Regeneration therapeutic strategy by microRNAs for boosting cardiomyocyte proliferation in treating myocardial infarction (MI) has the challenges of efficient delivery, and toxicity and risk of sudden death. Herein, oxidative stress-relief microgels were developed for miR-19a/b delivery, modulation of inflammatory tissue microenvironment, promotion of cardiomyocyte proliferation, and maintenance of heart function post MI. The cholesterol-modified miR-19a/b was encapsulated into the cavity of β-cyclodextrin in selenoketal-containing microgels. The microgels could effectively scavenge typical reactive oxygen species (ROS), and down-regulate the intracellular ROS level and the levels of typical inflammatory factors. The microgels could improve the acute inflammatory microenvironment for better cardiomyocyte survival and cellular uptake of miR-19a/b, leading to significant promotion of cardiomyocyte proliferation in vivo. In the rat and minipig models of MI, the microgels most effectively inhibited the acute inflammatory response and reduced the cardiomyocytes apoptosis, resulting in a significant improvement of cardiac function and restriction of pathological remodeling post MI, and thereby best heart function revealed by echocardiography and histological analysis.

Biomimetic Artificial Cells (ACs) are engineered systems that mimic the properties and functions of natural cells, offering significant potential for biomedical applications. The performance and applicability of these synthetic constructs depend on the choice of materials and fabrication methods. Our review delves into the materials, fabrication techniques, and diverse applications of ACs, emphasizing their transformative impact on the field of cancer therapy as smart vehicles for drug delivery, immune system stimulation, cancer cell targeting to minimize off-target effects and maximizing therapeutic efficacy as well as in vitro models for cancer research. By providing a comprehensive overview, we aim to elucidate how these synthetic cells can move the field forward, offering innovative solutions to longstanding challenges in cancer treatment and opening new frontiers in less toxic treatment options.

Human Adipose-derived stem cells (hADSCs), known for their mesenchymal stem cell properties, including multilineage differentiation and self-renewal, hold significant promise for chronic wound regeneration. Typically, hADSCs are utilized in cellular aggregates or hydrogels to enhance therapeutic efficacy. However, limitations such as reduced cell viability, inadequate mass transfer rates, and diminished paracrine effects hinder their clinical applications. This study explores an innovative approach by encapsulating hADSCs within a collagen/hyaluronic acid micro-fragmented collagen hydrogel wound dressing (MCWD). The resulting micro-fragmented collagen hydrogel-hADSC composite created through the integration of micro-sized hydrogel units and cells demonstrated markedly improved cell viability and activity, as well as superior therapeutic outcomes compared to conventional cell aggregates (CA) and collagen hydrogel wound dressings (CWD). In vitro assessments showed that the highly porous structure of MCWD promotes better mass transfer and enhances the viability and cytokine production of hADSCs associated with the paracrine effect. In vivo experiments further validated the effectiveness of the MCWD, revealing significant enhancements in cell proliferation, skin thickness restoration, collagen maturation, and blood vessel formation. These findings underscore the potential of MCWD as an advanced solution for wound healing applications.

Articular cartilage repair remains challenging due to the inherent poor self-healing capacity and acute inflammation resulting from the over expression of intracellular reactive oxygen species (ROS). Although microfracture is frequently used in practical surgery, the newborn cartilage always exhibits fibrosis, mainly attributed to the weak ROS scavenging and mismatched microenvironment that fails to induce chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Herein, a novel simvastatin (SIM)-incorporated kelp and cartilage acellular matrix hybrid (labeled as SIM@KACM/CACM) microgel assembly with enhanced ROS scavenging, endogenous BMSC recruitment, and chondrogenic differentiation capabilities is constructed to improve microfracture-based articular cartilage repair. The kelp acellular matrix exhibits low immunogenicity, high biocompatibility, and ROS scavenging properties, whilst the sustained SIM release promotes BMSC recruitment from the bone marrow cavity. Meanwhile, the microenvironment and bioactive factors conferred by CACM facilitate the BMSC proliferation and differentiation into hyaline cartilage. In addition, the construction of porous microgel assembly via dynamic Schiff's bonds endows excellent injectability and tissue adhesion, which not only enhances its retention in the defect site after injection but also provides abundant sites for BMSC anchoring and infiltration. Due to the synergetic effect of the above-mentioned multiple factors, the articular cartilage repair is improved dramatically.

Porous nanofibrous microspheres (PNMs) present a versatile and minimally invasive strategy for tissue regeneration, combining biomimetic morphology, tunable structure, and injectability. While self-assembly and co-axial electrospray are explored for PNM fabrication, these methods are limited in compositional versatility and production scalability. Here, a 3D-printed microfluidic platform is presented that enables large-scale fabrication of PNMs with precise control over size, pore architecture, and morphology. PNMs can be functionalized with bioactive molecules through UV crosslinking, enhancing their regenerative potential by promoting osteogenesis in human bone marrow stromal cells (hBMSCs), angiogenesis in human umbilical vein endothelial cells (HUVECs), and exerting anti-inflammatory effects on macrophages. Subcutaneous implantation in rats demonstrates that PNMs support cell infiltration, minimize fibrosis, and facilitate tissue integration, achieving complete cell penetration and tissue incorporation within 14 days. These findings establish PNMs as versatile, scalable, and customizable platforms, ideal for applications as injectable drugs or cell carriers, as well as powders, offering promising solutions for wound healing and tissue regeneration.

Rapid advances in biomedical applications and soft robotics demand load-bearing soft materials that can be processed into complex 3D shapes. Direct ink writing (DIW) enables the fabrication of customizable shapes with locally varying compositions. Hydrogels that are formulated as microgels meet the rheological requirements that DIW imparts on the inks if they are jammed. However, most granular hydrogels are soft because inter-particle interactions are weak. These hydrogels can be reinforced with a second hydrogel, yielding double network granular hydrogels (DNGHs). Yet, DNGHs suffer from low fracture energy. This limitation is addressed by electrostatically reinforcing them. The resulting materials exhibit Young's moduli and fracture energies similar to values of cartilage and muscles. An empirical model is proposed to predict the fracture energy of these reinforced DNGHs, based on the dissipation zone size, contact area, and adhesion energy. These DNGHs can be 3D-N, N-methylene bisacrylamideprinted into free-standing structures exhibiting tuneable mechanical properties at the centimeter scale without the need for supporting structures.

Injectable microgels, made from both natural and synthetic materials, are promising platforms for the encapsulation of cells or bioactive agents, such as drugs and growth factors, for delivery to injury sites. They can also serve as effective micro-scaffolds in bone tissue engineering (BTE), offering a supportive environment for cell proliferation or differentiation into osteoblasts. Microgels can be injected in the injury sites individually or in the form of aggregated/jammed ones named micro-granular hydrogels. This review focuses on common materials and fabrication techniques for preparing injectable microgels, as well as their characteristics and applications in BTE. These applications include their use as cell carriers, delivery systems for bioactive molecules, micro-granular hydrogels, bio-inks for bioprinting, three-dimensional microarrays, and the formation of microtissues. Furthermore, we discuss the current and potential future applications of microgels in bone tissue regeneration.

The unique structure of cartilage tissue, characterized by a robust collagen fiber framework and a dynamic proteoglycan hydrogel filling, is crucial for maintaining biomechanical and biochemical homeostasis. Herein, a cartilage-inspired microsphere with sponge framework and hydrogel filling (SponGel MS) is successfully prepared to restore cartilage homeostasis. Specifically, epigallocatechin gallate nanoparticles coated with MnO2 (MnO2@EGCG) are first synthesized, which can scavenge H2O2 and hydroxyl radicals. The formation of SponGel MS involves sequential fabrication of the sponge phase through cryogenic radical reaction and hydrogel phase via Schiff base reaction. The hydrogel phase can dynamically release MnO2@EGCG to inhibit inflammation and SDF-1 to recruit stem cells. Porous sponge phase with favorable compressive performance and His-Ala-Val (HAV) peptide provides stable stem cell niches to regulate stem cell condensation, co-assembly and chondrogenic differentiation. Animal experiments demonstrate that SponGel MS suppresses the expression of IL-1β and collagen I, ultimately achieving cartilage regeneration. This study represents a novel strategy for constructing cartilage repair materials.

Metal-protein hybrid materials represent a novel class of functional materials that exhibit exceptional physicochemical properties and tunable structures, rendering them remarkable applications in diverse fields, including materials engineering, biocatalysis, biosensing, and biomedicine. The design and development of multifunctional and biocompatible metal-protein hybrid materials have been the subject of extensive research and a key aspiration for practical applications in clinical settings. This review provides a comprehensive analysis of the design strategies, intrinsic properties, and biomedical applications of these hybrid materials, with a specific emphasis on their potential in cancer therapy, drug and vaccine delivery, antibacterial treatments, and tissue regeneration. Through rational design, stable metal-protein hybrid materials can be synthesized using straightforward methods, enabling them with therapeutic, delivery, immunomodulatory, and other desired functionalities. Finally, the review outlines the existing limitations and challenges associated with metal-protein hybrid materials and evaluates their potential for clinical translation, providing insights into their practical implementation within biomedical applications.

Granular hydrogel matrices have shown significant advantages in mesenchymal stem cell (MSC) delivery and tissue ingrowth due to their minimally invasive injection capabilities and porous structures. However, creating granular hydrogels that simultaneously mimic the nanofilamentous architecture of the natural extracellular matrix (ECM) and enhance stem cell retention and in vivo immunoregulation in a diabetic microenvironment remains challenging. In this study, we present a nanoengineered supramolecular granular hydrogel with a nanofibrillar structure designed to improve stem cell retention and regulate immune responses under diabetic conditions. The granular hydrogel matrix is assembled based on multiple hydrogen bonding and hydrophobic interactions, exhibiting a range of tunable features, including shear-thinning, injectability, self-healing, and 3D printability. Furthermore, enriched with manganese dioxide (MnO2)-amyloid fibril (AF) nanohybrids, the granular hydrogel supports MSC adhesion and stemness maintenance and can modulate the reactive oxygen species microenvironment by converting H2O2 into oxygen, thereby promoting cell viability and osteogenic differentiation of MSCs with the sustained release of Mn2+. In a two-week diabetic rat model study, the granular hydrogel demonstrates enhanced in vivo cell retention and anti-inflammatory immunomodulation properties, underscoring its potential as a promising matrix for stem cell therapy and immune regulation in diabetic conditions.

Cultured meat aims to produce meat mass by culturing cells and tissues based on the muscle regeneration mechanism, and is considered an alternative to raising and slaughtering livestock. Hydrogel building blocks are commonly used as substrates for cell culture in tissue engineering and cultured meat because of their high water content, biocompatibility, and similar three-dimensional (3D) environment to the cellular niche in vivo. With the characteristics of precise manipulation of fluids, microfluidics exhibits advantages in the fabrication of building blocks with different structures and components, which have been widely applied in tissue regeneration. Microfluidic building blocks show promising prospects in the field of cultured meat; however, few reviews on the application of microfluidic building blocks in cultured meat have been published. This review outlines the recent status and prospects of the use of microfluidic building blocks in cultured meat. Starting with the introduction of cells and materials for cultured meat tissue construction, we then describe the diverse structures of the fabricated building blocks, including microspheres, microfibers, and microsphere-microfiber hybrid systems. Next, the stacking strategies for tissue construction are highlighted in detail. Finally, challenges and future prospects for developing microfluidic building blocks for cultured meat are discussed.

Chronic wound poses a serious risk to diabetic patients, primarily due to damaged skin microvasculature and prolonged inflammation at the wound site. Mesenchymal stem cell (MSC) therapy utilizing microgels as a cell delivery system has shown promise in promoting wound healing by enhancing cell viability and the secretion of bioactive factors. Retaining sufficient MSCs at injury sites is crucial for optimal therapeutic outcomes. However, inadequate hierarchical structure and limited use of the microgel's interior space significantly reduce cell proliferation and infiltration efficiency, thereby compromising the therapeutic effect. To address this, a microfluidic approach is developed for fabricating porous hierarchical interconnected microgels with interior spiral canals (PHIGels) by employing a fluidic "viscous instability" effect and gas formation reaction during the microfluidic synthesis. These MSC-laden PHIGel scaffolds facilitate rapid proliferation and infiltration into the interior spiral canals through a hierarchical pore network, significantly increasing the number of viable cells that can be carried by the microgels. It is proved that these microgel-based deliveries of MSCs promote re-epithelialization, collagen synthesis, angiogenesis, and reduction in inflammation, thus enhancing cutaneous wound repair in a rat model of type I diabetes. The microporosity and hierarchical design of these microgels offer novel routes for tissue regeneration and repair.

In this study, we demonstrate the formation of a self-assembled microgel double layer on an electrode surface, utilizing the ability to form electro-responsive, reversible inclusion complexes between microgels modified with ferrocene and β-cyclodextrin in these systems. The bottom layer was based on microgels containing ferrocene moieties and derivatives of cysteine. The presence of the amino acid derivative enabled the formation of the well-packed monolayer on the gold surface through chemisorption, while ferrocene was responsible for electroactivity. The addition of βCD-modified microgel led to the formation of the second monolayer, ultimately creating the double layer. Our investigation focuses on the electrochemically controlled formation and deformation processes of the double microgel layer.

Although micron-sized microgels have become important building blocks in regenerative materials, offering decisive interactions with living matter, their chemical composition mostly significantly varies when their network morphology is tuned. Since cell behavior is simultaneously affected by the physical, chemical, and structural properties of the gel network, microgels with variable morphology but chemical equivalence are of interest. This work describes a new method to produce thermoresponsive microgels with defined mechanical properties, surface morphologies, and volume phase transition temperatures. A wide variety of microgels is synthesized by crosslinking monomers or star polymers at different temperatures using thermally assisted microfluidics. The diversification of microgels with different network structures and morphologies but of chemical equivalence offers a new platform of microgel building blocks with the ability to undergo phase transition at physiological temperatures. The method holds high potential to create soft and dynamic materials while maintaining the chemical composition for a wide variety of applications in biomedicine.

Granular hydrogels have recently attracted the attention for diverse tissue engineering applications due to their versatility and modularity. Despite previous studies showing enhanced viability and metabolism of cells encapsulated in these hydrogels, the in vitro immune response and long-term fibrotic response of these scaffolds have not been well characterized. Here, bulk and granular hydrogels are studied based on synthetic zwitterionic (ZI) and natural polysaccharide hyaluronic acid (HA) made with mechanical fragmentation. In vitro, immunomodulatory studies show an increased stimulatory effect of HA granular hydrogels compared to bulk, while both bulk and granular ZI hydrogels do not induce an inflammatory response. Subcutaneous implantation in mice shows that both ZI and HA granular hydrogels resulted in less collagen capsule deposition around implants compared to bulk HA hydrogels 10 weeks after implantation. Moreover, the HA granular hydrogels are infiltrated by host cells, including macrophages and mature blood vessels, in a porosity-dependent manner. However, a large number of cells, including multinucleated giant cells as well as blood vessels, surround bulk and granular ZI hydrogels and are not able to infiltrate. Overall, this study provides new insights on the long-term stability and fibrotic response of granular hydrogels, paving the way for future studies and applications.

Microgel suspensions have garnered significant interest in fundamental research due to their phase transition between liquid-like to paste-like behaviors stemming from tunable interparticle and particle-solvent interactions. Particularly, stimuli-responsive microgels undergo faster volume changes in response to external stimuli in comparison to their bulk counterparts, while maintaining their structural integrity. Here, concentrated and diluted suspensions of poly(N-isopropylacrylamide) (PNIPAm) microgels are dispersed to different packing fractions in water for the characterizations of temperature-responsive rheological responses. In the intrinsic volume phase transition (VPT), polymer chains collapse, and microgels shrink to smaller sizes. Additionally, the intermicrogel and microgel-solvent interactions vary in VPT, which results in microgel clusters that significantly affect the linear shear moduli of suspensions. The effect of the temperature ramp rate of PNIPAm microgel suspensions on rheological responses is characterized. Moreover, the effect of the mass fraction of microgels on the relative viscosity of dilute microgel suspensions is investigated. These results shed light on understanding the heating and cooling rate-dependent temperature responsiveness of PNIPAm microgel suspensions, establishing pathways to regulate the rheological characteristics in temperature-responsive microgel-based platforms. Therefore, this work envisions technological advancements in different fields such as drug delivery, tissue engineering, and diagnostic tools.

Microgels show advantages over bulk hydrogels due to convenient control over microgel size and composition, and the ability to use microgels to modularly construct larger hierarchical scaffold hydrogel materials. Here, supramolecular chemistry is used to formulate supramolecular polymer, dynamic microgels solely held together by non-covalent interactions. Four-fold hydrogen bonding ureido-pyrimidinone (UPy) monomers with different functionalities are applied to precisely tune microgel properties in a modular way, via variations in monomer concentration, bifunctional crosslinker ratio, and the incorporation of supramolecular dyes and peptides. Functionalization with a bioactive supramolecular cell-adhesive peptide induced selectivity of cells toward the bioactive microgels over non-active, non-functionalized versions. Importantly, the supramolecular microgels can also be applied as microscale building blocks into supramolecular bulk macrogels with tunable dynamic behavior: a robust and weak macrogel, where the micro- and macrogels are composed of similar molecular building blocks. In a robust macrogel, microgels act as modular micro-building blocks, introducing multi-compartmentalization, while in a weak macrogel, microgels reinforce and enhance mechanical properties. This work demonstrates the potential to modularly engineer higher-length-scale structures using small molecule supramolecular monomers, wherein microgels serve as versatile and modular micro-building units.

Recent explorations of bioengineering have generated new concepts and strategies for the processing of soft and functional materials. Droplet assembly techniques can address problems in the construction of extremely soft architectures by expanding the manufacturing capabilities using droplets containing liquid or hydrogels including weak hydrogels. This Perspective sets out to provide a brief overview of this growing field, and discusses the challenges and opportunities ahead. The study highlights the recent key advances of materials and architectures from hitherto effective droplet-assembly technologies, as well as the applications in biomedical and bioengineering fields from artificial tissues to bioreactors. It is envisaged that these assembled architectures, as nature-inspired models, will stimulate the discovery of biomaterials and miniaturized platforms for interdisciplinary research in health, biotechnology, and sustainability.

Granular biomaterials have found widespread applications in tissue engineering, in part because of their inherent porosity, tunable properties, injectability, and 3D printability. However, the assembly of granular hydrogels typically relies on spherical microparticles and more complex particle geometries have been limited in scope, often requiring templating of individual microgels by microfluidics or in-mold polymerization. Here, we use dithiolane-functionalized synthetic macromolecules to fabricate photopolymerized microgels via batch emulsion, and then harness the dynamic disulfide crosslinks to rearrange the network. Through unconfined compression between parallel plates in the presence of photoinitiated radicals, we transform the isotropic microgels are transformed into disks. Characterizing this process, we find that the areas of the microgel surface in contact with the compressive plates are flattened while the curvature of the uncompressed microgel boundaries increases. When cultured with C2C12 myoblasts, cells localize to regions of higher curvature on the disk-shaped microgel surfaces. This altered localization affects cell-driven construction of large supraparticle scaffold assemblies, with spherical particles assembling without specific junction structure while disk microgels assemble preferentially on their curved surfaces. These results represent a unique spatiotemporal process for rapid reprocessing of microgels into anisotropic shapes, providing new opportunities to study shape-driven mechanobiological cues during and after granular hydrogel assembly.

Stem cell-related therapeutic technologies have garnered significant attention of the research community for their multi-faceted applications. To promote the therapeutic effects of stem cells, the strategies for cell microencapsulation in hydrogel microparticles have been widely explored, as the hydrogel microparticles have the potential to facilitate oxygen diffusion and nutrient transport alongside their ability to promote crucial cell-cell and cell-matrix interactions. Despite their significant promise, there is an acute shortage of automated, standardized, and reproducible platforms to further stem cell-related research. Microfluidics offers an intriguing platform to produce stem cell-laden hydrogel microparticles (SCHMs) owing to its ability to manipulate the fluids at the micrometer scale as well as precisely control the structure and composition of microparticles. In this review, the typical biomaterials and crosslinking methods for microfluidic encapsulation of stem cells as well as the progress in droplet-based microfluidics for the fabrication of SCHMs are outlined. Moreover, the important biomedical applications of SCHMs are highlighted, including regenerative medicine, tissue engineering, scale-up production of stem cells, and microenvironmental simulation for fundamental cell studies. Overall, microfluidics holds tremendous potential for enabling the production of diverse hydrogel microparticles and is worthy for various stem cell-related biomedical applications.

Zwitterionic hydrogels have high potential for cartilage tissue engineering due to their ultra-hydrophilicity, nonimmunogenicity, and superior antifouling properties. However, their application in this field has been limited so far, due to the lack of injectable zwitterionic hydrogels that allow for encapsulation of cells in a biocompatible manner. Herein, a novel strategy is developed to engineer cartilage employing zwitterionic granular hydrogels that are injectable, self-healing, in situ crosslinkable and allow for direct encapsulation of cells with biocompatibility. The granular hydrogel is produced by mechanical fragmentation of bulk photocrosslinked hydrogels made of zwitterionic carboxybetaine acrylamide (CBAA), or a mixture of CBAA and zwitterionic sulfobetaine methacrylate (SBMA). The produced microgels are enzymatically crosslinkable using horseradish peroxidase, to quickly stabilize the construct, resulting in a microporous hydrogel. Encapsulated human primary chondrocytes are highly viable and able to proliferate, migrate, and produce cartilaginous extracellular matrix (ECM) in the zwitterionic granular hydrogel. It is also shown that by increasing hydrogel porosity and incorporation of SBMA, cell proliferation and ECM secretion are further improved. This strategy is a simple and scalable method, which has high potential for expanding the versatility and application of zwitterionic hydrogels for diverse tissue engineering applications.

Granular microporous hydrogels are emerging as effective biomaterial scaffolds for tissue engineering due to their improved characteristics compared to traditional nanoporous hydrogels, which better promote cell viability, cell migration, cellular/tissue infiltration, and tissue regeneration. Recent advances have resulted in the development of granular hydrogels made of non-spherical microgels, which compared to those made of spherical microgels have higher macroporosity, more stable mechanical properties, and better ability to guide the alignment and differentiation of cells in anisotropic tissue. The development of these hydrogels as an emerging research area is attracting increasing interest in regenerative medicine. This review first summarizes the fabrication techniques available for non-spherical microgels with different aspect-ratios. Then, it introduces the development of granular microporous hydrogels made of non-spherical microgels, their physicochemical characteristics, and their applications in tissue regeneration. The limitations and future outlook of research on microporous granular hydrogels are also critically discussed.

The integration of magnetic nanoparticles (MNPs) into biomaterials offers exciting opportunities for tissue engineering as they enable better control over cell guidance, release of bioactive factors and tissue maturation. Despite their potential, challenges such as the heterogeneity of MNPs, their cytotoxicity and the need for precise control of MNP`s properties hinder their widespread application. Overcoming these challenges will require new interdisciplinary efforts and technological advances, including the development of mathematical tools and additional elaborations to ensure the biocompatibility of MNPs.

Myocardial Infarction (MI) is a leading cause of death worldwide. Metabolic modulation is a promising therapeutic approach to prevent adverse remodeling after MI. However, whether material-derived cues can treat MI through metabolic regulation is mainly unexplored. Herein, a Cu2+ loaded casein microgel (CuCMG) aiming to rescue the pathological intramyocardial metabolism for MI amelioration is developed. Cu2+ is an important ion factor involved in metabolic pathways, and intracardiac copper drain is observed after MI. It is thus speculated that intramyocardial supplementation of Cu2+ can rescue myocardial metabolism. Casein, a milk-derived protein, is screened out as Cu2+ carrier through molecular-docking based on Cu2+ loading capacity and accessibility. CuCMGs notably attenuate MI-induced cardiac dysfunction and maladaptive remodeling, accompanied by increased angiogenesis. The results from unbiased transcriptome profiling and oxidative phosphorylation analyses support the hypothesis that CuCMG prominently rescued the metabolic homeostasis of myocardium after MI. These findings enhance the understanding of the design and application of metabolic-modulating biomaterials for ischemic cardiomyopathy therapy.

In the tissue engineering field, the supply of oxygen to three-dimensional (3D) tissues is an important aspect to avoid necrosis due to hypoxia. Although oxygen-releasing bulk materials containing calcium peroxide (CaO2, CP) have attracted much attention, micrometer-sized oxygen-releasing soft materials would be advantageous because of their highly controllable structures, which can be applied for cell scaffolds, injectable materials, and bioink components in 3D bioprinting. In this study, oxygen-releasing microgels were fabricated via a droplet-based microfluidic system. Homogeneous, monodisperse and stable oxygen-releasing microgels were obtained by photo-crosslinking of droplets composed of biocompatible dextran modified with methacrylate groups and CP nanoparticles as an oxygen source. We also used our microfluidic system for the in situ amorphous calcium carbonate (CaCO3, ACC) formation on the surface of CP nanoparticles to achieve the controlled release of oxygen from the microgel. Oxygen release from an ACC-CP microgel in a neutral cell culture medium was suppressed because incorporation of CP in the ACC suppressed the reaction with water. Strikingly, stimuli to dissolve ACC such as a weak acidic conditions triggered the oxygen release from microgels loaded with ACC-CP, as the dissolution of CaCO3 allows CP to react. Taken together, applications of this new class of biomaterials for tissue engineering are greatly anticipated. In addition, the developed microfluidic system can be used for a variety of oxygen-releasing microgels by changing the substrates of the hydrogel network.

Cancer immunotherapy has made significant progress in recent years, with numerous studies worldwide. Immunotherapy has had a transformative impact on oncology and autoimmune diseases. In the biomedical arena, hydrogels with good properties are widely used in cancer immunotherapy. Our study used bibliometrics to analyze the changing trends in using hydrogels for cancer immunotherapy.

From 2013 to 2023, a systematic search was conducted in the Web of Science Core Collection database to identify reviews and articles discussing the applications of hydrogels in cancer immunotherapy. The software CiteSpace was used to visually perform the bibliometric analysis in terms of research trends, countries, institutions, authors, journals, and keywords. Individual authors' productivity was assessed with the Lotka's law. The most relevant publication sources were identified by Bradford's law.

A total of 422 English-language publications related to hydrogels in cancer immunotherapy were collected. The number of annual publications increased rapidly after 2021 and remained constant for the past two years. China published the most articles in this field. The institution with the maximum number of published articles was the Chinese Academy of Sciences in China. Chen. Q was the most prolific author, and Liu. Z was the second most published author. In terms of journal contributions, the journal "Biomaterials" had the highest number of publications (n = 30). Biomaterials, Advanced Functional Materials and Journal of Controlled Release were the most influential journals. Keyword analysis revealed that cancer immunotherapy, drug delivery, immunogenic cell death, tumor microenvironment, injectable hydrogels, and immune checkpoint blockade were the primary research hotspots. In recent 3 years, adoptive T-cell therapy, black phosphorus, cell capture, adaptive cell therapy, tumor microenvironment, photodynamic therapy, and sustained release were the research hotspots in this field. Our study summarizes the objective of hydrogels in cancer immunotherapy in recent years, providing a reference for potential researchers in related field.

This bibliometric analysis shows the progress and trend of research on hydrogels in cancer immunotherapy. This study provides a significant avenue for future investigation into current concerns and trends in research within this field.

Cyanidin-3-O-glucoside (C3G), is an anthocyanin mainly found in berries, and can also be produced by microorganisms. It has been traditionally used as a natural coloring agent for decades. Recently, it has been investigated for its high antioxidant activity and anti-cancer attributes. C3G has low bioavailability and is sensitive to oxidation and gastric pH; therefore, it is encapsulated in nanoliposomes to enhance its bio-availability, targeted delivery- and efficacy against chronic disease.

In this review, the role of C3G nanoliposomes against major chronic diseases has been discussed. The focus was on research findings and the mechanism of action to affect the proliferation of cancer, neuro disease and cardiovascular problems. It also discussed the formulation of nanoliposomes, their role in nutraceutical delivery and enhancement in C3G bioavailability.

Data suggested that nanoliposomes safeguard C3G, enhance bioavailability, and ensure safe, adequate and targeted delivery. It can reduce the impact of cancer and inflammation by inhibiting the ß-catenin/O6-methylguanine-DNA methyltransferase (MGMT) pathway and upregulating miR-214-5p. Formation of C3G nanoliposomes significantly enhances the nutraceutical efficacy of C3G against major chronic disease therefore, C3G nanoliposomes might be a future-based nutraceutical to treat major chronic diseases, including cancer, neuro problems and CVD, but challenges remain in finding correct dose and techniques to maximize its efficacy.

3D bioprinting technology, a subset of 3D printing technology, is currently witnessing widespread utilization in tissue repair and regeneration endeavors. In particular, light-based 3D bioprinting technology has garnered significant interest and favor. Central to its successful implementation lies the judicious selection of photosensitive polymers. Moreover, by fine-tuning parameters such as light irradiation time, choice of photoinitiators and crosslinkers, and their concentrations, the properties of the scaffolds can be tailored to suit the specific requirements of the targeted tissue repair sites. In this comprehensive review, we provide an overview of commonly utilized bio-inks suitable for light-based 3D bioprinting, delving into the distinctive characteristics of each material. Furthermore, we delineate strategies for bio-ink selection tailored to diverse repair locations, alongside methods for optimizing printing parameters. Ultimately, we present a coherent synthesis aimed at enhancing the practical application of light-based 3D bioprinting technology in tissue engineering, while also addressing current challenges and future prospects.

The proficient handling of diabetic wounds, a rising issue coinciding with the global escalation of diabetes cases, poses significant clinical difficulties. A range of biofunctional dressings have been engineered and produced to expedite the healing process of diabetic wounds. This study proposes a multifunctional hydrogel dressing for diabetic wound healing, which is composed of Polyvinyl Alcohol (PVA) and N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-teramethylpropane-1, 3-diaminium (TSPBA), and a dual-drug loaded Gelatin methacryloyl (GM) microgel. The GM microgel is loaded with sodium fusidate (SF) and nanoliposomes (LP) that contain metformin hydrochloride (MH). Notably, adhesive and self-healing properties the hydrogel enhance their therapeutic potential and ease of application. In vitro assessments indicate that SF-infused hydrogel can eliminate more than 98% of bacteria within 24 h and maintain a sustained release over 15 days. Additionally, MH incorporated within the hydrogel has demonstrated effective glucose level regulation for a duration exceeding 15 days. The hydrogel demonstrates a sustained ability to neutralize ROS throughout the entire healing process, predominantly by electron donation and sequestration. This multifunctional hydrogel dressing, which integrated biological functions of efficient bactericidal activity against both MSSA and MRSA strains, blood glucose modulation, and control of active oxygen levels, has successfully promoted the healing of diabetic wounds in rats in 14 days. The hydrogel dressing exhibited significant effectiveness in facilitating the healing process of diabetic wounds, highlighting its considerable promise for clinical translation.

The present study aims to develop and characterize a controlled-release delivery system for protein therapeutics in skeletal muscle regeneration following an acute injury. The therapeutic protein, a membrane-GPI anchored protein called Cripto, was immobilized in an injectable hydrogel delivery vehicle for local administration and sustained release. The hydrogel was made of poly(ethylene glycol)-fibrinogen (PEG-Fibrinogen, PF), in the form of injectable microspheres. The PF microspheres exhibited a spherical morphology with an average diameter of approximately 100 micrometers, and the Cripto protein was uniformly entrapped within them. The release rate of Cripto from the PF microspheres was controlled by tuning the crosslinking density of the hydrogel, which was varied by changing the concentration of poly(ethylene glycol) diacrylate (PEG-DA) crosslinker. In vitro experiments confirmed a sustained-release profile of Cripto from the PF microspheres for up to 27 days. The released Cripto was biologically active and promoted the in vitro proliferation of mouse myoblasts. The therapeutic effect of PF-mediated delivery of Cripto in vivo was tested in a cardiotoxin (CTX)-induced muscle injury model in mice. The Cripto caused an increase in the in vivo expression of the myogenic markers Pax7, the differentiation makers eMHC and Desmin, higher numbers of centro-nucleated myofibers and greater areas of regenerated muscle tissue. Collectively, these results establish the PF microspheres as a potential delivery system for the localized, sustained release of therapeutic proteins toward the accelerated repair of damaged muscle tissue following acute injuries.

Microgel-based in vivo biosensor is an innovative technological concept that focuses on creating nano- and/or micro-scale sensors for health monitoring. Microgel-based sensor (MBS) enables highly sensitive detection of a phenomenon-of-interest through electromagnetic characteristics. This paper presents a novel MBS for implantable health monitoring, and the research contributions can be summarized into two main aspects. Firstly, a novel synthesis method for microgel nanoparticles designed for blood glucose detection is proposed, and a new MBS sensitive to the in vivo microenvironment conditions is successfully synthesized. Comprehensive material characterization is conducted, including analyzing the material's performance in different blood glucose environments and its temporal variations. Secondly, for this material, its dielectric constant is detected to respond to physiological signals in the human body. MBS is employed as in vivo sensors, converting biological signals within the body into morphological changes of microgel particles (i.e., switching between expansion and contraction forms). Through dielectric constant probes, we detect the dielectric properties of MBS for sensing applications, providing crucial insights for potential biomedical uses of microgels. To discuss the response of the proposed MBS to changes in blood glucose, we consider scenarios of high and low blood sugar. At 2 GHz, it is observed that the dielectric constant is 60.27 during low blood sugar and 20.13 during high blood sugar. These results indicate a high sensitivity of MBS to changes in blood glucose levels.

Photochemical cross-linking is a key step for manufacturing microgels in numerous applications, including drug delivery, tissue engineering, material production, and wound healing. Existing photochemical cross-linking techniques in microfluidic devices rely on UV curing, which can cause cell and DNA damage. We address this challenge by developing a microfluidic workflow for producing microgels using visible light-driven photochemical cross-linking of aqueous droplets dispersed in a continuous oil phase. We report a proof-of-concept to construct microgels from the protein Bovine Serum Albumin (BSA) with [Ru(bpy)3]2+ mediated cross-linking. By controlling the capillary number of the continuous and dispersed phases, the volumetric flow rate, and the photochemical reaction time within the microfluidic tubing, we demonstrate the construction of protein microgels with controllable and uniform dimensions. Our technique can, in principle, be applied to a wide range of different proteins with biological and responsive properties. This work therefore bridges the gap between hydrogel manufacturing using visible light and microfluidic microgel templating, facilitating numerous biomedical applications.

Injectable hydrogels find extensive application in the treatment of diabetic wound healing. However, traditional bulk hydrogels are significantly limited due to their nano-porous structure, which obstructs cell migration and tissue infiltration. Moreover, regulating inflammation and matrix metalloproteinase -9 (MMP-9) expression in diabetic wounds is crucial for enhancing wound healing. This study marks the first instance of introducing an efficient, scalable, and simple method for producing microfiber-gel granules encapsulating bioceramics powders. Utilizing this method, an injectable microporous granular microgel-fiber hydrogel (MFgel) is successfully developed by assembling microgel-fibers made from hyaluronic acid (HA) and sodium alginate (SA) loaded with small interfering RNA (siRNA) and bioglass (BG) particles. Compared to traditional hydrogels (Tgel), MFgel possesses a highly interconnected network with micron-sized pores, demonstrating favorable properties for cell adhesion and penetration in in vitro experiments. Additionally, MFgel exhibits a higher compressive modulus and superior mechanical stability. When implanted subcutaneously in mice, MFgel promotes cellular and tissue infiltration, facilitating cell proliferation. Furthermore, when applied to skin defects in diabetic rats, MFgel not only effectively regulates inflammation and suppresses MMP-9 expression but also enhances angiogenesis and collagen deposition, thereby significantly accelerating diabetic wound healing. Taken together, this hydrogel possesses great potential in diabetic wound healing applications.

In response to the growing demand for organ substitutes, tissue engineering has evolved significantly. However, it is still challenging to create functional tissues and organs. Tissue engineering from the 'bottom-up' is promising on solving this problem due to its ability to construct tissues with physiological complexity. The workflow of this strategy involves two key steps: the creation of building blocks, and the subsequent assembly. There are many techniques developed for the two pivotal steps. Notably, bioprinting is versatile among these techniques and has been widely used in research. With its high level of automation, bioprinting has great capacity in engineering tissues with precision and holds promise to construct multi-material tissues. In this review, we summarize the techniques applied in fabrication and assembly of building blocks. We elaborate mechanisms and applications of bioprinting, particularly in the 'bottom-up' strategy. We state our perspectives on future trends of bottom-up tissue engineering, hoping to provide useful reference for researchers in this field.

Critical limb ischemia (CLI) is a devastating disease characterized by the progressive blockage of blood vessels. Although the paracrine effect of growth factors in stem cell therapy made it a promising angiogenic therapy for CLI, poor cell survival in the harsh ischemic microenvironment limited its efficacy. Thus, an imperative need exists for a stem-cell delivery method that enhances cell survival. Here, a collagen microgel (CMG) cell-delivery scaffold (40 × 20 μm) was fabricated via micro-fragmentation from collagen-hyaluronic acid polyionic complex to improve transplantation efficiency. Culturing human adipose-derived stem cells (hASCs) with CMG enabled integrin receptors to interact with CMG to form injectable 3-dimensional constructs (CMG-hASCs) with a microporous microarchitecture and enhanced mass transfer. CMG-hASCs exhibited higher cell survival (p < 0.0001) and angiogenic potential in tube formation and aortic ring angiogenesis assays than cell aggregates. Injection of CMG-hASCs intramuscularly into CLI mice increased blood perfusion and limb salvage ratios by 40 % and 60 %, respectively, compared to cell aggregate-treated mice. Further immunofluorescent analysis revealed that transplanted CMG-hASCs have greater muscle regenerative and angiogenic potential, with enhanced cell survival than cell aggregates (p < 0.05). Collectively, we propose CMG as a cell-assembling platform and CMG-hASCs as promising therapeutics to treat CLI.

Advancements in 3D bioprinting have been hindered by the trade-off between printability and biological functionality. Existing bioinks struggle to meet both requirements simultaneously. However, new types of bioinks composed of densely packed microgels promise to address this challenge. These bioinks possess intrinsic porosity, allowing for cell growth, oxygen and nutrient transport, and better immunomodulatory properties, leading to superior biological functions. In this review, we highlight key trends in the development of these granular bioinks. Using examples, we demonstrate how granular bioinks overcome the trade-off between printability and cell function. Granular bioinks show promise in 3D bioprinting, yet understanding their unique structure-property-function relationships is crucial to fully leverage the transformative capabilities of these new types of bioinks in bioprinting.

Three-dimensional (3D) bioprinting has emerged as a groundbreaking technology for fabricating intricate and functional tissue constructs. Central to this technology are the bioinks, which provide structural support and mimic the extracellular environment, which is crucial for cellular executive function. This review summarizes the latest developments in microparticulate inks for 3D bioprinting and presents their inherent challenges. We categorize micro-particulate materials, including polymeric microparticles, tissue-derived microparticles, and bioactive inorganic microparticles, and introduce the microparticle ink formulations, including granular microparticles inks consisting of densely packed microparticles and composite microparticle inks comprising microparticles and interstitial matrix. The formulations of these microparticle inks are also delved into highlighting their capabilities as modular entities in 3D bioprinting. Finally, existing challenges and prospective research trajectories for advancing the design of microparticle inks for bioprinting are discussed.

Foreign body response (FBR) is a pervasive problem for biomaterials used in tissue engineering. Zwitterionic hydrogels have emerged as an effective solution to this problem, due to their ultra-low fouling properties, which enable them to effectively inhibit FBRin vivo. However, no versatile zwitterionic bioink that allows for high resolution extrusion bioprinting of tissue implants has thus far been reported. In this work, we introduce a simple, novel method for producing zwitterionic microgel bioink, using alginate methacrylate (AlgMA) as crosslinker and mechanical fragmentation as a microgel fabrication method. Photocrosslinked hydrogels made of zwitterionic carboxybetaine acrylamide (CBAA) and sulfobetaine methacrylate (SBMA) are mechanically fragmented through meshes with aperture diameters of 50 and 90µm to produce microgel bioink. The bioinks made with both microgel sizes showed excellent rheological properties and were used for high-resolution printing of objects with overhanging features without requiring a support structure or support bath. The AlgMA crosslinker has a dual role, allowing for both primary photocrosslinking of the bulk hydrogel as well as secondary ionic crosslinking of produced microgels, to quickly stabilize the printed construct in a calcium bath and to produce a microporous scaffold. Scaffolds showed ∼20% porosity, and they supported viability and chondrogenesis of encapsulated human primary chondrocytes. Finally, a meniscus model was bioprinted, to demonstrate the bioink's versatility at printing large, cell-laden constructs which are stable for furtherin vitroculture to promote cartilaginous tissue production. This easy and scalable strategy of producing zwitterionic microgel bioink for high resolution extrusion bioprinting allows for direct cell encapsulation in a microporous scaffold and has potential forin vivobiocompatibility due to the zwitterionic nature of the bioink.

Tissue engineering is an advanced and potential biomedical approach to treat patients suffering from lost or failed an organ or tissue to repair and regenerate damaged tissues that increase life expectancy. The biopolymers have been used to fabricate smart hydrogels to repair damaged tissue as they imitate the extracellular matrix (ECM) with intricate structural and functional characteristics. These hydrogels offer desired and controllable qualities, such as tunable mechanical stiffness and strength, inherent adaptability and biocompatibility, swellability, and biodegradability, all crucial for tissue engineering. Smart hydrogels provide a superior cellular environment for tissue engineering, enabling the generation of cutting-edge synthetic tissues due to their special qualities, such as stimuli sensitivity and reactivity. Numerous review articles have presented the exceptional potential of hydrogels for various biomedical applications, including drug delivery, regenerative medicine, and tissue engineering. Still, it is essential to write a comprehensive review article on smart hydrogels that successfully addresses the essential challenging issues in tissue engineering. Hence, the recent development on smart hydrogel for state-of-the-art tissue engineering conferred progress, highlighting significant challenges and future perspectives. This review discusses recent advances in smart hydrogels fabricated from biological macromolecules and their use for advanced tissue engineering. It also provides critical insight, emphasizing future research directions and progress in tissue engineering.

In this report, a versatile method is demonstrated to create colloidal suprastructures by assembly and supramolecular interlinking of microgels using droplet-based microfluidics. The behavior of the microgels is systematically investigated to evaluate the influence of their concentration on their distribution between the continuous, the droplet phase, and the interface. At low concentrations, microgels are mainly localized at the water-oil interface whereas an excess of microgels results, following the complete coverage of the water-oil interface, in their distribution in the continuous phase. To stabilize the colloidal suprastructure, on-chip gelation is introduced by adding natural polyphenol tannic acid (TA) in the water phase. TA forms interparticle linking between the poly(N-vinylcaprolactam) (PVCL) microgels by supramolecular interactions. The combination of supramolecular interlinking with the variation of the microgel concentration in microfluidic droplets enables on-chip fabrication of defined colloidal suprastructures with morphologies ranging from colloidosomes to colloidal supraballs. The obtained supracolloidal structures exhibit a pH-responsive behavior with a disintegration at alkaline conditions within a scale of seconds. The destabilization process results from the deprotonation of phenolic groups and destruction of hydrogen bonds with PVCL chains at higher pH.