Showing papers in "Advanced Healthcare Materials in 2023"

Treatment with Mesenchymal Stem Cell‐Derived Nanovesicle‐Containing Gelatin Methacryloyl Hydrogels Alleviates Osteoarthritis by Modulating Chondrogenesis and Macrophage Polarization

Abstract: Osteoarthritis is a degenerative disorder that can severely affect joints, and new treatment strategies are urgently needed. Administration of mesenchymal stem cell (MSC)‐derived exosomes is a promising therapeutic strategy in osteoarthritis treatment. However, the poor yield of exosomes is an obstacle to the use of this modality in the clinic. Herein, a promising strategy is developed to fabricate high‐yield exosome‐mimicking MSC‐derived nanovesicles (MSC‐NVs) with enhanced regenerative and anti‐inflammatory capabilities. MSC‐NVs are prepared using an extrusion approach and are found to increase chondrocyte and human bone marrow MSC differentiation, proliferation, and migration, in addition to inducing M2 macrophage polarization. Furthermore, gelatin methacryloyl (GelMA) hydrogels loaded with MSC‐NVs (GelMA‐NVs) are formulated, which exhibit sustained release of MSC‐NVs and are shown to be biocompatible with excellent mechanical properties. In a mouse osteoarthritis model constructed by surgical destabilization of the medial meniscus (DMM), GelMA‐NVs effectively ameliorate osteoarthritis severity, reduce the secretion of catabolic factors, and enhance matrix synthesis. Furthermore, GelMA‐NVs induce M2 macrophage polarization and inflammatory response inhibition in vivo. The findings demonstrate that GelMA‐NVs hold promise for osteoarthritis treatment through modulation of chondrogenesis and macrophage polarization.

A Biomimetic Lubricating Nanosystem with Responsive Drug Release for Osteoarthritis Synergistic Therapy

Abstract: Osteoarthritis (OA) is associated with lubrication failure of articular cartilage and severe inflammatory response of joint capsule. Synergistic therapy combining joint lubrication and anti‐inflammation emerges as a novel treatment of OA. In this study, bioinspired by ultralow friction of natural articular synovial fluid and mussel adhesion chemistry, a biomimetic nanosystem with dual functions of enhanced lubrication and stimuli‐responsive drug release is developed. A dopamine mediated strategy realizes one step biomimetic grafting of hyaluronic acid (HA) on fluorinated graphene. The polymer modified sheets exhibit highly efficient near‐infrared absorption, and show steady lubrication with a long time under various working conditions, in which the coefficient of friction is reduced by 75% compared to H2O. Diclofenac sodium (DS) with a high loading capacity of 29.2% is controllably loaded, and responsive and sustained drug release is adjusted by near‐infrared light. Cell experiments reveal that the lubricating nanosystem is taken up by endocytosis, and anti‐inflammation results confirm that the nanosystem inhibits osteoarthritis deterioration by upregulating cartilage anabolic gene and downregulating catabolic proteases and pain‐related gene. This work proposes a promising biomimetic approach to integrate polymer modified fluorinated graphene as a dual‐functional nanosystem for effective synergistic therapy of OA.

Zero‐Valence Selenium‐Enriched Prussian Blue Nanozymes Reconstruct Intestinal Barrier against Inflammatory Bowel Disease via Inhibiting Ferroptosis and T Cells Differentiation

Abstract: The structural disruption of mechanical barrier and dysfunction of immune barrier in intestinal, are important factors, that aggravate inflammatory bowel disease (IBD). To tackle this challenge, a multifunctional nanozyme capable of scavenging reactive oxygen species (ROS) and inhibiting ferroptosis or T cells differentiation for IBD therapy is here reported. In this work, zero‐valence selenium‐enriched Prussian blue nanozymes (Se‐HMPB nanozymes) are prepared via the hard template method. PB nanozymes with multi‐enzyme activities can effectively scavenge various ROS in inflammatory tissues. Meanwhile, the presence of selenium element endows the glutathione peroxidase activity of Se‐HMPB nanozymes, which can inhibit ferroptosis and reverse the lipid peroxidation of intestinal epithelial cells to protect the intestinal mechanical barrier in ulcerative colitis (UC) model. In addition, selenium supplementation can realize efficient inhibition on the differentiation of T cells in Crohn's disease (CD) model, regulating the intestinal immune barrier. Thus, the Se‐HMPB nanozymes reconstructed intestinal barrier via inhibiting ferroptosis and T cells differentiation in UC and CD models, depicting great potential to alleviate IBD.

Stimuli‐Responsive Self‐Degradable DNA Hydrogels: Design, Synthesis, and Applications

Abstract: DNA hydrogels play an increasingly important role in biomedicine and bioanalysis applications. Due to their high programmability, multifunctionality and biocompatibility, they are often used as effective carriers for packing drugs, cells, or other bioactive cargoes in vitro and in vivo. However, the stability of the DNA hydrogels prevents their in‐demand rapid release of cargoes to achieve a full therapeutic effect in time. For bioanalysis, the generation of signals sometimes needs the DNA hydrogel to be rapidly degraded when sensing target molecules. To meet these requirements, stimulus‐responsive DNA hydrogels are designed. By responding to different stimuli, self‐degradable DNA hydrogels can switch from gel to solution for quantitative bioanalysis and precision cargo delivery. This review summarizes the recently developed innovative methods for designing stimuli‐responsive self‐degradable DNA hydrogels and showed their applications in the bioanalysis and biomedicines fields. Challenges, as well as prospects, are also discussed.

Tumor Microenvironment Responsive Hollow Nanoplatform for Triple Amplification of Oxidative Stress to Enhance Cuproptosis‐Based Synergistic Cancer Therapy

Abstract: Cuproptosis is a recently discovered form of programmed cell death and shows great potential in cancer treatment. Herein, a copper‐dithiocarbamate chelate‐doped and artemisinin‐loaded hollow nanoplatform (HNP) is developed via a chelation competition‐induced hollowing strategy for cuproptosis‐based combination therapy. The HNP exhibits tumor microenvironment‐triggered catalytic activity, wherein liberated Cu2+ catalyzes artemisinin and endogenous H2O2 to produce C‐centered radicals and hydroxyl radicals, respectively. Meanwhile, the disulfide bonds‐rich HNP can deplete intracellular glutathione, thus triply amplifying tumor oxidative stress. The augmented oxidative stress sensitizes cancer cells to the cuproptosis, causing prominent dihydrolipoamide S‐acetyltransferase oligomerization and mitochondrial dysfunction. Moreover, the HNP can activate ferroptosis via inhibiting GPX4 activity and trigger apoptosis via dithiocarbamate‐copper chelate‐mediated ubiquitinated proteins accumulation, resulting in potent antitumor efficacy. Such a cuproptosis/ferroptosis/apoptosis synergetic strategy opens a new avenue for cancer therapy.

Enzyme‐Triggered l‐α/d‐Peptide Hydrogels as a Long‐Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs (Adv. Healthcare Mater. 18/2023)

Abstract: Eradicating HIV/AIDS by 2030 is a central goal of the World Health Organization. Patient adherence to complicated dosage regimens remains a key barrier. There is a need for convenient long-acting formulations that deliver drugs over sustained periods. This paper presents an alternative platform, an injectable in situ forming hydrogel implant to deliver a model antiretroviral drug (zidovudine) over 28 days. The formulation is a self-assembling ultrashort D or L-α peptide hydrogelator, namely phosphorylated (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-OH (NapFFKY[p]-OH), covalently conjugated to zidovudine via an ester linkage. Rheological analysis demonstrated phosphatase enzyme instructed self-assembly, with hydrogels forming within minutes. Small angle neutron scattering data suggested hydrogels form narrow radius (∼2 nm), large length fibers closely fitting the flexible cylinder elliptical model. D-peptides were particularly promising for long-acting delivery, displaying protease resistance for 28 days. Drug release, via hydrolysis of the ester linkage, progressed under physiological conditions (37 °C, pH 7.4, H2 O). Subcutaneous administration of Napffk(AZT)Y[p]G-OH in Sprague Dawley rats demonstrated zidovudine blood plasma concentrations within the IC50 range (30 - 130 ng/mL) for 35 days. This work is a proof-of-concept for the development of a long-acting combined injectable in situ forming peptide hydrogel implant. These products are imperative given their potential impact on society. This article is protected by copyright. All rights reserved.

Sustained Release of Human Adipose Tissue Stem Cell Secretome from Star‐Shaped Poly(ethylene glycol) Glycosaminoglycan Hydrogels Promotes Motor Improvements after Complete Transection in Spinal Cord Injury Rat Model

Abstract: Adipose tissue-derived stem cells (ASCs) have been shown to assist regenerative processes after spinal cord injury (SCI) through their secretome, which promotes several regenerative mechanisms, such as inducing axonal growth, reducing inflammation, promoting cell survival, and vascular remodeling, thus ultimately leading to functional recovery. However, while systemic delivery (e.g., i.v. [intravenous]) may cause off-target effects in different organs, the local administration has low efficiency due to fast clearance by body fluids. Herein, a delivery system for human ASCs secretome based on a hydrogel formed of star-shaped poly(ethylene glycol) (starPEG) and the glycosaminoglycan heparin (Hep) that is suitable to continuously release pro-regenerative signaling mediators such as interleukin (IL)-4, IL-6, brain-derived neurotrophic factor, glial-cell neurotrophic factor, and beta-nerve growth factor over 10 days, is reported. The released secretome is shown to induce differentiation of human neural progenitor cells and neurite outgrowth in organotypic spinal cord slices. In a complete transection SCI rat model, the secretome-loaded hydrogel significantly improves motor function by reducing the percentage of ameboid microglia and systemically elevates levels of anti-inflammatory cytokines. Delivery of ASC-derived secretome from starPEG-Hep hydrogels may therefore offer unprecedented options for regenerative therapy of SCI.

Solid‐Phase Screening and Synthesis of Molecularly Imprinted Nanoparticles for Selective Recognition and Detection of Brain Natriuretic Peptide

Abstract: A new recognition method is explored for the rapid detection of B‐type natriuretic peptide (BNP) based on the rational design and solid‐phase synthesis of molecularly imprinted nanoparticles (nanoMIP) encapsulated with carbon dots. The nanosized magnetic template is first prepared by attaching the epitope of BNP on amino‐functionalized magnetic carriers. High‐dilution polymerization of monomers in the presence of magnetic template generates lightly crosslinked imprinted nanoparticles. To obtain the optimal MIP formulation, a new combinatorial screening approach is developed by a competitive fluorescence assay using the magnetic template. The resultant nanoMIP exhibits high affinity and selectivity toward BNP with an equilibrium dissociation constant (KD) of ≈10−11 m. The proposed assay allows fast BNP detection within ≈7 min with a linear range of its concentration from 0.25 to 5000 pg mL−1 and a limit of detection of 0.208 pg mL−1 (S/N = 3). To demonstrate its practicability in clinical diagnosis, unknown real serum samples from 160 individuals are analyzed and the relative standard deviation is less than 4.43%. Compared with the routine electrochemiluminescence detection method that is widely used in hospital, the relative error is less than 4.98% and the correlation coefficient is 0.994.

Polymer‐Based mRNA Delivery Strategies for Advanced Therapies

Abstract: Messenger RNA (mRNA)‐based therapies offer great promise for the treatment of a variety of diseases. In 2020, two FDA approvals of mRNA‐based vaccines have elevated mRNA vaccines to global recognition. However, the therapeutic capabilities of mRNA extend far beyond vaccines against infectious diseases. They hold potential for cancer vaccines, protein replacement therapies, gene editing therapies, and immunotherapies. For realizing such advanced therapies, it is crucial to develop effective carrier systems. Recent advances in materials science have led to the development of promising nonviral mRNA delivery systems. In comparison to other carriers like lipid nanoparticles, polymer‐based delivery systems often receive less attention, despite their unique ability to carefully tune their chemical features to promote mRNA protection, their favorable pharmacokinetics, and their potential for targeting delivery. In this review, the central features of polymer‐based systems for mRNA delivery highlighting the molecular design criteria, stability, and biodistribution are discussed. Finally, the role of targeting ligands for the future of RNA therapies is analyzed.

3D Bioprinting in Otolaryngology: A Review.

Abstract: The evolution of tissue engineering and 3D bioprinting has allowed for increased opportunities to generate musculoskeletal tissue grafts that can enhance functional and aesthetic outcomes in otolaryngology- head and neck surgery. Despite literature reporting successes in the fabrication of cartilage and bone scaffolds for applications in the head and neck, the full potential of this technology has yet to be realized. Otolaryngology as a field has always been at the forefront of new advancements and technology and is well poised to spearhead clinical application of these engineered tissues. In this review, we describe current 3D bioprinting methods and present an overview of potential cell types, bioinks, and bioactive factors available for musculoskeletal engineering using this technology. We review the otologic, nasal, tracheal, and craniofacial bone applications of 3D bioprinting with a focus on engineered graft implantation in animal models to highlight the status of functional outcomes in vivo; a necessary step to future clinical translation. Continued multidisciplinary efforts between material chemistry, biological sciences, and otolaryngologists will play a key in role in the translation of engineered, 3D bioprinted constructs for head and neck surgery. This article is protected by copyright. All rights reserved.

Highly Sensitive and Omnidirectionally Stretchable Bioelectrode Arrays for In Vivo Neural Interfacing

Abstract: Flexible electrode array, a new‐generation neural microelectrode, is a crucial tool for information exchange between living tissues and external electronics. Till date, advances in flexible neural microelectrodes are limited because of their high impedance and poor mechanical consistency at tissue interfaces. Herein, a highly sensitive and omnidirectionally stretchable polymeric electrode array (PEA) is introduced. Micropyramid–nanowire composite structures are constructed to increase the effective surface area of PEA, achieving an exponential reduction in impedance compared with gold (Au) and flat polypyrrole electrodes. Moreover, for the first time, a suspended umbrella structure to enable PEA with omnidirectional stretchability of up to ≈20% is designed. The PEA can withstand 1000 cycles of mechanical loads without decrease in performance. As a proof of concept, PEA is conformally attached to a rat heart and tibialis anterior muscle, and electrophysiological signals (electrocardiogram and electromyogram) of the rat are successfully recorded. This strategy provides a new perspective toward highly sensitive and omnidirectionally stretchable PEA that can facilitate the practical application of neural electrodes.

A One‐Stone‐Two‐Birds Strategy for Osteochondral Regeneration Based on a 3D Printable Biomimetic Scaffold with Kartogenin Biochemical Stimuli Gradient

Abstract: Osteochondral defect (OCD) regeneration remains challenging because of the hierarchy of the native tissue including both the articular cartilage and the subchondral bone. Constructing an osteochondral scaffold with biomimetic composition, structure, and biological functionality is the key to achieve its high‐quality repair. In the present study, an injectable and 3D printable bilayered osteochondral hydrogel based on compositional gradient of methacrylated sodium alginate, gelatin methacryloyl, and β‐tricalcium phosphate (β‐TCP), as well as the biochemical gradient of kartogenin (KGN) in the two well‐integrated zones of chondral layer hydrogel (CLH) and osseous layer hydrogel (OLH) is developed. In vitro and subcutaneous in vivo evaluations reveal that apart from the chondrogenesis of the embedded bone mesenchymal stem cells induced by CLH with a high concentration of KGN, a low concentration of KGN with β‐TCP in the OLH synergistically achieves superior osteogenic differentiation by endochondral ossification, instead of the intramembranous ossification using OLH with only β‐TCP. The biomimetic construct leveraging KGN as the only biochemical inducer can facilitate cartilage and subchondral bone restoration in the in vivo osteochondral defect. This one‐stone‐two‐birds strategy opens up a new facile approach for OCD regeneration by exploiting the biological functions of the bioactive drug molecule KGN.

A Strategy of Fenton Reaction Cycloacceleration for High‐Performance Ferroptosis Therapy Initiated by Tumor Microenvironment Remodeling

Abstract: The emerging tumor ferroptosis therapy confronts impediments of the tumor microenvironment (TME) with weak intrinsic acidity, inadequate endogenous H2O2, and a powerful intracellular redox balance system that eliminates toxic reactive oxygen species (ROS). Herein, a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)‐guided high‐performance ferroptosis therapy of tumors is proposed. The synthesized nanocomplex exhibits enhanced accumulation at carbonic anhydrase IX (CAIX)‐positive tumors based on the CAIX‐mediated active targeting, and increased acidification via the inhibition of CAIX by 4‐(2‐aminoethyl) benzene sulfonamide (ABS) (remodeling TME). This accumulated H+ and abundant glutathione in TME synergistically trigger biodegradation of the nanocomplex to release the loaded cuprous oxide nanodots (CON), β‐lapachon (LAP), Fe3+, and gallic acid‐ferric ions coordination networks (GF). The Fenton and Fenton‐like reactions are cycloaccelerated via the catalytic loop of Fe‐Cu, and the LAP‐triggered and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase1‐mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides accumulation for ferroptosis of tumor cells. The detached GF network has improved relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME is promising for MRI‐guided high‐performance ferroptosis therapy of tumors.

Injectable Intrinsic Photothermal Hydrogel Bioadhesive with On‐Demand Removability for Wound Closure and MRSA‐Infected Wound Healing

Abstract: Photothermal hydrogel adhesives have yielded promising results for wound closure and infected wound treatment in recent years. However, photothermal hydrogel bioadhesives with on‐demand removability without additional nanomaterials‐based photothermal agents have rarely been reported in the literature. In this work, an injectable intrinsic photothermal hydrogel bioadhesive with an on‐demand removal trait is developed through dynamic cross‐linking of gelatin (Gel), tannic acid (TA) quinone, and borax for closing skin incisions and accelerating methicillin‐resistant Staphylococcus aureus (MRSA) infected wound healing. The TA quinone containing polyphenol and quinone groups with multifunctional adhesiveness and intrinsic photothermal performance confer the hydrogel adhesive with near‐infrared (NIR) responsive antibacterial activity. The cross‐linking of pH‐sensitive boronic ester (polyphenol−B) and Schiff base bonds endow the hydrogel with great self‐healing capacity and on‐demand removability. Moreover, the hydrogel possesses good biocompatibility, injectability, and hemostasis. The in vivo experiment in a rat cutaneous incision model and full‐thickness MRSA‐infected wound model indicate that the smart hydrogel can close wounds efficiently and treat infected ones, demonstrating its superiority in noninvasive treatment of cutaneous incisions and enhancing infected full‐thickness wound healing.

Microneedle Patch Loaded with Exosomes Containing MicroRNA‐29b Prevents Cardiac Fibrosis after Myocardial Infarction

Abstract: Myocardial infarction (MI) is a cardiovascular disease that poses a serious threat to human health. Uncontrolled and excessive cardiac fibrosis after MI has been recognized as a primary contributor to mortality by heart failure. Thus, prevention of fibrosis or alleviation of fibrosis progression is important for cardiac repair. To this end, a biocompatible microneedle (MN) patch based on gelatin is fabricated to load exosomes containing microRNA‐29b (miR‐29b) mimics with antifibrotic activity to prevent excessive cardiac fibrosis after MI. Exosomes are isolated from human umbilical cord mesenchymal stem cells and loaded with miR‐29b mimics via electroporation, which can be internalized effectively in cardiac fibroblasts to upregulate the expression of miR‐29b and downregulate the expression of fibrosis‐related proteins. After being implanted in the infarcted heart of a mouse MI model, the MN patch can increase the retention of loaded exosomes in the infarcted myocardium, leading to alleviation of inflammation, reduction of the infarct size, inhibition of fibrosis, and improvement of cardiac function. This design explored the MN patch as a suitable platform to deliver exosomes containing antifibrotic biomolecules locally for the prevention of cardiac fibrosis, showing the potential for MI treatment in clinical applications.

Reactive Oxygen Species-Scavenging Nanosystems in the Treatment of Diabetic Wounds.

Abstract: Diabetic wounds are characterized by drug-resistant bacterial infections, biofilm formation, impaired angiogenesis and perfusion, and oxidative damage to the microenvironment. Given their complex nature, diabetic wounds remain a major challenge in clinical practice. Reactive oxygen species (ROS), which have been shown to trigger hyperinflammation and excessive cellular apoptosis, play a pivotal role in the pathogenesis of diabetic wounds. ROS-scavenging nanosystems have recently emerged as smart and multifunctional nanomedicines with broad synergistic applicability. The documented anti-inflammatory and pro-angiogenic ability of ROS-scavenging treatments predestine these nanosystems as promising options for the treatment of diabetic wounds. Yet, in this context, the therapeutic applicability and efficacy of ROS-scavenging nanosystems remain to be elucidated. Herein, we decipher the role of ROS in diabetic wounds and summarize the properties and strengths of nanosystems with ROS-scavenging capacity for the treatment of diabetic wounds. In addition, we discuss the current challenges of such nanosystems and their potential future directions through a clinical-translational lens. This article is protected by copyright. All rights reserved.

Preparation of 2D Polyaniline/MoO3−x Superlattice Nanosheets via Intercalation‐Induced Morphological Transformation for Efficient Chemodynamic Therapy

Abstract: Organic intercalation of layered nanomaterials is an attractive strategy to fabricate organic/inorganic superlattices for a wide range of promising applications. However, the synthesis of 2D organic/inorganic superlattice nanosheets remains a big challenge. Herein, the preparation of 2D polyaniline/MoO3−x (PANI/MoO3−x) superlattice nanosheets via intercalation‐induced morphological transformation from MoO3 nanobelts, as efficient Fenton‐like reagents for chemodynamic therapy (CDT), is reported. Micrometer‐long MoO3 nanobelts are co‐intercalated with Na+/H2O followed by the guest exchange with aniline monomer for in situ polymerization to obtain PANI/MoO3−x nanosheets. Intriguingly, the PANI intercalation can induce the morphological transformation from long MoO3 nanobelts to 2D PANI/MoO3−x nanosheets along with the partial reduction of Mo6+ to Mo5+, and generation of rich oxygen vacancies. More importantly, thanks to the PANI intercalation‐induced activation, the PANI/MoO3−x nanosheets exhibit excellent Fenton‐like catalytic activity for generation of hydroxyl radical (·OH) by decomposing H2O2 compared with the MoO3 nanobelts. It is speculated that the good conductivity of PANI can facilitate electron transport during the Fenton‐like reaction, thereby enhancing the efficiency of CDT. Thus, the polyvinylpyrrolidone‐modified PANI/MoO3−x nanosheets can function as Fenton‐like reagents for highly efficient CDT to kill cancer cells and eradicate tumors.

Bone‐Targeted Exosomes: Strategies and Applications

Abstract: As the global population ages, bone‐related diseases have increasingly become a major social problem threatening human health. Exosomes, as natural cell products, have been used to treat bone‐related diseases due to their superior biocompatibility, biological barrier penetration, and therapeutic effects. Moreover, the modified exosomes exhibit strong bone‐targeting capabilities that may improve efficacy and avoid systemic side effects, demonstrating promising translational potential. However, a review of bone‐targeted exosomes is still lacking. Thus, the recently developed exosomes for bone‐targeting applications in this review are focused. The biogenesis and bone‐targeting regulatory functions of exosomes, the constructive strategies of modified exosomes to improve bone‐targeting, and their therapeutic effects for bone‐related diseases are introduced. By summarizing developments and challenges in bone‐targeted exosomes, It is striven to shed light on the selection of exosome constructive strategies for different bone diseases and highlight their translational potential for future clinical orthopedics.

Amyloid Fibrils Enhance the Topical Bio‐Adhesivity of Liquid Crystalline Mesophase‐Based Drug Formulations

Abstract: Despite their distinctive secondary structure based on cross β‐strands, amyloid fibrils (AF) are stable fibrous protein aggregates with features similar to collagen, one of the main components of the extracellular matrix, and thus constitute a potential scaffold for enhancing cell adhesion for topical applications. Here, the contribution of AF to skin bio‐adhesivity aiming toward topical treatments is investigated. Liquid crystalline mesophase (LCM) based on phytantriol is formulated, with the aqueous phase containing either water or a solution of 4 wt% amyloid fibrils. Then resveratrol is added as a model anti‐inflammatory molecule. The developed LCM presents a double gyroid Ia3d mesophase. The incorporation of AF into the LCM increases its bio‐adhesive properties. In vitro release and ex vivo permeation and retention confirm the controlled release property of the system, and that resveratrol is retained in epidermis and dermis, but is also permeated through the skin. All formulations are biocompatible with L929 cells. The in vivo assay confirms that systems with AF lead to a higher anti‐inflammatory effect of resveratrol. These results confirm the hypothesis that the incorporation of AF in the LCM increases the bio‐adhesiveness and efficiency of the system for topical treatment, and consequently, the therapeutical action of the encapsulated drug.

3D printing of collagen scaffold with enhanced resolution in a citrate-modulated Gellan gum microgel bath.

Abstract: 3D printing in a microgel-based supporting bath enables the construction of complex structures with soft and watery biomaterials but the low print resolution is usually an obstacle to its practical application in tissue engineering. Herein, the high-resolution printing of a 3D collagen organ scaffold is realized by using an engineered Gellan gum (GG) microgel bath containing trisodium citrate (TSC). The introduction of TSC into the bath system not only mitigates the aggregation of GG microgels, leading to a more homogeneous bath morphology, but also suppresses the diffusion of the collagen ink in the bath due to the dehydration effect of TSC, both of which contribute to the improvement of print resolution. 3D collagen organ structures such as hand, ear and heart are successfully constructed with high shape fidelity in the developed bath. After printing, the GG and TSC can be easily removed by washing with water, and the obtained collagen product exhibits good cell affinity in a tissue scaffold application. This work offers an easy-to-operate strategy for developing a microgel bath for high-resolution printing of collagen, providing an alternative path to in vitro 3D organ construction. This article is protected by copyright. All rights reserved.

Advanced Biomaterials for Promoting Endometrial Regeneration

Abstract: The endometrium, as the innermost structure of the uterine cavity, plays a direct role in the implantation of the fertilized egg, its conception, and the formation of normal menstruation. In recent years, with the increasing rate of uterus‐related surgeries, the damaged endometrium often fails to repair itself to its original state, resulting in a high incidence of menstrual disorders and reduced fertility in women in their reproductive years. Therefore, it is essential to repair the damaged endometrium to reduce menstrual disorders, pregnancy difficulties, and other adverse events. Biomaterials have become an important medical tool for tissue repair due to their excellent biocompatibility, shape plasticity, and functional versatility. Functional biomedical materials play an important role in endometrial repair through rational design, which is expected to fundamentally address the current shortcomings of endometrial repair to maximize repair, maintain female fertility, and solve the problem of medically induced endometrial destruction. This review describes the potential and several aspects of the design, function, and application of different biomedical materials capable of repairing endometrium. In brief, this review provides a comprehensive summary and outlook of biomaterials for endometrial repair.

Electrical Stimulation Promotes the Vascularization and Functionalization of an Engineered Biomimetic Human Cardiac Tissue.

Abstract: The formation of multiscale vascular networks is essential for the in vitro construction of large-scale biomimetic cardiac tissues/organs. Although a variety of bioprinting processes have been developed to achieve the construction of mesoscale and large-scale blood vessels, the formation of microvascular networks still mainly depends on the self-assembly behavior of endothelial cells, which is inefficient and demanding without appropriate stimulus. To address this problem, We seek to promote the elongation and connection of endothelial cells in engineered cardiac tissue (ECT) by electrical stimulation (ES) to achieve vascularization. As proof of the concept, bio-inks are composed of GelMA / fibrin hydrogel, human pluripotent stem cells induced cardiomyocytes (iPSC-CM), and human umbilical vein endothelial cells (HUVEC) are used for the bioprinting of ECTs. We demonstrate that electrical stimulation significantly promotes the elongation, migration, and interconnection of HUVECs in ECT and increases the expression of related genes. Moreover, ES also enhances the secretion of signal factors interacting between CMs and HUVECs. It seems that the HUVECs further strengthen the contractility of cardiac tissue. Taken together, electrical stimulation promotes vascularization and CMs functionalization in ECT, which has important application potential in the fabrication of vascularized ECT and its clinical transplantation. This article is protected by copyright. All rights reserved.

Advances in Gelatin Bioinks to Optimize Bioprinted Cell Functions

Abstract: Gelatin is a widely utilized bioprinting biomaterial due to its cell-adhesive and enzymatically cleavable properties, which improve cell adhesion and growth. Gelatin is often covalently cross-linked to stabilize bioprinted structures, yet the covalently cross-linked matrix is unable to recapitulate the dynamic microenvironment of the natural extracellular matrix (ECM), thereby limiting the functions of bioprinted cells. To some extent, a double network bioink can provide a more ECM-mimetic, bioprinted niche for cell growth. More recently, gelatin matrices are being designed using reversible cross-linking methods that can emulate the dynamic mechanical properties of the ECM. This review analyzes the progress in developing gelatin bioink formulations for 3D cell culture, and critically analyzes the bioprinting and cross-linking techniques, with a focus on strategies to optimize the functions of bioprinted cells. This review discusses new cross-linking chemistries that recapitulate the viscoelastic, stress-relaxing microenvironment of the ECM, and enable advanced cell functions, yet are less explored in engineering the gelatin bioink. Finally, this work presents the perspective on the areas of future research and argues that the next generation of gelatin bioinks should be designed by considering cell-matrix interactions, and bioprinted constructs should be validated against currently established 3D cell culture standards to achieve improved therapeutic outcomes.

Strategic Design of Conquering Hypoxia in Tumor for Advanced Photodynamic Therapy.

Abstract: Photodynamic therapy (PDT), with its advantages of high targeting, minimally invasive, and low toxicity side effects, has been widely used in the clinical therapy of various tumors, especially superficial tumors. However, the tumor microenvironment (TME) presents hypoxia due to the low oxygen (O2 ) supply caused by abnormal vascularization in neoplastic tissues and high O2 consumption induced by the rapid proliferation of tumor cells. The PDT process generally relies on the presence of O2 , so the efficacy of PDT can be hampered by a hypoxic TME. To address this problem, researchers have been developing advanced nanoplatforms and strategies to enhance the therapeutic effect of PDT in tumor treatment. This review summarizes recent advanced PDT therapeutic strategies to against the hypoxic TME during the PDT treatment, thus enhancing PDT efficacy, including increasing O2 content in TME through delivering O2 to the tumors and in situ generations of O2 ; decreasing the O2 consumption during PDT by design of type I photosensitizers. To boost the PDT therapeutic effect, recent synergistically combination therapy of PDT and other therapeutic methods such as chemotherapy, photothermal therapy (PTT), immunotherapy, gas therapy is accounted by addressing the challenging problems of mono PDT in hypoxic environments, including tumor resistance, proliferation, and metastasis. Finally, we provide perspectives of the opportunities and challenges of PDT in future clinical research and translations. This article is protected by copyright. All rights reserved.

Advances in Injectable Hydrogel Strategies for Heart Failure Treatment.

Abstract: Heart failure (HF) affects 60 million people worldwide and has developed into a global public health problem surpassing cancer and urgently needs to be solved. According to the etiological spectrum, HF due to myocardial infarction (MI) has become the dominant cause of morbidity and mortality. Possible treatments include pharmacology, medical device implantation, and cardiac transplantation, which are limited in their ability to promote long-term functional stabilization of the heart. Injectable hydrogel therapy has emerged as a minimally invasive tissue engineering treatment approach. Hydrogels can provide the necessary mechanical support for the infarcted myocardium and serve as carriers of various drugs, bioactive factors and cells to improve the cellular microenvironment in the infarcted region and induce myocardial tissue regeneration. Herein, we explored the pathophysiological mechanism of HF and summarized injectable hydrogels as a potential solution for current clinical trials and applications. Specifically, mechanical support hydrogels, decellularized ECM hydrogels, a variety of biotherapeutic agent-loaded hydrogels and conductive hydrogels for cardiac repair were discussed, and the mechanism of action of these hydrogel-based therapies was emphasized. Finally, the limitations and future prospects of injectable hydrogel therapy for HF post MI were proposed to inspire novel therapeutic strategies. This article is protected by copyright. All rights reserved.

Recent Progress in Advanced Hydrogel‐Based Embolic Agents: From Rational Design Strategies to Improved Endovascular Embolization

Abstract: Transcatheter arterial embolization, a minimally invasive treatment to deliberately occlude the blood vessels, has become a safe and effective procedure for the management of vascular diseases and benign/malignant tumors. Particularly, hydrogel‐based embolic agents have garnered much attention because of their potential to address some of the limitations of clinically used embolic agents and can be rationally designed to impart more favorable characteristics or functions. In this review, the recent progress toward the development of polymer‐based hydrogels for effective endovascular embolization, including the in situ gelling hydrogels mediated by physically or chemically crosslinking, imageable hydrogels for intraprocedural and postprocedural feedback, use of hydrogels as the drug depot for local delivery of therapeutic drugs, hemostatic hydrogels inducing extrinsic or intrinsic coagulation of blood, stimuli‐responsive shape memory hydrogels as the smart embolization devices, and hydrogels incorporating external‐stimuli functional materials for multidisciplinary therapy, is systemically summarized. Moreover, the potential considerations of hydrogel‐based embolic agents confronted in therapeutic embolization are pointed out. Finally, the perspectives for the development of more effective embolic hydrogels are also highlighted.

Crystalline Antibody‐Laden Alginate Particles: A Platform for Enabling High Concentration Subcutaneous Delivery of Antibodies

Abstract: Subcutaneous (SC) administration is a desired route for monoclonal antibodies (mAbs). However, formulating mAbs for small injection volumes at high concentrations with suitable stability and injectability is a significant challenge. Here, this work presents a platform technology that combines the stability of crystalline antibodies with injectability and tunability of soft hydrogel particles. Composite alginate hydrogel particles are generated via a gentle centrifugal encapsulation process which avoids use of chemical reactions or an external organic phase. Crystalline suspension of anti‐programmed cell death protein 1 (PD‐1) antibody (pembrolizumab) is utilized as a model therapeutic antibody. Crystalline forms of the mAb encapsuled in the hydrogel particles lead to stable, high concentration, and injectable formulations. Formulation concentrations as high as 315 mg mL−1 antibody are achieved with encapsulation efficiencies in the range of 89–97%, with no perceivable increase in the number of antibody aggregates. Bioanalytical studies confirm superior maintained quality of the antibody in comparison with formulation approaches involving organic phases and chemical reactions. This work illustrates tuning the alginate particles’ disintegration by using partially oxide alginates. Crystalline mAb‐laden particles are evaluated for their biocompatibility using cell‐based in vitro assays. Furthermore, the pharmacokinetics (PK) of the subcutaneously delivered human anti‐PD‐1 mAb in crystalline antibody‐laden alginate hydrogel particles in Wistar rats is evaluated.

Phototheranostic Agents Based on Nonionic Heptamethine Cyanine for Realizing Synergistic Cancer Phototherapy

Abstract: Asymmetrical heptamethine cyanine with near‐infrared (NIR) absorption is used for photothermal therapy (PTT) of cancer. Aiming to overcome the drawbacks caused by the high temperature of PTT, the development of asymmetrical heptamethine cyanine with photothermal and photodynamic properties is still an attractive strategy. Different from the traditional method of the heavy atom effect, in this work, the carboxyl or sulfonic groups are introduced into the indole ring or branch chain of asymmetrical heptamethine cyanine to afford a series of new phototherapy agents. After being encapsulated by DSPE‐PEG2000, BSS‐Et NPs exhibit robust photostability, efficient reactive oxygen species generation (49%), and excellent photothermal conversion efficiency of about 37.6% under 808 nm laser irradiation. BSS‐Et NPs possess passive tumor‐targeting properties in vivo to not only visualize the tumor by NIR fluorescence imaging but also eliminate the tumor without any recurrence by photodynamic therapy and PTT synergistic therapy under laser irradiation. In addition, benefitting from the characteristics of organic small molecules, they can be metabolized quickly through the liver without inducing toxicity in the whole body. In general, this study provides a new direction for the development of multifunctional phototherapy agents for cancer treatment.

Adhesive Hydrogel Patch‐Mediated Combination Drug Therapy Induces Regenerative Wound Healing through Reconstruction of Regenerative Microenvironment

Abstract: Regenerative wound healing involves the scarless wound healing as observed in fetal skin. Multiple features of regenerative wound healing have been well studied; however, the practical application of pro‐regenerative materials to recapitulate the regenerative wound healing in adult skins has not yet been achieved. In this study, the authors identified that their novel pro‐regenerative material, pyrogallol‐functionalized hyaluronic acid (HA‐PG) patches in combination with protein transduction domain‐fused Dishevelled (Dvl)‐binding motif (PTD‐DBM), a peptide inhibiting the CXXC‐type zinc finger protein 5 (CXXC5)‐Dvl interaction, promoted regenerative wound healing in mice. The HA‐PG patches loaded with this competitor peptide and valproic acid (VPA), a glycogen synthase kinase 3β (GSK3β) inhibitor, significantly inhibited scar formation during wound healing. The HA‐PG patches with PTD‐DBM and/or VPA inhibit the expression of differentiated cell markers such as α‐smooth muscle actin (α‐SMA) while inducing the expression of stem cell markers such as CD105 and Nestin. Moreover, Collagen III, an important factor for regenerative healing, is critically induced by the HA‐PG patches with PTD‐DBM and/or VPA, as also seen in VPA‐treated Cxxc5−/− mouse fibroblasts. Overall, these findings suggest that the novel regeneration‐promoting material can be utilized as a potential therapeutic agent to promote both wound healing and scar attenuation.

Antibacterial Collagen‐Based Nanocomposite Dressings for Promoting Infected Wound Healing

Abstract: Pathogenic bacterial infection is the most frequent wound complication, which has become a major clinical and healthcare challenge in wound management worldwide, leading to impaired healing processes, the risk of amputation, and even death. Here, collagen‐based nanocomposite dressings (APZC) with broad‐spectrum antibacterial activity are developed to promote the infected full‐thickness wound healing. Short rod‐like shaped ZnO NPs are synthesized and then coated with polydopamine (PDA) to obtain PDA coated ZnO NPs (PDA@ZnO NPs). Afterward, PDA@ZnO NPs are conjugated on the backbone of a collagen chain, and the obtained collagen‐PDA@ZnO NPs conjugate is crosslinked by dialdehyde sodium alginate to fabricate APZC dressings. PDA@ZnO NPs show well dispersibility and are uniformly incorporated into the collagen matrix. APZC dressings have interconnected microporous structure and great physicochemical properties, besides good blood coagulation performance and well cytocompatibility. APZC dressings demonstrate long‐lasting and excellently broad‐spectrum antimicrobial activity, which can relieve the inflammatory reaction by killing pathogenic bacteria and induce the generation of blood vessels and the orderly deposition of collagen in the wound site, thus promoting infected full‐thickness wound healing without obvious scar formation. Overall, the functionalized collagen‐based nanocomposite dressings have great potential in the clinical treatment against bacteria‐associated wound infection.