Marine-Derived Hydrogels for Biomedical Applications

Marine organisms provide novel and broad sources for the preparations and applications of biomaterials. Since the urgent requirement of bio-hydrogels to mimic tissue extracellular matrix (ECM), the natural biomacromolecule hydrogels derived from marine sources have received increasing attention. Benefiting from their outstanding bioactivity and biocompatibility, many attempts have been made to reconstruct ECM components by applying marine-derived natural hydrogels. Moreover, marine hydrogels have been successfully applied in biomedicine by means of microfluidics, electrospray, and bioprinting. In this review, the classification and characteristics of marine-derived hydrogels are summarized. In particular, their role in the development of biomaterials is also introduced. Then, the recent advances in bio-fabrication strategies for various hydrogel materials are focused upon. Besides, the influences of hydrogel types on their functions in biomedical applications are discussed in depth. Finally, critical reflections on the limitations and future development of marine-derived hydrogels are presented.     

DNA Hydrogels as Functional Materials and Their Biomedical Applications

With the remarkable development of DNA nanotechnology, interest in DNA molecules has expanded beyond its biological role to building blocks in materials science. As a unique branch of DNA-based materials, DNA hydrogels have exhibited many fascinating characteristics, including broad biocompatibility, precise programmability, convenient modification, and tunable mechanical properties, which make DNA hydrogels ideal biomaterials. Moreover, by combining with functional nucleic acids, such as aptamers, i-motif nanostructures, CpG oligodeoxynucleotides, and DNAzymes, DNA hydrogels can be further tailored to provide additional target recognition, therapeutic potential, and catalytic activities, allowing them to play important roles in biosensing and medical applications. This review, aims to provide readers with an up-to-date overview of the important developments of biomedical DNA hydrogels. First, it introduces different synthetic strategies of hydrogels that utilize DNA as building materials and functional units within the hydrogel networks and discuss their advantages in biomedical applications. Subsequently, new approaches and applications of biomedical DNA hydrogels in the recent years are highlighted, such as therapeutic systems, cell culture platforms, tissue engineering materials, and biosensors. Finally, future perspectives and remaining challenges of DNA hydrogels in biomedicine are presented.     

Functional Nanomaterials on 2D Surfaces and in 3D Nanocomposite Hydrogels for Biomedical Applications

An emerging approach to improve the physicobiochemical properties and the multifunctionality of biomaterials is to incorporate functional nanomaterials (NMs) onto 2D surfaces and into 3D hydrogel networks. This approach is starting to generate promising advanced functional materials such as self‐assembled monolayers (SAMs) and nanocomposite (NC) hydrogels of NMs with remarkable properties and tailored functionalities that are beneficial for a variety of biomedical applications, including tissue engineering, drug delivery, and developing biosensors. A wide range of NMs, such as carbon‐, metal‐, and silica‐based NMs, can be integrated into 2D and 3D biomaterial formulations due to their unique characteristics, such as magnetic properties, electrical properties, stimuli responsiveness, hydrophobicity/hydrophilicity, and chemical composition. The highly ordered nano‐ or microscale assemblies of NMs on surfaces alter the original properties of the NMs and add enhanced and/or synergetic and novel features to the final SAMs of the NM constructs. Furthermore, the incorporation of NMs into polymeric hydrogel networks reinforces the (soft) polymer matrix such that the formed NC hydrogels show extraordinary mechanical properties with superior biological properties.     

Functionalized TiO2 Based Nanomaterials for Biomedical Applications

As baby boomers age, diabetes mellitus, cancer, osteoarthritis, cardiovascular diseases, and orthopedic disorders are more widespread and the demand for better biomedical devices and functional biomaterials is increasing rapidly. Owing to the good biocompatibility, chemical stability, catalytic efficiency, plasticity, mechanical properties, as well as strength‐to‐weight ratio, titanium dioxide (TiO₂) based nanostructured materials are playing important roles in tissue reconstruction and diagnosis of these diseases. Here, recent advance in the research of nanostructured TiO₂ based biomaterials pertaining to bone tissue engineering, intravascular stents, drug delivery systems, and biosensors is described.     

Magnetic Hydrogels and Their Potential Biomedical Applications

Hydrogels find widespread applications in biomedical engineering due to their hydrated environment and tunable properties (e.g., mechanical, chemical, biocompatible) similar to the native extracellular matrix (ECM). However, challenges still exist regarding utilizing hydrogels in applications such as engineering 3D tissue constructs and active targeting in drug delivery, due to the lack of controllability, actuation, and quick‐response properties. Recently, magnetic hydrogels have emerged as a novel biocomposite for their active response properties and extended applications. In this review, the state‐of‐the‐art methods for magnetic hydrogel preparation are presented and their advantages and drawbacks in applications are discussed. The applications of magnetic hydrogels in biomedical engineering are also reviewed, including tissue engineering, drug delivery and release, enzyme immobilization, cancer therapy, and soft actuators. Concluding remarks and perspectives for the future development of magnetic hydrogels are addressed.     

Bio-Inspired Stimuli-Responsive Ti3C2Tx/PNIPAM Anisotropic Hydrogels for High-Performance Actuators

Near-infrared (NIR) light-responsive hydrogels have the advantages of high precision, remote control and excellent biocompatibility, which are widely used in soft biomimetic actuators. The process by which water molecules diffuse can directly affect the deformation of hydrogel. Therefore, it remains a serious challenge to improve the response speed of hydrogel actuator. Herein, an anisotropic photo-responsive conductive hydrogel is designed by a directional freezing method. Due to the anisotropy of the MXene-based PNIPAM/MXene directional (PMD) hydrogel, its mechanical properties and conductivity are enhanced in a specific direction. At the same time, with the presence of the internal directional channels and the assistance of capillary force, the PMD hydrogel can achieve a volume deswelling of 70% in 2 s under light irradiation, further building a hydrogel actuator with a fast response performance. Additionally, the hydrogel actuator can lift an object 40 times its weight by a distance of 6 mm, realizing the advantages of both rapid responsiveness and high driving strength, which makes the hydrogel actuator have important application significance in remote control, microflow valve, and soft robot.     

Engineered Sulfated Polysaccharides for Biomedical Applications

Sulfated polysaccharides are ubiquitous in living systems and have central roles in biological functions such as organism development, cell proliferation and differentiation, cellular communication, tissue homeostasis, and host defense. Engineered sulfated polysaccharides (ESPs) are structural derivatives not found in nature but generated through chemical and enzymatic modification of natural polysaccharides, as well as chemically synthesized oligo- and polysaccharides. ESPs exhibit novel and augmented biological properties compared with their unmodified counterparts, mainly through facilitating interactions with other macromolecules. These interactions are closely linked to their sulfation patterns and backbone structures, providing a means to fine-tune biological properties and characterize structural–functional relationships by employing well-characterized polysaccharides and strategies for regioselective modification. The following review provides a comprehensive overview of the synthesis and characterization of ESPs and of their biological properties. Through the pioneering research presented here, key emerging application areas for ESPs, which can lead to novel breakthroughs in biomedical research and clinical treatments, are highlighted.     

Tailoring Hyaluronic Acid Hydrogels for Biomedical Applications

Hyaluronic acid (HA) is an attractive anionic polysaccharide polymer with inherent pharmacological properties and versatile chemical groups for modification. Due to their water retention ability, biocompatibility, biodegradation, cluster of differentiation-44 targeting, and highly designable capacity, HA hydrogels have been an emerging biomaterial, showing tailoring performance in terms of chemical modifications and hydrogel forms. Various preparation technologies have been developed for the fabrication of the tailoring HA hydrogels with unique structures and functions. They have been utilized in diverse biomedical applications like drug delivery and tissue engineering scaffolds. Herein, this review comprehensively summarizes the HA derivatives with different molecule weights and functional modifications. Then the various fabrication methods to obtain tailoring hydrogels in the forms of nanogel, nanofiber, microparticle, microneedle patch, injectable hydrogel, and scaffold are reviewed as well. The emphasis is focused on the shining biomedical applications of these tailoring HA hydrogels in anti-bacteria, anti-inflammation, wound healing, cancer treatment, regenerative medicine, psoriasis treatment, diagnosis, etc. The potentials and prospects are subsequently given to inspire further investigation, aiming at accelerating product translation from research to clinic.     

Injectability of Biosynthetic Hydrogels: Consideration for Minimally Invasive Surgical Procedures and 3D Bioprinting

Injectable hydrogels are often preferred when designing carriers for cell therapy or developing new bio-ink formulations. Biosynthetic hydrogels, which are a class of materials made with a hybrid design strategy, can be advantageous for endowing injectability while maintaining biological activity of the material. The chemical modification required to make these gels injectable by specific crosslinking pathways can be challenging and also make the hydrogels inhospitable to cells. Therefore, most efforts to functionalize biosynthetic hydrogel precursors toward injectability in the presence of cells try to balance between chemical and biological functionality, in order to preserve cell compatibility while addressing the injectability design challenges. Accordingly, hydrogel crosslinking strategies have evolved to include the use of photoinitiated “click” chemistry or bio-orthogonal reactions with rapid gelation kinetics and minimal cyto-toxicity required when working with cell-compatible hydrogel systems. With many new injectable biosynthetic materials emerging, their impact in cell-based regenerative medicine and bioprinting is also becoming more apparent. This review covers the main strategies that are used to endow biosynthetic polymers with injectability through rapid, cyto-compatible physical or covalent crosslinking and the main considerations for using the resulting injectable hydrogels in cell therapy, tissue regeneration, and bioprinting.     

Stimuli-Responsive Peptide Self-Assembly to Construct Hydrogels with Actuation and Shape Memory Behaviors

Hydrogel actuators, capable of generating reversible deformation in response to external stimulus, are widely considered as new emerging intelligent materials for applications in soft robots, smart sensors, artificial muscles, and so on. Peptide self-assembly is widely applied in the construction of intelligent hydrogel materials due to their excellent stimulus response. However, hydrogel actuators based on peptide self-assembly are rarely reported and explored. In this study, a pH-responsive peptide (MA-FIID) is designed and introduced into a poly(N-isopropyl acrylamide) backbone (PNIPAM) to construct bilayer and heterogeneous hydrogel actuators based on the assembly and disassembly of peptide molecules under different pH conditions. These peptide-containing hydrogel actuators can perform controllable bending, bucking, and complex deformation under pH stimulation. Meanwhile, the Hofmeister effect of PNIPAM hydrogels endows these peptide-containing hydrogels with enhanced mechanical strength, ionic stimulus response (CaCl₂), and excellent shape-memory property. This work broadens the application of supramolecular self-assembly in the construction of intelligent hydrogels, and also provides new inspirations for peptide self-assembly to construct smart materials.     

A Review of Design and Fabrication Methods for Nanoparticle Network Hydrogels for Biomedical,Environmental, and Industrial Applications

Nanoparticle network hydrogels (NNHs) in which nanoparticles are used as a key building block to build the gel network have attracted significant interest given their potential to leverage the favorable properties of both hydrogels (e.g., hydrophilicity, tunable pore sizes, mechanics, etc.) and a variety of different nanoparticles (e.g., high surface area, chemical activity, independently tunable porosity, mechanics) to create new functional materials. Herein, recent progress in the design and use of NNHs is comprehensively reviewed, with an emphasis on defining the typical gel morphologies/architectures that can be achieved with NNHs, the typical crosslinking approaches used to fabricate NNHs, the fundamental properties and functional benefits of NNHs, and the reported applications of NNHs in electronics (flexible electronics, sensors), environmental (sorbents, separations), agriculture, self-cleaning-materials, and biomedical (drug delivery, tissue engineering) applications. In particular, the way in which the NNH structure is applied to improve the performance of the hydrogel in each application is emphasized, with the aim to develop a set of principles that can be used to rationally design NNHs for future uses.     

Surface-Bound Microgels for Separation,Sensing, and Biomedical Applications

This study presents a comprehensive survey of microgel-coated materials and their functional behavior, describing the complex interplay between the physicochemical and mechanical properties of the microgels and the chemical and morphological features of substrates. The cited literature is articulated in four main sections: i) properties of 2D and 3D substrates, ii) synthesis, modification, and characterization of the microgels, iii) deposition techniques and surface patterning, and iv) application of microgel-coated surfaces focusing on separations, sensing, and biomedical applications. Each section discusses – by way of principles and examples – how the various design parameters work in concert to deliver functionality to the composite systems. The case studies presented herein are viewed through a multi-scale lens. At the molecular level, the surface chemistry and the monomer make-up of the microgels endow responsiveness to environmental and artificial physical and chemical cues. At the micro-scale, the response effects shifts in size, mechanical, and optical properties, and affinity towards species in the surrounding liquid medium, ranging from small molecules to cells. These phenomena culminate at the macro-scale in measurable, reversible, and reproducible effects, aiming in a myriad of directions, from lab-scale to industrial applications.     

Recent Advances in Design of Functional Biocompatible Hydrogels for Bone Tissue Engineering

Bone related diseases have caused serious threats to human health owing to their complexity and specificity. Fortunately, owing to the unique 3D network structure with high aqueous content and functional properties, emerging hydrogels are regarded as one of the most promising candidates for bone tissue engineering, such as repairing cartilage injury, skull defect, and arthritis. Herein, various design strategies and synthesis methods (e.g., 3D-printing technology and nanoparticle composite strategy) are introduced to prepare implanted hydrogel scaffolds with tunable mechanical strength, favorable biocompatibility, and excellent bioactivity for applying in bone regeneration. Injectable hydrogels based on biocompatible materials (e.g., collagen, hyaluronic acid, chitosan, polyethylene glycol, etc.) possess many advantages in minimally invasive surgery, including adjustable physicochemical properties, filling irregular shapes of defect sites, and on-demand release drugs or growth factors in response to different stimuli (e.g., pH, temperature, redox, enzyme, light, magnetic, etc.). In addition, drug delivery systems based on micro/nanogels are discussed, and its numerous promising designs used in the application of bone diseases (e.g., rheumatoid arthritis, osteoarthritis, cartilage defect) are also briefed in this review. Particularly, several key factors of hydrogel scaffolds (e.g., mechanical property, pore size, and release behavior of active factors) that can induce bone tissue regeneration are also summarized in this review. It is anticipated that advanced approaches and innovative ideas of bioactive hydrogels will be exploited in the clinical field and increase the life quality of patients with the bone injury.     

Biomedical Applications of DNA‐Based Hydrogels

Nucleic acids are gaining significant attention as versatile building blocks for the next generation of soft materials. Due to significant advances in the chemical synthesis and biotechnological production, DNA becomes more widely available enabling its usage as bulk material in various applications. This has prompted researchers to actively explore the unique features offered by DNA‐containing materials like hydrogels. In this review article, recent developments in the field of hydrogels that feature DNA as a component either in the construction of the material or as functional unit within the construct and their biomedical applications are discussed in detail. First, different synthetic approaches for obtaining DNA hydrogels are summarized, which allows classification of DNA materials according to their structure. Then, new concepts, properties, and applications are highlighted such as DNA‐based biosensor devices, drug delivery platforms, and cell scaffolds. With the 2018 Nobel Prize in Physiology or Medicine being awarded to cancer immunotherapy underscoring the importance of this therapy, DNA hydrogel systems designed to modulate the immune system are introduced. This review aims to give the reader a timely overview of the most important and recent developments in this emerging class of therapeutically useful materials of DNA‐based hydrogels.     

Hydrogel−Solid Hybrid Materials for Biomedical Applications Enabled by Surface‐Embedded Radicals

Combinations of hydrogels and solids provide high level functionality for devices such as tissue engineering scaffolds and soft machines. However, the weak bonding between hydrogels and solids hampers functionality. Here, a versatile strategy to develop mechanically robust solid?hydrogel hybrid materials using surface embedded radicals generated through plasma immersion ion implantation (PIII) of polymeric surfaces is reported. Evidence is provided that the reactive radicals play a dual role: inducing surface‐initiated, spontaneous polymerization of hydrogels; and binding the hydrogels to the surfaces. Acrylamide and silk hydrogels are formed and covalently attached through spontaneous reactions with the radicals on PIII activated polymer surfaces without cross‐linking agents or initiators. The hydrogel amount increases with incubation time, monomer concentration, and temperature. Stability tests indicate that 95% of the hydrogel is retained even after 4 months in PBS solution. T‐peel tests show that failure occurs at the tape?hydrogel interface and the hydrogel‐PIII‐treated PTFE interfacial adhesion strength is over 300 N m^?1. Cell assays show no adhesion to the as‐synthesized hydrogels; however, hydrogels synthesized with fibronectin enable cell adhesion and spreading. These results show that polymers functionalized with surface‐embedded radicals provide excellent solid platforms for the generation of robust solid?hydrogel hybrid structures for biomedical applications.     

Multiphoton Lithography as a Promising Tool for Biomedical Applications

Multiphoton lithography (MPL) is a powerful and useful structuring tool capable of generating 2D and 3D arbitrary micro- and nanometer features of various materials with high spatial resolution down to nm-scale. This technology has received tremendous interest in tissue engineering and medical device manufacturing, due to its ability to print sophisticated structures, which is difficult to achieve through traditional printing methods. Thorough consideration of two-photon photoinitiators (PIs) and photoreactive biomaterials is key to the fabrication of such complex 3D micro- and nanostructures. In the current review, different types of two-photon PIs are discussed for their use in biomedical applications. Next, an overview of biomaterials (both natural and synthetic polymers) along with their crosslinking mechanisms is provided. Finally, biomedical applications exploiting MPL are presented, including photocleaving and photopatterning strategies, biomedical devices, tissue engineering, organoids, organ-on-chip, and photodynamic therapy. This review offers a helicopter view on the use of MPL technology in the biomedical field and defines the necessary considerations toward selection or design of PIs and photoreactive biomaterials to serve a multitude of biomedical applications.     

2D Covalent Organic Frameworks for Biomedical Applications

Covalent organic frameworks (COFs) are an emerging class of organic crystalline polymers with well‐defined molecular geometry and tunable porosity. COFs are formed via reversible condensation of lightweight molecular building blocks, which dictate its geometry in two or three dimensions. Among COFs, 2D COFs have garnered special attention due to their unique structure composed of two‐dimensionally extended organic sheets stacked in layers generating periodic columnar π‐arrays, functional pore space, and their ease of synthesis. These unique features in combination with their low density, high crystallinity, large surface area, and biodegradability have made them an excellent candidate for a plethora of applications ranging from energy to biomedical sciences. In this article, the evolution of 2D COFs is briefly discussed in terms of different types of chemical linkages, synthetic strategies of bulk and nanoscale 2D COFs, and their tunability from a biomedical perspective. Next, the biomedical applications of 2D COFs specifically for drug delivery, phototherapy, biosensing, bioimaging, biocatalysis, and antibacterial activity are summarized. In addition, current challenges and emerging approaches in designing 2D COFs for advanced biomedical applications are discussed.     

Squaraine Dyes for Photovoltaic and Biomedical Applications

Squaraine dyes (SQs) are an important class of polymethine dyes with a unique reasonable-stabilized zwitterionic structure, in which electrons are highly delocalized over the conjugated bridge. These dyes can not only be easily synthesized via a condensation, but also exhibit intense absorption and emission in the visible and near-infrared region with excellent photochemical stability, making them attractive material candidates for many photoelectric and biomedical applications. Thus, in this review, after an introduction of SQs, the recent advances of SQs in the photovoltaic field are comprehensively summarized including dye-sensitized solar cells, organic solar cells, and perovskite solar cells. Then, the important advances in the use of SQs as the biosensors, biological imaging, and photodynamic/photothermal therapy reagents in the biomedical field are also discussed. Finally, a summary and outlook will be provided with some new perspectives for the future design of SQs.     

Designed Multifunctional Nanocomposites for Biomedical Applications

The assembly of multifunctional nanocomposite materials is demonstrated by exploiting the molecular sieving property of SBA‐16 nanoporous silica and using it as a template material. The cages of the pore networks are used to host iron oxide magnetic nanoparticles, leaving a pore volume of 0.29 cm³ g^?1 accessible for drug storage. This iron oxide–silica nanocomposite is then functionalized with amine groups. Finally the outside of the particle is decorated with antibodies. Since the size of many protein molecules, including that of antibodies, is too large to enter the pore system of SBA‐16, the amine groups inside the pores are preserved for drug binding. This is proven using a fluorescent protein, fluorescein‐isothiocyanate‐labeled bovine serum albumin (FITC‐BSA), with the unreacted amine groups inside the pores dyed with rhodamine B isothiocyanate (RITC). The resulting nanocomposite material offers a dual‐targeting drug delivery mechanism, i.e., magnetic and antibody‐targeting, while the functionalization approach is extendable to other applications, e.g., fluorescence–magnetic dual‐imaging diagnosis.