ve). Favorable mechanical, thermal properties and biodegradation nature of the hydrogels, as well as antimicrobial property indicate that prepared hydrogels are suitable for tissue engineering applications.     

光聚合水凝胶及其在组织工程中的应用

水凝胶是一种亲水性聚合物网络,可以溶胀大量水,其物理性质接近软组织.光聚合与传统的聚合方法相比,具有反应速率快、反应条件缓和、反应放热低等特点.因此,光聚合水凝胶广泛应用于生物医学领域.本文介绍了光聚合水凝胶材料,并详细论述了光聚合水凝胶在药物释放体系、组织工程支架材料、细胞受控生长、细胞微囊化和可注射水凝胶等方面的应用.可以预见光聚合水凝胶作为生物材料在组织工程及再生医学领域中具有良好的应用前景.     

Microfluidic fabrication of microengineered hydrogels and their application in tissue engineering

Microfluidic technologies are emerging as an enabling tool for various applications in tissue engineering and cell biology. One emerging use of microfluidic systems is the generation of shape-controlled hydrogels (i.e., microfibers, microparticles, and hydrogel building blocks) for various biological applications. Furthermore, the microfluidic fabrication of cell-laden hydrogels is of great benefit for creating artificial scaffolds. In this paper, we review the current development of microfluidic-based fabrication techniques for the creation of fibers, particles, and cell-laden hydrogels. We also highlight their emerging applications in tissue engineering and regenerative medicine.     

A study on the bioactivity of chitosan/nano-hydroxyapatite composite scaffolds for bone tissue engineering

In order to increase the biocompatibility and bioactivity of chitosan, hydroxyapatite had been in situ combined into chitosan scaffolds. The bioactivity of the composite scaffolds was studied by examining the apatite formed on the scaffolds by incubating in simulated body fluid and the activity of preosteoblasts cultured on them. The apatite layer was assessed using scanning electronic microscope (SEM), X-ray diffraction (XRD), Fourier-Transformed Infrared spectroscopy (FTIR) and weight measurement. Composite analysis showed that after incubation in simulated body fluid on both of the scaffolds carbonate hydroxyapatite was formed. With increasing nano-hydroxyapatite content in the composite, the quantity of the apatite formed on the scaffolds increased. Compared with pure chitosan, the composite with nano-hydroxyapatite could form apatite more readily during the biomimetic process, which suggests that the composite possessed better mineralization activity. Furthermore, preosteoblast cells cultured on the apatite-coated scaffolds showed different behavior. On the apatite-coated composite scaffolds cells presented better proliferation than on apatite-coated chitosan scaffolds. In addition, alkaline phosphatase activities of cells cultured on the scaffolds in conditioned medium were assessed. The cells on composite scaffolds showed a higher alkaline phosphatase activity which suggested a higher differentiation level. The results indicated that the addition of nano-hydroxyapatite improved the bioactivity of chitosan/nano-hydroxyapatite composite scaffolds. On the other hand, that is to say composition of substrates could affect the apatite formation on them, and pre-loaded hydroxyapatite can enhance the apatite-coating. It will also be significant in preparation of apatite-coating polymer scaffolds for bone tissue engineering.