PVA-based hydrogels for tissue engineering: A review

Poly (vinyl alcohol) (PVA) is a hydrophilic polymer with excellent biocompatibility and has been applied in various biomedical areas due to its favorable properties. PVA-based hydrogels have been recognized as promising biomaterials and suitable candidates for tissue engineering applications and can be manipulated to act various critical roles. However, due to some disadvantages (i.e., lack of cell-adhesive property), they needs further modification for desired and targeted applications. This review highlights recent progress in the design and fabrication of PVA-based hydrogels, including crosslinking and processing techniques. Finally, major challenges and future perspectives in tissue engineering are briefly discussed.     

The synthesis,mechanisms, and additives for bio-compatible polyvinyl alcohol hydrogels: A review on current advances,trends, and future outlook

Vinyl polymers are widely used in biological, textile and industrial applications and are currently attracting research attention for specialized bio-based applications. Polyvinyl alcohol (PVA) hydrogels show great advantages as a material with high biocompatibility, permeability, hydrophilicity, and low-friction coefficient, allowing applications as smart materials, wound dressings, and flexible sensors. However, the poor mechanical properties of PVA hydrogels and biocompatibility less than natural polymers make them unsuitable in practical applications. Additives are often added to PVA hydrogels to enhance mechanical properties, endow more compatibility, functionality and expand their application range. Among them, bio-additives such as nanocellulose, natural polysaccharides and proteins are biodegradable, biocompatible, and inexpensive, broadening their applications in the biomedical and tissue engineering fields. This work reviews the synthesis of PVA hydrogels, methods to enhance their mechanical properties, types of bio-additives incorporated for biocompatibility, their mechanism of interaction with PVA and future prospects of PVA composite bio-hydrogels for application in various fields. Representative cases are carefully selected and discussed with regard to their composition and pros and cons are discussed. Finally, future requirements, as well as the opportunities and challenges of these bio-additives for improving the multifunctionality of PVA hydrogels are also presented.     

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.     

The Role of Permeability and Related Properties in the Design of Synthetic Hydrogels for Biomedical Applications

Synthetic hydrogels are a versatile range of materials which are of value in several biomedical applications, particularly those where permeability is important. Because the equilibrium water content of the gel governs permeability processes and has a marked influence on other important properties, the permeability requirements of a material often influence other aspects of its behaviour. The design of hydrogels for contact lenses demands an understanding of these interrelationships and thus provides a valuable basis for extending hydrogel design to other applications.     

ATRP in the design of functional materials for biomedical applications

Atom Transfer Radical Polymerization (ATRP) is an effective technique for the design and preparation of multifunctional, nanostructured materials for a variety of applications in biology and medicine. ATRP enables precise control over macromolecular structure, order, and functionality, which are important considerations for emerging biomedical designs. This article reviews recent advances in the preparation of polymer-based nanomaterials using ATRP, including polymer bioconjugates, block copolymer-based drug delivery systems, cross-linked microgels/nanogels, diagnostic and imaging platforms, tissue engineering hydrogels, and degradable polymers. It is envisioned that precise engineering at the molecular level will translate to tailored macroscopic physical properties, thus enabling control of the key elements for realized biomedical applications.     

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.     

Fabrication and Properties of Gelatin/Chitosan Composite Hydrogel

Gelatin/chitosan hydrogels were prepared by using glutaraldehyde as crosslinker. The porous structure was confirmed by scanning electron microscope (SEM). Swelling ratios of the hydrogels with various ratio of gelatin to chitosan and crosslinker reagent dosage were studied in phosphate-buffered saline (PBS). In addition, in-vitro cytotoxicity was assessed via MTT assay with fibroblastic cell cultured in hydrogel extractions. It was found that by increasing glutaraldehyde dosage and chitosan content, the swelling ratio of the hydrogels decreased in buffer solutions. The MTT test showed that the gelatin/chitosan hydrogel clearly presented adequate cell viability, non-toxicity, and suitable properties. Therefore, these developed blends, based on gelatin and chitosan has broadened the number of choices of biomaterials to be potentially used in biomedical applications such as biomaterial, drug delivery vehicles and skin tissue engineering.     

疏水改性温敏水凝胶的合成及应用研究进展

N-异丙基丙烯酰胺（NIPAM）类水凝胶是典型的温敏水凝胶,通常含有亲水性酰胺基和疏水性异丙基,具有随温度变化而发生可逆溶胀/收缩的特殊性质,作为一种新型的智能材料得到广泛的应用。本文主要论述了NIPAM类疏水改性温敏水凝胶的合成,在骨架中引入疏水单体可以改善其疏水特性,同时提高其温度敏感性,使其在药物释放、物质分离及生物医用材料等领域具有独特的应用价值。目前对疏水改性温敏水凝胶的理论研究尚浅,仍需拓展其在实际方面的应用,今后可考虑改善疏水单体的官能团结构提高疏水性能,合成更具温度响应性和环境友好性的智能温敏水凝胶,拓展其在催化、水处理、生物化工等领域的广泛应用。     

Super-tough hydrogels using ionically crosslinked networks

Alginate and polyacrylamide hydrogels were produced by a facile one-pot method with varied ionic crosslinkers in this article. These hydrogels display outstanding mechanical properties compared to the pristine polyacrylamide (PAAm) hydrogels. The alginate network is ionically crosslinked by multivalent cation, whereas N,N′-methylenebis (acrylamide) (MBAA) is used as covalent crosslinker for the PAAm network. Particularly, the obtained hydrogels by using trivalent cations (Fe³⁺ and Al³⁺) as crosslinkers are much stronger than that of using divalent cations (Ca²⁺ and Ba²⁺) as crosslinkers. In addition, with increasing concentration of cations, the compressive properties of gels are improved, whereas when the concentration is higher than 0.3 M, the compressive properties of gels are damaged due to mono-bindings. Interestingly, the hydrogels with higher chemical crosslinker concentration depicts better mechanical properties than those hydrogels with lower chemical crosslinker, which is different from that of common double network hydrogels. These hydrogels with excellent mechanical properties are promising candidates for biomedical application like load-bearing tissues. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 48182.     

Synthesis and Evaluation of AlgNa-g-Poly(QCL-co-HEMA) Hydrogels as Platform for Chondrocyte Proliferation and Controlled Release of Betamethasone

Hydrogels obtained from combining different polymers are an interesting strategy for developing controlled release system platforms and tissue engineering scaffolds. In this study, the applicability of sodium alginate-g-(QCL-co-HEMA) hydrogels for these biomedical applications was evaluated. Hydrogels were synthesized by free-radical polymerization using a different concentration of the components. The hydrogels were characterized by Fourier transform-infrared spectroscopy, scanning electron microscopy, and a swelling degree. Betamethasone release as well as the in vitro cytocompatibility with chondrocytes and fibroblast cells were also evaluated. Scanning electron microscopy confirmed the porous surface morphology of the hydrogels in all cases. The swelling percent was determined at a different pH and was observed to be pH-sensitive. The controlled release behavior of betamethasone from the matrices was investigated in PBS media (pH = 7.4) and the drug was released in a controlled manner for up to 8 h. Human chondrocytes and fibroblasts were cultured on the hydrogels. The MTS assay showed that almost all hydrogels are cytocompatibles and an increase of proliferation in both cell types after one week of incubation was observed by the Live/Dead^® assay. These results demonstrate that these hydrogels are attractive materials for pharmaceutical and biomedical applications due to their characteristics, their release kinetics, and biocompatibility.     

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     

La3+ modified poly(γ-glutamic acid) hydrogels with high strength and anti-swelling property for cartilage regeneration

The applications of synthetic hydrogels in cartilage regeneration are usually limited by their weak mechanical properties, uncontrolled swelling/degradation, and insufficient osteogenic activity. Developing tough hydrogels have been attracting great attention in biomedical engineering. In this study, a high strength and tough poly(γ-glutamic acid) (γ-PGA) hydrogels with excellent anti-swelling property were developed by immersing as-prepared γ-PGA hydrogels in LaCl₃ aqueous solution. Results revealed that the concentration of LaCl₃ aqueous solution has great influence on the mechanical properties of γ-PGA hydrogels. The tensile strength of γ-PGA hydrogels improved from 0.12 ± 0.02 MPa to 14.65 ± 0.48 MPa when LaCl₃ concentration was 0.15 M. Moreover, the swelling ratio decreased from 1035.75 ± 33.16% to 18.21 ± 3.08%. The morphology and microstructure of La³⁺ reinforced γ-PGA hydrogels were characterized by SEM/EDS, FT-IR and XPS. Furthermore, in vitro cytocompatibility of La³⁺ reinforced γ-PGA hydrogels was evaluated via MC3T3-E1 cells. Finally, this study provides a facile and effective strategy for modifying the mechanical and swelling properties of γ-PGA-based hydrogels, which offers great potential applications in cartilage repair and regeneration.     

Injectable self-healing nanocellulose hydrogels crosslinked by aluminum: Cellulose nanocrystals vs. cellulose nanofibrils

With excellent biocompatibility and unique physiochemical properties, nanocelluloses including cellulose nanocrystals (CNCs) and cellulose nanofibrils (CNFs) are promising candidates for preparing biomedical hydrogels. CNCs and CNFs are different in morphology and surface charges. Herein, CNCs and two CNFs (CNFs-C, Carboxylated CNFs; CNFs-P, Phosphorylated CNFs) were synthesized and applied to fabricate hydrogels through metal crosslinking. Aluminum crosslinking was found to be the best choice for enhancing the strength. This study systematically compared the morphologies, storage modulus, loss factor, continuous shear ramp, self-healing, swelling, in vitro degradation and injectable properties of the fabricated hydrogels. Further, a radar chart is summarized as guidelines to direct the rational selection to meet the specific requirements of further biomedical applications. At the same nanocellulose concentration and after Al³⁺ crosslinking, CNCs hydrogels had strong water holding capacity twice as much as that of CNFs hydrogels. While CNFs hydrogels showed higher hardness and stronger resistance to degradation than that of CNCs. These results provide detailed insights into nanocellulose hydrogels, making it possible to use these guidelines to select hydrogels for desired performance.     

Calcium phosphate and calcium carbonate mineralization of bioinspired hydrogels based on β-chitin isolated from biomineral of the common cuttlefish (<Emphasis Type="Italic">Sepia officinalis</Emphasis>, L.)

Chitin, a bioactive, antibacterial and biodegradable polymer is commonly utilized by diverse marine organisms as the main scaffold material during biomineralization. Due to its properties, chitin is also of interest as a component of organo-inorganic composites for diverse biomedical applications. In this study, chitinous fibers isolated from the cuttlebone of the common cuttlefish (Sepia officinalis, L.) are characterized and evaluated for use as an integral part of mineralized hydrogels for biomedical applications. Since marine organisms use calcium carbonates (CaCO₃), while vertebrates use calcium phosphates (CaP) as the main inorganic hard tissue components, and both minerals are used in hard tissue engineering, they were compared to determine which composite is potentially a better biomaterial. Hydrogel mineralization was conducted by subsequent dipping into cationic and anionic reactant solutions, resulting in the formation of a CaCO₃ or CaP coating that penetrated into the hydrogel. Obtained composites were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), scanning electron microscopy (SEM), rheology, swelling tests and simple compression. The results indicate that β-chitin can be used for the preparation of moldable hydrogels that are easily mineralized. Mineralized hydrogels have higher elasticity than non-mineralized ones while swelling is better if the extent of mineralization is lower. Further optimization of the hydrogels composition could improve their stress response and Young’s modulus, where the current hydrogel with a higher extent of CaP mineralization excels in comparison to all other investigated composites.     

生物医用高强度水凝胶的研究进展

水凝胶是一种高含水量的三维网状聚合物,广泛应用于各个领域,但力学性能较差的特点限制了其在生物医用领域的应用。因此,如何提高水凝胶的力学强度成为国内外专家学者研究的重点。本文主要介绍了几种新型高强度水凝胶的合成及研究进展,包括滑动水凝胶、双网络水凝胶、复合水凝胶以及其它水凝胶,详细分析了影响这些水凝胶力学性能的因素。指出研制具有生物相容性、可生物降解、可注射、可负载活性因子并且具备良好的力学性能水凝胶是今后的研究方向。     

组织工程用海藻酸盐水凝胶的研究进展

海藻酸钠已经被广泛应用于生物医学领域。本文从组织工程角度出发,综述了海藻酸盐水凝胶的形成机理、制备方法以及应用研究进展。     

Chemical structure and remarkably enhanced mechanical properties of chitosan-graft-poly(acrylic acid)/polyacrylamide double-network hydrogels

The novel double-network (DN) hydrogels were prepared using the chitosan-g-poly(acrylic acid) as the first network, and polyacrylamide as the second. The effects of the concentrations of the second network on chemical structure, intermolecular interactions and mechanical properties for the DN gels were investigated. The DN hydrogels had decreased swelling capacities and significantly improved glassy modulus and strength with the increase of the acrylamide concentration, owing to the enhanced intermolecular interaction and physical entanglement, and reduced molecular motion. It is worth noting that DN hydrogels with 5.50 mol/L acrylamide content had the greatest mechanical strength and still relatively high water content (~82 wt%), resulting from the effectiveness of the intermolecular penetration and intermolecular interactions between two independent polymer networks. Therefore, the reported novel chitosan-based DN hydrogels exhibit good potentials in some applications, for example biomedical engineering applications.     

Dehydropeptide Supramolecular Hydrogels and Nanostructures as Potential Peptidomimetic Biomedical Materials

Supramolecular peptide hydrogels are gaining increased attention, owing to their potential in a variety of biomedical applications. Their physical properties are similar to those of the extracellular matrix (ECM), which is key to their applications in the cell culture of specialized cells, tissue engineering, skin regeneration, and wound healing. The structure of these hydrogels usually consists of a di- or tripeptide capped on the N-terminus with a hydrophobic aromatic group, such as Fmoc or naphthalene. Although these peptide conjugates can offer advantages over other types of gelators such as cross-linked polymers, they usually possess the limitation of being particularly sensitive to proteolysis by endogenous proteases. One of the strategies reported that can overcome this barrier is to use a peptidomimetic strategy, in which natural amino acids are switched for non-proteinogenic analogues, such as D-amino acids, β-amino acids, or dehydroamino acids. Such peptides usually possess much greater resistance to enzymatic hydrolysis. Peptides containing dehydroamino acids, i.e., dehydropeptides, are particularly interesting, as the presence of the double bond also introduces a conformational restraint to the peptide backbone, resulting in (often predictable) changes to the secondary structure of the peptide. This review focuses on peptide hydrogels and related nanostructures, where α,β-didehydro-α-amino acids have been successfully incorporated into the structure of peptide hydrogelators, and the resulting properties are discussed in terms of their potential biomedical applications. Where appropriate, their properties are compared with those of the corresponding peptide hydrogelator composed of canonical amino acids. In a wider context, we consider the presence of dehydroamino acids in natural compounds and medicinally important compounds as well as their limitations, and we consider some of the synthetic strategies for obtaining dehydropeptides. Finally, we consider the future direction for this research area.     

Synthesis of dual physical self-healing starch-based hydrogels for repairing tissue defects

Hydrogels have the potential to simulate and permeate body tissues. They can be used in many biomedical applications, such as drug delivery, wound dressings, contact lenses, synthetic implants, biosensors, and tissue engineering. Despite recent significant advances in hydrogel fabrication, with the introduction of double network hydrogels, with ionic or hydrogen bonds, there is still the challenge of achieving optimal mechanical properties with appropriate self-healing ability. To solve the above problem, in this study, a new type of starch/chitosan/PVA/borax hydrogel was synthesized by adopting the one-pot method. The effect of concentration and ratio of raw materials on the final properties of hydrogels, such as the degree of hydrophilicity, morphology, degradation, mechanical strength, and drug release rate, was investigated. The properties of hydrogels were examined by scanning electron microscopy, thermogravimetric analysis, Fourier-transform infrared spectroscopy, X-ray diffractometry, and contact angle, which confirmed the composite synthesis and uniform distribution of HNT and curcumin. In addition, the composite hydrogel showed excellent mechanical properties. Drug release studies confirmed that the drug is slowly released from the nanocomposite hydrogels. The results showed that starch-based nanocomposite hydrogels could provide appropriate repairing potential for defects exposed to changeable parameters.     

Synthesis,Properties and Applications of Biodegradable Polymers Derived from Diols and Dicarboxylic Acids: From Polyesters to Poly(ester amide)s

Poly(alkylene dicarboxylate)s constitute a family of biodegradable polymers with increasing interest for both commodity and speciality applications. Most of these polymers can be prepared from biobased diols and dicarboxylic acids such as 1,4-butanediol, succinic acid and carbohydrates. This review provides a current status report concerning synthesis, biodegradation and applications of a series of polymers that cover a wide range of properties, namely, materials from elastomeric to rigid characteristics that are suitable for applications such as hydrogels, soft tissue engineering, drug delivery systems and liquid crystals. Finally, the incorporation of aromatic units and α-amino acids is considered since stiffness of molecular chains and intermolecular interactions can be drastically changed. In fact, poly(ester amide)s derived from naturally occurring amino acids offer great possibilities as biodegradable materials for biomedical applications which are also extensively discussed.