可注射水凝胶在组织工程中应用进展

组织工程采用可注射原位形成水凝胶,与预成型支架相比具有特定的优势：能填充任意形状的缺损,并在很大程度上降低植入对机体组织的侵入性,且能与各种治疗药物混合。本文介绍了可注射凝胶形成过程及几种水凝胶系统．并以实例说明可注射水凝胶在组织工程中的应用。     

Recent advances in shear-thinning and self-healing hydrogels for biomedical applications

Shear-thinning and self-healing hydrogels are being investigated in various biomedical applications including drug delivery, tissue engineering, and 3D bioprinting. Such hydrogels are formed through dynamic and reversible interactions between polymers or polypeptides that allow these shear-thinning and self-healing properties, including physical associations (e.g., hydrogen bonds, guest–host interactions, biorecognition motifs, hydrophobicity, electrostatics, and metal–ligand coordination) and dynamic covalent chemistry (e.g., Schiff base, oxime chemistry, disulfide bonds, and reversible Diels–Alder). Their shear-thinning properties allow for injectability, as the hydrogel exhibits viscous flow under shear, and their self-healing nature allows for stabilization when shear is removed. Hydrogels can be formulated as uniform polymer and polypeptide assemblies, as hydrogel nanocomposites, or in granular hydrogel form. This review focuses on recent advances in shear-thinning and self-healing hydrogels that are promising for biomedical applications. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48668.     

导电水凝胶的制备及应用研究进展

导电水凝胶是一类将亲水性基质和导电介质有机结合的新型水凝胶,具有较高的柔韧性、可调的力学性能和优异的电化学性能,在柔性电子设备等领域具有广阔的应用前景。本文综述了导电水凝胶材料的研究前沿和动态,介绍了导电水凝胶的分类及制备方法,讨论了导电水凝胶的结构设计与性能,重点阐述了导电水凝胶材料的应用研究进展,归纳了导电水凝胶材料面临的问题与挑战,并展望了导电水凝胶材料的发展趋势,指出采用天然可再生资源为原料开发具有高导电性、力学性能稳定、耐极端温度、生物相容性和生物可降解的导电水凝胶将成为下一步研究重点,同时优化柔性电子装置、提高器件输出稳定性也将成为重要的研究方向之一。导电水凝胶的制备及应用研究将促进柔性电子功能材料领域的快速发展。     

Irreversible and Self-Healing Electrically Conductive Hydrogels Made of Bio-Based Polymers

Electrically conductive materials that are fabricated based on natural polymers have seen significant interest in numerous applications, especially when advanced properties such as self-healing are introduced. In this article review, the hydrogels that are based on natural polymers containing electrically conductive medium were covered, while both irreversible and reversible cross-links are presented. Among the conductive media, a special focus was put on conductive polymers, such as polyaniline, polypyrrole, polyacetylene, and polythiophenes, which can be potentially synthesized from renewable resources. Preparation methods of the conductive irreversible hydrogels that are based on these conductive polymers were reported observing their electrical conductivity values by Siemens per centimeter (S/cm). Additionally, the self-healing systems that were already applied or applicable in electrically conductive hydrogels that are based on natural polymers were presented and classified based on non-covalent or covalent cross-links. The real-time healing, mechanical stability, and electrically conductive values were highlighted.     

Biodegradable polymers exhibiting temperature-responsive sol–gel transition as injectable biomedical materials

Injectable biodegradable copolymer hydrogels, which exhibit temperature-responsive sol-to-gel transition, have recently drawn much attention as promising biomedical materials such as drug delivery, cell implantation, and tissue engineering. These injectable hydrogels can be implanted in the human body with minimal surgical invasion. Temperature-responsive gelling copolymers usually possess block- and/or branched architectures and amphiphilicity with a delicate hydrophobic/hydrophilic balance. Poly(ethylene glycol) (PEG) has typically been used as hydrophilic segments due to its biocompatibility and temperature-dependent dehydration nature. Aliphatic polyesters such as polylactide, poly(lactide-co-glycolide), poly(ε-caprolactone), and their modified copolymers have been used as hydrophobic segments based on their biodegradability and biocompatibility. Copolymers of PEG with other hydrophobic polymers such as polypeptides, polydepsipeptides have also been recently reported as injectable hydrogels. In this review, brief history and recent advances in injectable biodegradable polymer hydrogels are summarized especially focusing on the relationship between polymer architecture and their gelation properties. Moreover, the applications of these injectable polymer gels for biomedical use such as drug delivery and tissue engineering are also described.     

Intrinsically Conductive Polymers for Striated Cardiac Muscle Repair

One of the most important features of striated cardiac muscle is the excitability that turns on the excitation-contraction coupling cycle, resulting in the heart blood pumping function. The function of the heart pump may be impaired by events such as myocardial infarction, the consequence of coronary artery thrombosis due to blood clots or plaques. This results in the death of billions of cardiomyocytes, the formation of scar tissue, and consequently impaired contractility. A whole heart transplant remains the gold standard so far and the current pharmacological approaches tend to stop further myocardium deterioration, but this is not a long-term solution. Electrically conductive, scaffold-based cardiac tissue engineering provides a promising solution to repair the injured myocardium. The non-conductive component of the scaffold provides a biocompatible microenvironment to the cultured cells while the conductive component improves intercellular coupling as well as electrical signal propagation through the scar tissue when implanted at the infarcted site. The in vivo electrical coupling of the cells leads to a better regeneration of the infarcted myocardium, reducing arrhythmias, QRS/QT intervals, and scar size and promoting cardiac cell maturation. This review presents the emerging applications of intrinsically conductive polymers in cardiac tissue engineering to repair post-ischemic myocardial insult.     

Preparation of ‘click’ hydrogels from polyaspartamide derivatives

Lately, copper‐assisted azide–alkyne cycloaddition (CuAAC) has become a very interesting tool for synthesizing biocompatible polymer‐based materials such as hydrogels or microgels, which can be used as biomaterials for tissue engineering and drug delivery. Novel poly(2‐hydroxyethyl aspartamide)s (PHEAs) functionalized with pendent acetylene or azide groups were prepared from polysuccinimide, which is the thermal polycondensation product of aspartic acid, through successful ring‐opening reactions using propargylamine, 1‐azido‐2‐aminoethane and ethanolamine. The composition of the prepared copolymers was analyzed using ¹H NMR spectroscopy. Clickable PHEA derivatives were crosslinked by mixing together in water with a catalyst system of Cu(I) and N, N, N′, N′, N″‐pentamethyldiethylenetriamine, a type of Huisgen's 1,3‐dipolar azide‐alkyne cycloaddition. The reaction of the polymers resulted in a chemoselective coupling between alkynyl and azido functional groups with multiple formation of triazole crosslinks to give hydrogels. The triazole linkages in the hydrogels are highly stable and may also play a role in swelling behavior. PHEA‐based hydrogels were also obtained by the crosslinking of azide‐ or alkyne‐modified PHEA with a small‐molecule crosslinker. The hydrogels prepared using these two methods were characterized by their degree of swelling and the morphology of the hydrogels was confirmed using scanning electron microscopy. The approach we describe here presents a promising alternative to common chemical hydrogel preparation techniques, and these hydrogels seem to possess structures having potential for a variety of industrial and biomedical applications. © 2012 Society of Chemical Industry     

Advanced Hydrogels as Exosome Delivery Systems for Osteogenic Differentiation of MSCs: Application in Bone Regeneration

Hydrogels are known as water-swollen networks formed from naturally derived or synthetic polymers. They have a high potential for medical applications and play a crucial role in tissue repair and remodeling. MSC-derived exosomes are considered to be new entities for cell-free treatment in different human diseases. Recent progress in cell-free bone tissue engineering via combining exosomes obtained from human mesenchymal stem cells (MSCs) with hydrogel scaffolds has resulted in improvement of the methodologies in bone tissue engineering. Our research has been actively focused on application of biotechnological methods for improving osteogenesis and bone healing. The following text presents a concise review of the methodologies of fabrication and preparation of hydrogels that includes the exosome loading properties of hydrogels for bone regenerative applications.     

Injectable Human Hair Keratin–Fibrinogen Hydrogels for Engineering 3D Microenvironments to Accelerate Oral Tissue Regeneration

Traumatic injury of the oral cavity is atypical and often accompanied by uncontrolled bleeding and inflammation. Injectable hydrogels have been considered to be promising candidates for the treatment of oral injuries because of their simple formulation, minimally invasive application technique, and site-specific delivery. Fibrinogen-based hydrogels have been widely explored as effective materials for wound healing in tissue engineering due to their uniqueness. Recently, an injectable foam has taken the spotlight. However, the fibrin component of this biomaterial is relatively stiff. To address these challenges, we created keratin-conjugated fibrinogen (KRT-FIB). This study aimed to develop a novel keratin biomaterial and assess cell–biomaterial interactions. Consequently, a novel injectable KRT-FIB hydrogel was optimized through rheological measurements, and its injection performance, swelling behavior, and surface morphology were investigated. We observed an excellent cell viability, proliferation, and migration/cell–cell interaction, indicating that the novel KRT-FIB-injectable hydrogel is a promising platform for oral tissue regeneration with a high clinical applicability.     

An Injectable Enzymatically Crosslinked and Mechanically Tunable Silk Fibroin/Chondroitin Sulfate Chondro-Inductive Hydrogel

An injectable hybrid hydrogel is synthesized, comprising silk fibroin (SF) and chondroitin sulfate (CS) through di-tyrosine formation bond of SF chains. CS and SF are reported with excellent biocompatibility as tissue engineering scaffolds. Nonetheless, the rapid degradation rate of pure CS scaffolds presents a challenge to effectively recreate articular cartilage. As CS is one of the cartilage extracellular matrix (ECM) components, it has the potential to enhance the biological activity of SF-based hydrogel in terms of cartilage repair. Therefore, altering the CS concentrations (i.e., 0 wt%, 0.25 wt%, 0.5 wt%, 1 wt%, and 2 wt%), which are interpenetrated between SF β-sheets and chains, can potentially adjust the physical, chemical, and mechanical features of these hybrid hydrogels. The formation of β-sheets by 30 days of immersion in de-ionized (DI) water can improve the compression strength of the SF/CS hybrid hydrogels in comparison with the same SF/CS hybrid hydrogels in the dried state. Biological investigation and observation depicts proper cell attachment, proliferation and cell viability for C28/I2 cells. Gene expression of sex-determining region YBox 9 (SOX9), Collagen II α1, and Aggrecan (AGG) exhibits positive C3H10T1/2 growth and expression of cartilage-specific genes in the 0.25 wt% and 0.5 wt% SF/CS hydrogels.     

Insight into hydrogels

The development and introduction of injectable biomaterials and the identification of methods through which materials may form in situ are currently the topics of interest in materials science, specifically in the field of biomaterials. Over the last few decades, hydrogels which refers to the swellable polymeric matrices have gained wide attention due to their excellent characteristics such as swelling in different media, pH and temperature sensitivity, and sensitivity to other stimuli. Nowadays, injectable hydrogels have widely been studied due to their excellent insitu gelation at body temperature. These injectable insitu gels serve as depot system which ensures the local and systemic drug and gene delivery. These insitu gels also protect the proteins and peptide drugs invivo from environmental effect. The current review is made to report latest extensive literature regarding hydrogels, their classification, synthesis methods, structure of hydrogel network, methods of crosslinking, environment-sensitive hydrogel system, drug loading, and release, hydrogels as biosensors and applications of hydrogels.     

Cryogel‐Based Electronic–Tissue Interfaces with Soft,Highly Compressible,and Tunable Mechanics

Electrically conductive materials with soft, tough, and tunable mechanics have utility in a wide range of applications including neuroprosthetics. Such materials can serve as interfaces between electrical components and tissues, providing mechanical matches with and better conformations to soft, irregularly shaped surfaces. Hydrogels can potentially provide these attributes while remaining hydrated for long periods of time—providing a long‐term and stable electronic–tissue interface. Additionally, in applications that demand implantation, hydrogels can be formulated to locally deliver enhancing therapeutics. Here, hydrogels are developed by entrapping a conducting polymer within a crosslinked poly(acrylic acid) (pAAc) network. Critically, these hydrogels are cast under freezing conditions which produces cryogels that exhibit macroporous, soft, and highly tunable mechanics (0.2–20 kPa, by varying pAAc and crosslinker concentrations). Additionally, these cryogels are tough enough to survive over 90% compression, which enables survival after being passed through 16‐gauge needles. Cryogels also exhibit electrical conductivities that are sufficient to record alpha waves from the scalp of human subjects. Growth of fibroblasts cultures in the presence of these cryogels produce statistically similar viabilities compared to controls and do not disrupt fibroblast cell cycles. Finally, cryogels are capable of being loaded with and delivering proteins that can potentially combat inflammation.     

Hydroxyapatite-Integrated,Heparin- and Glycerol-Functionalized Chitosan-Based Injectable Hydrogels with Improved Mechanical and Proangiogenic Performance

The investigation of natural bioactive injectable composites to induce angiogenesis during bone regeneration has been a part of recent minimally invasive regenerative medicine strategies. Our previous study involved the development of in situ-forming injectable composite hydrogels (Chitosan/Hydroxyapatite/Heparin) for bone regeneration. These hydrogels offered facile rheology, injectability, and gelation at 37 °C, as well as promising pro-angiogenic abilities. In the current study, these hydrogels were modified using glycerol as an additive and a pre-sterile production strategy to enhance their mechanical strength. These modifications allowed a further pH increment during neutralisation with maintained solution homogeneity. The synergetic effect of the pH increment and further hydrogen bonding due to the added glycerol improved the strength of the hydrogels substantially. SEM analyses showed highly cross-linked hydrogels (from high-pH solutions) with a hierarchical interlocking pore morphology. Hydrogel solutions showed more elastic flow properties and incipient gelation times decreased to just 2 to 3 min at 37 °C. Toluidine blue assay and SEM analyses showed that heparin formed a coating at the top layer of the hydrogels which contributed anionic bioactive surface features. The chick chorioallantoic membrane (CAM) assay confirmed significant enhancement of angiogenesis with chitosan-matrixed hydrogels comprising hydroxyapatite and small quantities of heparin (33 µg/mL) compared to basic chitosan hydrogels.     

Injectable and thermosensitive poly(organophosphazene) hydrogels for a 5‐fluorouracil delivery

The drug solubility and its release profiles of an anticancer drug from an injectable thermosensitive poly(organophosphazene) hydrogel bearing hydrophobic L ‐isoleucine ethyl ester and hydrophilic α‐amino‐ω‐methoxy‐poly(ethylene glycol) with and without hydrolysis‐sensitive glycyl lactate ethyl ester or functional glycyl glycine have been investigated. 5‐Fluorouracil (5‐FU) was used as a model anticancer drug. The aqueous solutions of 5‐FU incorporated poly(organophosphazenes) were an injectable fluid state at room temperature and formed a transparent gel at body temperature. The poly(organophosphazene) solution could enhance the solubility of 5‐FU and its solubility (34.26 mg/mL) was increased up to 10‐fold compared to that in phosphate‐buffered saline (3.39 mg/mL, pH 7.4, 4°C). The in vitro drug release profiles from poly(organophosphazene) hydrogels were established in phosphate‐buffered saline at pH 7.4 at 37°C and the release of 5‐FU was significantly affected by the diffusion‐controlled stage. The results suggest that the injectable and thermosensitive poly(organophosphazene) hydrogel is a potential carrier for 5‐FU to increase its solubility, control a relatively sustained and localized release at target sites and thus decrease systemic side effects. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Stretchable,Antifreezing, Non-Drying,and Fast-Response Sensors Based on Cellulose Nanocomposite Hydrogels for Signal Detection

Conductive hydrogels have received widespread attention in the applications of biosensors, human–machine interface, and health recording electrodes. Herein, the conductive hydrogels integrated with antifreezing, water retention, reusable, and sensing performances are fabricated by introducing polyvinyl alcohol, cellulose nanofibril, MXene nanosheets, and glycerol. The as-prepared hydrogels present prominent electrical conductivity (2.58 mS cm⁻¹) and flexibility even at −18 °C. In addition, the hydrogels have favorable water retention performance and can reuse after heating and cooling. When used as sensors, the hydrogels illustrate high sensitivity (gauge factor of 2.30), fast response time (0.165 s), wide working strain range (559%), favorable linearity (R² = 0.999), and wide operating temperature range (−18 to 60 °C). The hydrogels can detect not only large strains of 10–200%, but also small strains of 1–5%, making them promising candidates for wearable sensors to monitor large and subtle movements.     

Tunable Engineering of Heparinized Injectable Hydrogels for Affinity‐Based Sustained Delivery of Bioactive Factors

Here, the design of an in situ‐forming injectable hydrogel is reported based on pH‐ and temperature‐responsive copolymers finely engineered with heparin for the sustained delivery of bioactive factors. In order to develop such heparinized injectable hydrogels, pH‐ and temperature‐responsive copolymers based on poly(ethylene glycol) and poly(urethane sulfamethazine) (PEG‐PUSSM) are synthesized and acrylated, and subsequently coupled with thiolated heparin through Michael‐addition reaction. The content of heparin in the bioconjugates (Hep‐PUSSM) is finely tuned to control the release of heparin‐binding bioactive factors. The free‐flowing bioconjugate sols at room temperature transform to stable viscoelastic gel in physiological conditions, indicating that heparin modification does not affect the sol–gel transition. The subcutaneous administration of bioconjugate sols to the dorsal‐region of Sprague‐Dawley rats forms a hydrogel depot and shows controlled degradation. The bioconjugates effectively bind with bioactive factors (VEGF) through simple mixing, and the release is controlled over a period of 4 weeks without an initial burst. As a result, the implantation of VEGF‐loaded bioconjugate gel induces angiogenesis throughout the hydrogel network. The tunable engineering of the injectable hydrogel by heparinization with independent controllable physical properties sustains the release of bioactive factors, indicating that it may be a promising platform for the delivery of bioactive factors.     

Chitosan‐based hydrogels: recent design concepts to tailor properties and functions

Chitosan (CS) has received much attention as a functional biopolymer for designing various hydrogels for biomedical applications. This review provides an overview of the different types of CS‐based hydrogels, the approaches that can be used to fabricate hydrogel matrices with specific features and their applications in controlled drug delivery and tissue engineering. Emphasis is laid on the recent design concepts of hybrid hydrogels based on mixtures of CS and natural or synthetic polymers, interpenetrating polymer networks as well as composite hydrogels prepared by embedding nanoparticles into CS matrices. © 2017 Society of Chemical Industry     

An innovative approach to fabricate a thermosensitive melatonin-loaded conductive pluronic/chitosan hydrogel for myocardial tissue engineering

This study aimed at designing and fabrication of a novel injectable and thermosensitive melatonin-loaded pluronic/chitosan hydrogel containing gold nanoparticles (GNPs) and poly glycerol sebacate (PGS) for myocardial tissue engineering. The PGS nanoparticles were used as the melatonin (drug model) carrier. The gelation time, syringeability, stability, and swelling of the hydrogel were scrutinized. Rheological properties, chemical composition, and morphology of the samples were also investigated. The effect of GNPs addition on the electrical conductivity of hydrogel was assessed. The cytotoxicity of hydrogels was assessed through MTT assay in the exposure of H9C2 cells up to 7 days. Scanning electron microscopy was applied to evaluate the morphology of seeded cells. The synthesis parameters of PGS nanoparticles were optimized through which 2.5%w/v of PGS and 1:10 organic phase to aqueous phase (O/A) ratio were found desirable. The optimum hydrogel illustrated 2 min gelation time and was stable up to 20 days with 5% swelling in the first 12 h into phosphate buffered saline. The GNPs with a uniform distribution rendered the hydrogel electrically conductive (1500 μS/cm). According to the MTT assay results, 3.125 μM melatonin was considered as the suitable concentration by which a significant increase in the cell viability was observed. The results exhibited that the prepared hydrogel composed of pluronic/chitosan/GNPs, and 3.125 μM melatonin-loaded PGS nanoparticles could be applied as a promising scaffold for myocardial tissue engineering.     

Recent advances on injectable nanocomposite hydrogels towards bone tissue rehabilitation

There has been significant interest in the recent past to develop injectable hydrogel scaffolds that follow minimally invasive implantation procedures towards efficient healing and regeneration of defective bone tissues. Such scaffolds offer several advantages, as they can be injected into the irregularly shaped defect and can act as a low-density aqueous reservoir, incorporating necessary components for bone tissue repair and augmentation. Considering that bone is a biocomposite of natural biopolymer and bioapatite nanofiller, there has been a growing trend to develop nanocomposite scaffolds by combining biopolymers and inorganic nanofillers to biomimic the hierarchical nanostructure and composition of natural bone. Furthermore, the nanocomposite scaffolds can be tailored to have patient-specific bone properties, which can lead to better biological responses. The present article begins with the introduction, followed by an overview of polymer matrices, property requirements, and crosslinking techniques employed for injectable hydrogels. Various strategies to develop injectable composites, with emphasis on nanocomposite hydrogels incorporating bioinert and bioactive nanofillers have been discussed. The fundamental challenges related to the development of injectable hydrogel nanocomposite scaffolds and the research efforts directed towards solving these problems have also been reviewed. Finally, future trends and conclusions on new generation injectable hydrogel nanocomposite bone scaffolds have been discussed in this article.     

Highly Stretchable,Fast Self‐Healing,Responsive Conductive Hydrogels for Supercapacitor Electrode and Motion Sensor

Conductive hydrogels as potential soft materials have attracted tremendous attention in wearable electronic devices. Nonetheless, manufacturing intelligent materials that integrate mouldability, stretchability, responsive ability, fast self‐healing ability, as well as mechanical and electrochemical properties is still a challenge. Here, multifunctional conductive hydrogels composed of poly(vinyl alcohol) (PVA) and polypyrrole (PPy) nanotube are prepared using borax as cross‐linker. The existence of multicomplexation, entangled PVA chains, and interconnected PPy nanotubes, as well as extensive hydrogen bonding results in the fabrication of hierarchical network of PVA‐PPy hydrogels. PVA‐PPy hydrogels exhibit high stretchability (more than 1000%), multiresponsiveness, low density (0.95 g cm^?3), high water content (96%), and 15 s self‐healing features. Furthermore, the self‐healing supercapacitor electrode and motion sensor based on PVA‐PPy hydrogels demonstrate ideal performances. This facile strategy in this work would be promising to construct an excellent multifunctional soft material for various flexible electrode and biosensor.