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.     

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.     

Synthesis and Applications of Stimuli‐Responsive DNA‐Based Nano‐ and Micro‐Sized Capsules

Stimuli‐responsive, drug‐loaded, DNA‐based nano‐ and micro‐capsules attract scientific interest as signal‐triggered carriers for controlled drug release. The methods to construct the nano‐/micro‐capsules involve i) the layer‐by‐layer deposition of signal‐reconfigurable DNA shells on drug‐loaded microparticles acting as templates, followed by dissolution of the core templates; ii) the assembly of three‐dimensional capsules composed of reconfigurable DNA origami units; and iii) the synthesis of stimuli‐responsive drug‐loaded capsules stabilized by DNA?polymer hydrogels. Triggers to unlock the nano‐/micro‐capsules include enzymes, pH, light, aptamer?ligand complexes, and redox agents. The capsules are loaded with fluorescent polymers, metal nanoparticles, proteins or semiconductor quantum dots as drug models, with anti‐cancer drugs, e.g., doxorubicin, or with antibodies inhibiting cellular networks or enzymes over‐expressed in cancer cells. The mechanisms for unlocking the nano‐/micro‐capsules and releasing the drugs are discussed, and the applications of the stimuli‐responsive nano‐/micro‐capsules as sense‐and‐treat systems are addressed. The scientific challenges and future perspectives of nano‐capsules and micro‐capsules in nanomedicine are highlighted.     

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.     

Ascidian‐Inspired Fast‐Forming Hydrogel System for Versatile Biomedical Applications: Pyrogallol Chemistry for Dual Modes of Crosslinking Mechanism

Exploitation of unique biochemical and biophysical properties of marine organisms has led to the development of functional biomaterials for various biomedical applications. Recently, ascidians have received great attention, owing to their extraordinary properties such as strong underwater adhesion and rapid self‐regeneration. Specific polypeptides containing 3,4,5‐trihydroxyphenylalanine (TOPA) in the blood cells of ascidians are associated with such intrinsic properties generated through complex oxidative processes. In this study, a bioinspired hydrogel platform is developed, demonstrating versatile applicability for tissue engineering and drug delivery, by conjugating pyrogallol (PG) moiety resembling ascidian TOPA to hyaluronic acid (HA). The HA–PG conjugate can be rapidly crosslinked by dual modes of oxidative mechanisms using an oxidant or pH control, resulting in hydrogels with different mechanical and physical characteristics. The versatile utility of HA–PG hydrogels formed via different crosslinking mechanisms is tested for different biomedical platforms, including microparticles for sustained drug delivery and tissue adhesive for noninvasive cell transplantation. With extraordinarily fast and different routes of PG oxidation, ascidian‐inspired HA–PG hydrogel system may provide a promising biomaterial platform for a wide range of biomedical applications.     

Smart Hydrogels Co‐switched by Hydrogen Bonds and π–π Stacking for Continuously Regulated Controlled‐Release System

A series of hydrogels with continuously regulatable release behavior can be achieved by incorporating hydrogen bonding and π–π stacking co‐switches in polymers. A poly(nitrophenyl methacrylate‐co‐methacrylic acid) hydrogel (NPMAAHG) for control over drug release is fabricated by copolymerizing 4‐nitrophenyl methacrylate and methacrylic acid using ethylene glycol dimethacrylate as a crosslinker. The carboxylic acid groups and nitrylphenyl groups form hydrogen bonds and π–π stacking interactions, respectively, which act as switches to control the release of guest molecules from the polymers. As revealed by the simulated gastrointestinal tract drug release experiments, the as‐synthesized NPMAAHG hydrogels can be regulated to release only 4.7% of drugs after 3 h in a simulated stomach and nearly 92.6% within 43 h in the whole digestive tract. The relation between the release kinetics and structures and the mechanism of the smart release control are analyzed in terms of diffusion exponent, swelling interface number, drug diffusion coefficient, and velocity of the swelling interface in detail. The results reveal that the release of guest molecules from the hydrogels can be continuously regulated for systemic administration by controlling the ratio of the hydrophilic hydrogen bonds and the hydrophobic π–π stacking switches.     

Protein‐Release Behavior of Self‐Assembled PEG–β‐Cyclodextrin/PEG–Cholesterol Hydrogels

This paper reports on the degradation and protein release behavior of a self‐assembled hydrogel system composed of β‐cyclodextrin‐ (βCD) and cholesterol‐derivatized 8‐arm star‐shaped poly(ethylene glycol) (PEG₈). By mixing βCD‐ and cholesterol‐derivatized PEG₈ (molecular weights 10, 20 and 40 kDa) in aqueous solution, hydrogels with different rheological properties are formed. It is shown that hydrogel degradation is mainly the result of surface erosion, which depends on the network swelling stresses and initial crosslink density of the gels. This degradation mechanism, which is hardly observed for other water‐absorbing polymer networks, leads to a quantitative and nearly zero‐order release of entrapped proteins. This system therefore offers great potential for protein delivery.     

Self‐Assembling Doxorubicin Silk Hydrogels for the Focal Treatment of Primary Breast Cancer

Standard care for early stage breast cancer includes tumor resection and local radiotherapy to achieve long‐term remission. Systemic chemotherapy provides only low locoregional control of the disease; to address this, self‐assembling silk hydrogels that can retain and then deliver doxorubicin locally are described. Self‐assembling silk hydrogels show no swelling, are readily loaded with doxorubicin under aqueous conditions, and release drug over 4 weeks in amounts that can be fine‐tuned by varying the silk content. Following successful in vitro studies, locally injected silk hydrogels loaded with doxorubicin show excellent antitumor response in mice, outperforming the equivalent amount of doxorubicin delivered intravenously. In addition to reducing primary tumor growth, doxorubicin‐loaded silk hydrogels reduce metastatic spread and are well tolerated in vivo. Thus, silk hydrogels are well suited for the local delivery of chemotherapy and provide a promising approach to improve locoregional control of breast cancer.     

Hydrophobized Hydrogels: Construction Strategies,Properties, and Biomedical Applications

Hydrogels, as 3D networks containing huge amount of water, display similarity to soft tissues, and thus they are of wide interest in tissue engineering. Hydrogels, due to biocompatibility and porous structure, are valuable therapeutic platforms for hydrophilic drugs. Over the last decade, there has been a strong emphasis on the development of hydrogel platforms with the ability to increase the solubility of hydrophobic drugs. However, the pronounced discrepancy between the hydrophilic character of hydrogels and the hydrophobic nature of numerous pharmacologically active compounds is problematic. In recent years, different strategies are applied using special polymer constructs or composite materials exploiting the advanced scientific knowledge in the area of polymer and lipid-based nano- and microcarriers hydrophobization of the hydrogel turns out to be not only valuable in terms of achieving the ability to dissolve poorly soluble drugs in water, but also proves to be crucial in obtaining bioadhesion in wet conditions, but also, unexpected abnormal water swelling behavior, as well as in mechanical properties such as the dissipation mechanism and self-healable hydrogel properties. This review is mainly focused on recent advances in the usage of hydrophobized hydrogels in biomedical applications.     

Molybdenum Disulfide‐Based Tubular Microengines: Toward Biomedical Applications

2D molybdenum disulfide (MoS₂) is herein explored as an advanced surface material in the fabrication of powerful tubular microengines. The new catalytic self‐propelled open‐tube bilayer microengines have been fabricated using a template electrodeposition and couple the unique properties of sp² hybridized MoS₂ with highly reactive inner granular Pt catalytic structures. The MoS₂/metal microengines display extremely efficient bubble propulsion, reflecting the granular structure of the inner catalytic platinum or gold layers (compared to the smooth metal surfaces of common micromotors). The efficient movement of functionalized MoS₂ micromotors can address challenges imposed by slow mass transport processes involved in various applications of MoS_2. The delocalized electron network of the MoS₂ outer layer facilitates π–π stacking interactions and endows the tubular microengines with a diverse array of capabilities. These are demonstrated here for efficient loading and release of the drug doxorubicin, and rapid and sensitive “OFF–ON” fluorescent detection of important nucleic acids (miRNA‐21) and proteins (thrombin) using microengines modified with dye‐labeled single‐stranded DNA and aptamer, respectively. Such coupling of the attractive capabilities of 2D‐MoS₂ nanosheets with rapidly moving microengines provides an opportunity to develop multifunctional micromachines for diverse biomedical applications ranging from efficient drug delivery to the detection of important bioanalytes.     

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.     

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.     

Supertough Hybrid Hydrogels Consisting of a Polymer Double‐Network and Mesoporous Silica Microrods for Mechanically Stimulated On‐Demand Drug Delivery

Despite their potential in various fields of bioapplications, such as drug/cell delivery, tissue engineering, and regenerative medicine, hydrogels have often suffered from their weak mechanical properties, which are attributed to their single network of polymers. Here, supertough composite hydrogels are proposed consisting of alginate/polyacrylamide double‐network hydrogels embedded with mesoporous silica particles (SBA‐15). The supertoughness is derived from efficient energy dissipation through the multiple bondings, such as ionic crosslinking of alginate, covalent crosslinking of polyacrylamide, and van der Waals interactions and hydrogen bondings between SBA‐15 and the polymers. The superior mechanical properties of these hybrid hydrogels make it possible to maintain the hydrogel structure for a long period of time in a physiological solution. Based on their high mechanical stability, these hybrid hydrogels are demonstrated to exhibit on‐demand drug release, which is controlled by an external mechanical stimulation (both in vitro and in vivo). Moreover, different types of drugs can be separately loaded into the hydrogel network and mesopores of SBA‐15 and can be released with different speeds, suggesting that these hydrogels can also be used for multiple drug release.     

Rational Design of Bioactive Hydrogels toward Periodontal Delivery: From Pathophysiology to Therapeutic Applications

Periodontitis is a biofilm-induced, host-mediated inflammatory disease that results in periodontal tissue destruction. The design of functional biomaterials based on disease pathophysiology is essential for enhancing their therapeutic effects in periodontitis treatment. As promising localized drug delivery systems and tissue engineering scaffolds, hydrogels have gained significant interest for controlled and sustained release of bioactive agents in periodontal applications. The rational design of bioactive hydrogels can facilitate bacterial control and modulate destructive host inflammation, thereby preventing the progression of periodontitis. In this review, the pathophysiological mechanisms underlying periodontitis as fundamental principles for the design of functional hydrogel systems are first introduced. In the following part, an overview is systematically provided of the types and functions of the bioactive hydrogel systems loaded with anti-bacterial and anti-inflammatory agents for periodontal delivery. Finally, the remaining challenges and future perspectives of hydrogel delivery systems for periodontal applications are proposed. It is believed that this review will inspire the rational design and development of innovative functional hydrogel biomaterials toward periodontal therapy.