Injectable hydrogels

Hydrogels are promising for a variety of medical applications due to their high water content and mechanical similarity to natural tissues. When made injectable, hydrogels can reduce the invasiveness of application, which in turn reduces surgical and recovery costs. Key schemes used to make hydrogels injectable include in situ formation due to physical and/or chemical cross‐linking. Advances in polymer science have provided new injectable hydrogels for applications in drug delivery and tissue engineering. A number of these injectable hydrogel systems have reached the clinic and impact the health care of many patients. However, a significant remaining challenge is translating the ever‐growing family of injectable hydrogels developed in laboratories around the world to the clinic. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

Oligopeptide‐based supramolecular hydrogels hold promise in a range of applications. The gelation of these systems is hard to control, with minor alterations in the peptide sequence significantly influencing the self‐assembly process. We explored three pentapeptide sequences with different charge distributions and discovered that they formed robust, pH‐responsive hydrogels. By altering the concentration and charge distribution of the peptide sequence, the stiffness of the hydrogels could be tuned across two orders of magnitude (2–200 kPa). Also, through reassembly of the β‐sheet interactions the hydrogels could self‐heal and they demonstrated shear‐thin behavior. Using spectroscopic and cryo‐imaging techniques, we investigated the relationship between peptide sequence and molecular structure, and how these influence the mechanical properties of the hydrogel. These pentapeptide hydrogels with tunable morphology and mechanical properties have promise in tissue engineering, injectable delivery vectors, and 3D printing applications.     

Injectable Supramolecular Hydrogel/Microgel Composites for Therapeutic Delivery

Shear‐thinning hydrogels are useful for biomedical applications, from 3D bioprinting to injectable biomaterials. Although they have the appropriate properties for injection, it may be advantageous to decouple injectability from the controlled release of encapsulated therapeutics. Toward this, composites of hydrogels and encapsulated microgels are introduced with microgels that are fabricated via microfluidics. The microgel cross‐linker controls degradation and entrapped molecule release, and the concentration of microgels alters composite hydrogel rheological properties. For the treatment of myocardial infarction (MI), interleukin‐10 (IL‐10) is encapsulated in microgels and released from composites. In a rat model of MI, composites with IL‐10 reduce macrophage density after 1 week and improve scar thickness, ejection fraction, cardiac output, and the size of vascular structures after 4 weeks when compared to saline injection. Improvements are also observed with the composite without IL‐10 over saline, emphasizing the role of injectable hydrogels alone on tissue repair.     

An Injectable Self‐Healing Hydrogel Based on Chain‐Extended PEO‐PPO‐PEO Multiblock Copolymer

Injectable hydrogels have been commonly used as drug‐delivery vehicles and tried in tissue engineering. Injectable self‐healing hydrogels have great advantage over traditional injectable hydrogels because they can be injected as a liquid and then rapidly form bulk gels in situ at the target site under physiological conditions. This study develops an injectable thermosensitive self‐healing hydrogel based on chain‐extended F127 (PEO₉₀‐PPO₆₅‐PEO₉₀) multi‐block copolymer (m‐F127). The rapid sol–gel transition ability under body temperature allows it to be used as injectable hydrogel and the self‐healing property allows it to withstand repeated deformation and quickly recover its mechanical properties and structure through the dynamic covalent bonds. It is hoped that the novel strategy and the fascinating properties of the hydrogel as presented here will provide new opportunities with regard to the design and practical application of injectable self‐healing hydrogels.

     

Shear‐reversibly Crosslinked Alginate Hydrogels for Tissue Engineering

Injectable delivery vehicles in tissue engineering are often required for successful tissue formation in a minimally invasive manner. Shear‐reversibly crosslinked hydrogels, which can recover gel structures from shear‐induced breakdown, can be useful as an injectable, because gels can flow as a liquid when injected but re‐gel once placed in the body. In this study, injectable and shear‐reversible alginate hydrogels were prepared by combination crosslinking using cell‐crosslinking and ionic crosslinking techniques. The addition of a small quantity of calcium ions decreased the number of cells that were required to form cell‐crosslinked hydrogels without changing the shear reversibility of the system. The physical properties and gelation behavior of the gels were dependent on the concentration of both the cells and the calcium ions. We found that gels crosslinked by combination crosslinking methods were effective to engineer cartilage tissues in vivo. Using both ionic and cell‐crosslinking methods to control the gelation behavior may allow the design of novel injectable systems that can be used to deliver cells and other therapeutics for minimally invasive therapy, including tissue engineering.

     

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.     

Recent Strategies in Fabrication of Gradient Hydrogels for Tissue Engineering Applications

Hydrogels are widely used as scaffold in tissue engineering field because of their ability to mimic the cellular microenvironment. However, mimicking a completely natural cellular environment is complicated due to the differences in various physical and chemical properties of cellular environments. Recently, gradient hydrogels provide excellent heterogeneous environment to mimic the different cellular microenvironments. To create hydrogels with an anisotropic distribution, gradient hydrogels have been widely developed by adopting several gradient generation techniques. Herein, the various gradient hydrogel fabrication techniques, including dual syringe pump systems, microfluidic device, photolithography, diffusion, and bio‐printing are summarized. As the effects of gradient 3D hydrogels with stems have been reviewed elsewhere, this review focuses principally on gradient hydrogel fabrication for multi‐model tissue regeneration. This review provides new insights into the key points for fabrication of gradient hydrogels for multi‐model tissue regeneration.     

Injectable Polysaccharide Hydrogels as Biocompatible Platforms for Localized and Sustained Delivery of Antibiotics for Preventing Local Infections

Biocompatible and antibacterial hydrogels have received increasing attention for preventing local bacterial infections. In this study, a type of polysaccharide hydrogels is prepared via the Schiff‐based reaction at physiological conditions. The gelation time and mechanical property of the hydrogels are found to be dependent on the polysaccharide concentration and the polysaccharide weight ratio. 3‐(4,5‐Dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay and live/dead assay indicate that the hydrogels display nontoxicity in vitro. After subcutaneous injection into rats, the hydrogels exhibit an acceptable biocompatibility in vivo. Furthermore, the bacterial inhibition tests by shaking flask method and agar disc‐diffusion method demonstrate that the ceftriaxone‐sodium‐loaded hydrogels have remarkable antibacterial properties in vitro. The in vivo anti‐infective tests further display that the antibiotic‐loaded hydrogels display excellent anti‐infective efficacies in both superficial and deep tissue infection. Consequently, the injectable and biocompatible polysaccharide hydrogels may serve as promising platforms for localized, sustained delivery of antibiotics for preventing local infections.

     

Self‐Healing Supramolecular Hydrogels for Tissue Engineering Applications

Self‐healing supramolecular hydrogels have emerged as a novel class of biomaterials that combine hydrogels with supramolecular chemistry to develop highly functional biomaterials with advantages including native tissue mimicry, biocompatibility, and injectability. These properties are endowed by the reversibly cross‐linked polymer network of the hydrogel. These hydrogels have great potential for realizing yet to be clinically translated tissue engineering therapies. This review presents methods of self‐healing supramolecular hydrogel formation and their uses in tissue engineering as well as future perspectives.     

Enzymatic Extraction of Bioactive and Self‐Assembling Wool Keratin for Biomedical Applications

Keratin is widely recognized as a high‐quality renewable protein resource for biomedical applications. Despite their extensive existence, keratin resources such as feathers, wool, and hair exhibit high stability and mechanical properties because of their high disulfide bond content. Consequently, keratin extraction is challenging and its application is greatly hindered. In this work, a biological extraction strategy is proposed for the preparation of bioactive keratin and the fabrication of self‐assembled keratin hydrogels (KHs). Based on moderate and controlled hydrolysis by keratinase, keratin with a high molecular weight of approximately 45 and 28 kDa that retain its intrinsic bioactivities is obtained. The keratin products show excellent ability to promote cell growth and migration and are conferred with significant antioxidant ability because of their intrinsically high cysteine content. In addition, without the presence of any cross‐linking agent, the extracted keratin can self‐assemble into injectable hydrogels. The KHs exhibit a porous network structure and 3D culture ability, showing potential in promoting wound healing. This enzyme‐driven keratin extraction strategy opens up a new approach for the preparation of keratin that can self‐assemble into injectable hydrogels for biomedical engineering.     

Bioinspired dual dynamic network hydrogels promote cartilage regeneration through regulating BMSC chondrogenic differentiation

How to improve the therapeutic efficacy of cell delivery during mechanical injection has been a great challenge for tissue engineering. Here, we present a facile strategy based on dynamic chemistry to prepare injectable hydrogels for efficient stem cell delivery using hyaluronic acid (HA) and poly(γ-glutamic acid) (γ-PGA). The combination of the guest–host (GH) complexation and dynamic hydrazone bonds enable the HA/γ-PGA hydrogels with physical and chemical dual dynamic network and endow hydrogels a stable structure, rapid self-healing ability, and injectability. The mechanical properties, self-healing ability, and adaptability can be programmed by changing the ratio of GH network to hydrazine bond cross-linked network. Benefitting from the dynamic cross-linking networks, mild preparation process, and cytocompatibility of HA/γ-PGA hydrogels, bone marrow mesenchymal stem cells (BMSCs) show high cell viability in this system following mechanical injection. Moreover, HA/γ-PGA hydrogels can promote BMSC proliferation and upregulate the expression of cartilage-critical genes. Notably, in a rabbit auricular cartilage defect model, BMSC-laden HA/γ-PGA hydrogels can effectively promote cartilage regeneration. Together, we propose a general strategy to develop injectable self-healing HA/γ-PGA hydrogels for effective stem cell delivery in cartilage tissue engineering.     

Applications of Gelatin Methacryloyl (GelMA) Hydrogels in Microfluidic Technique-Assisted Tissue Engineering

In recent years, the microfluidic technique has been widely used in the field of tissue engineering. Possessing the advantages of large-scale integration and flexible manipulation, microfluidic devices may serve as the production line of building blocks and the microenvironment simulator in tissue engineering. Additionally, in microfluidic technique-assisted tissue engineering, various biomaterials are desired to fabricate the tissue mimicking or repairing structures (i.e., particles, fibers, and scaffolds). Among the materials, gelatin methacrylate (GelMA)-based hydrogels have shown great potential due to their biocompatibility and mechanical tenability. In this work, applications of GelMA hydrogels in microfluidic technique-assisted tissue engineering are reviewed mainly from two viewpoints: Serving as raw materials for microfluidic fabrication of building blocks in tissue engineering and the simulation units in microfluidic chip-based microenvironment-mimicking devices. In addition, challenges and outlooks of the exploration of GelMA hydrogels in tissue engineering applications are proposed.     

Injectable Biodegradable Hydrogels

Injectable biodegradable copolymer hydrogels, which exhibit a sol–gel phase transition in response to external stimuli, such as temperature changes or both pH and temperature (pH/temperature) alterations, have found a number of uses in biomedical and pharmaceutical applications, such as drug delivery, cell growth, and tissue engineering. These hydrogels can be used in simple pharmaceutical formulations that can be prepared by mixing the hydrogel with drugs, proteins, or cells. Such formulations are administered in a straightforward manner, through site‐specific control of release behavior, and the hydrogels are compatible with biological systems. This review will provide a summary of recent progress in biodegradable temperature‐sensitive polymers including polyesters, polyphosphazenes, polypeptides, and chitosan, and pH/temperature‐sensitive polymers such as sulfamethazine‐, poly(β‐amino ester)‐, poly(amino urethane)‐, and poly(amidoamine)‐based polymers. The advantages of pH/temperature‐sensitive polymers over simple temperature‐sensitive polymers are also discussed. A perspective on the future of injectable biodegradable hydrogels is offered.

     

Injectable Hyaluronic Acid/Poly(γ-glutamic acid) Hydrogel with Step-by-step Tunable Properties for Soft Tissue Engineering

Injectable hydrogels as an important class of biomaterials have gained much attention in tissue engineering. However, their crosslinking degree is difficult to be controlled after being injected into body. As we all know, the crosslinking degree strongly influences the physicochemical properties of hydrogels. Therefore, developing an injectable hydrogel with tunable crosslinking degree in vivo is important for tissue engineering. Herein, we present a dual crosslinking strategy to prepare injectable hydrogels with step-by-step tunable crosslinking degree using Schiff base reaction and photopolymerization. The developed hyaluronic acid/poly(γ-glutamic acid)(HA/γ-PGA) hydrogels exhibit step-bystep tunable swelling behavior, enzymatic degradation behavior and mechanical properties. Mechanical performance tests show that the storage moduli of HA/γ-PGA hydrogels are all less than 2000 Pa and the compressive moduli are in kilopascal, which have a good match with soft tissue. In addition, NIH 3 T3 cells encapsulated in HA/γ-PGA hydrogel exhibit a high cell viability, indicating a good cytocompatibility of HA/γ-PGA hydrogel.Therefore, the developed HA/γ-PGA hydrogel as an injectable biomaterial has a good potential in soft tissue engineering.     

Synthesis and Characterization of PEG‐Based Drug‐Responsive Biohybrid Hydrogels

Interactive materials being responsive to a biocompatible stimulus represent a promising approach for future therapeutic applications. In this study, we present a novel biohybrid material synthesized from biocompatible components being stimulus‐responsive to the pharmaceutically approved small‐molecule novobiocin. The hydrogel design is based on the gyrase B (GyrB) protein, which is covalently grafted to multi‐arm polyethylene glycol (PEG) using a Michael‐type addition reaction. Upon addition of the GyrB‐dimerizing substance coumermycin, stable hydrogels form which can be dissolved in a dose‐adjustable manner by the antibiotic novobiocin. The switchable properties of this PEG‐based hydrogel are favorable for future applications in tissue engineering and as externally controlled drug depot.     

基于动态共价键的自愈性水凝胶及其在医学领域的应用

自愈性水凝胶作为一种新型仿生智能材料受到了科研人员的广泛关注.近年来,人们利用动态共价键、超分子作用,发展了一系列自愈性水凝胶,并将其应用于药物控释、细胞三维培养、组织工程等生物医用领域.本文总结和评述了基于动态共价键的自愈性水凝胶及这些水凝胶作为药物载体的相关研究,并展望了基于动态化学的自愈性水凝胶的未来发展.     

Non‐Anticoagulant Heparin Prodrug Loaded Biodegradable and Injectable Thermoresponsive Hydrogels for Enhanced Anti‐Metastasis Therapy

Metastasis is a pathogenic spread of cancer cells from the primary site to surrounding tissues and distant organs, making it one of the primary challenges for effective cancer treatment and the major cause of cancer mortality. Heparin‐based biomaterials exhibit significant inhibition of cancer cell metastasis. In this study, a non‐anticoagulate heparin prodrug is developed for metastasis treatment with a localized treatment system using temperature sensitive, injectable, and biodegradable (poly‐(ε‐caprolactone‐co‐lactide)‐b‐poly(ethylene glycol)‐b‐poly(ε‐caprolactone‐co‐lactide) polymeric hydrogel. The drug molecule (heparin) is conjugated with the polymer via esterification, and its sustained release is ensured by hydrolysis and polymeric biodegradation. An aqueous solution of the polymer could be used as an injectable solution at below 25 °C and it achieves gel formation at 37 °C. The anti‐metastasis effect of the hydrogels is investigated both in vitro and in vivo. The results demonstrated that local administration of injectable heparin‐loaded hydrogels effectively promote an inhibitory effect on cancer metastasis.     

Oxidized Xanthan Gum Crosslinked NOCC: Hydrogel System and Their Biological Stability from Oxidation Levels of the Polymer

Dynamic hydrogel systems from N,O-carboxymethyl chitosan (NOCC) are investigated in the past years, which has facilitated their widespread use in many biomedical engineering applications. However, the influence of the polymer's oxidation levels on the hydrogel biological properties is not fully investigated. In this study, chitosan is converted into NOCC and introduced to react spontaneously with oxidized xanthan gum (OXG) to form several injectable hydrogels with controlled degradability. Different oxidation levels of xanthan gum, as well as NOCC/OXG volume ratios, are trialed. The infrared spectroscopy spectra verify chemical modification on OXG and successful crosslinking. With increasing oxidation levels, more dialdehyde groups are introduced into the OXG, resulting in changes in physical properties including gelation, swelling, and self-healing efficiency. Under different volume ratios, the hydrogel shows a stable structure and rigidity with higher mechanical properties, and a slower degradation rate. The shear-thinning and self-healing properties of the hydrogels are confirmed. In vitro assays with L929 cells show the biocompatibility of all formulations although the use of a high amount of OXG15 and OXG25 limited the cell proliferation capacity. Findings in this study suggested a suitable amount of OXG at different oxidation levels in NOCC hydrogel systems for tissue engineering applications.     

Visible Light Cross‐Linking of Gelatin Hydrogels Offers an Enhanced Cell Microenvironment with Improved Light Penetration Depth

In this study, the cyto‐compatibility and cellular functionality of cell‐laden gelatin‐methacryloyl (Gel‐MA) hydrogels fabricated using a set of photo‐initiators which absorb in 400–450 nm of the visible light range are investigated. Gel‐MA hydrogels cross‐linked using ruthenium (Ru) and sodium persulfate (SPS), are characterized to have comparable physico‐mechanical properties as Gel‐MA gels photo‐polymerized using more conventionally adopted photo‐initiators, such as 1‐[4‐(2‐hydroxyethoxy)‐phenyl]‐2‐hydroxy‐2‐methyl‐1‐propan‐1‐one (Irgacure 2959) and lithium phenyl(2,4,6‐trimethylbenzoyl) phosphinate (LAP). It is demonstrated that the Ru/SPS system has a less adverse effect on the viability and metabolic activity of human articular chondrocytes encapsulated in Gel‐MA hydrogels for up to 35 days. Furthermore, cell‐laden constructs cross‐linked using the Ru/SPS system have significantly higher glycosaminoglycan content and re‐differentiation capacity as compared to cells encapsulated using I2959 and LAP. Moreover, the Ru/SPS system offers significantly greater light penetration depth as compared to the I2959 system, allowing thick (10 mm) Gel‐MA hydrogels to be fabricated with homogenous cross‐linking density throughout the construct. These results demonstrate the considerable advantages of the Ru/SPS system over traditional UV polymerizing systems in terms of clinical relevance and practicability for applications such as cell encapsulation, biofabrication, and in situ cross‐linking of injectable hydrogels.     

Amphiphilic Metallopolymers for Photoswitchable Supramolecular Hydrogels

A series of amphiphilic metallopolymers is described that features zinc(II) bis‐terpyridine coordination nodes as well as a backbone with hydrophobic azoaryl moieties and hydrophilic phenylene‐ethynylene units decorated with PEG brushes. Using such metallopolymers at very low concentration, stable, photo‐responsive and self‐healing hydrogels are obtained. UV irradiation of the gel allows modulation of the degree of hydrophobic π‐π interactions between photoisomerizable azoaryl units and a polarity switch that overall induces a fast gel‐to‐sol transition. Finally, the material phase can be readily and fully restored to the thermodynamically stable state either thermally or photochemically by using visible light. The presented strategy can be further generalized towards modular supramolecular metallopolymers for injectable gels in drug delivery and bio‐engineering applications.