Stimuli-Mediated Macrophage Switching, Unraveling the Dynamics at the Nanoplatforms-Macrophage Interface.

Macrophages play an essential role in immunotherapy and tissue regeneration owing to their remarkable plasticity and diverse functions. Recent bioengineering developments have focused on using external physical stimuli such as electric and magnetic fields, temperature, and compressive stress, among others, on micro/nanostructures to induce macrophage polarization, thereby increasing their therapeutic potential. However, it is difficult to find a concise review of the interaction between physical stimuli, advanced micro/nanostructures, and macrophage polarization. This review examines the present research on physical stimuli-induced macrophage polarization on micro/nanoplatforms, emphasizing the synergistic role of fabricated structure and stimulation for advanced immunotherapy and tissue regeneration. A concise overview of the research advancements investigating the impact of physical stimuli, including electric fields, magnetic fields, compressive forces, fluid shear stress, photothermal stimuli, and multiple stimulations on the polarization of macrophages within complex engineered structures, is provided. The prospective implications of these strategies in regenerative medicine and immunotherapeutic approaches are highlighted. This review will aid in creating stimuli-responsive platforms for immunomodulation and tissue regeneration.

Unzipped carbon nanotubes assisted 3D printable functionalized chitosan hydrogels for strain sensing applications.

Developing multifunctional hydrogels for wearable strain sensors has received significant attention due to their diverse applications, including human motion detection, personalized healthcare, soft robotics, and human-machine interfaces. However, integrating the required characteristics into one component remains challenging. To overcome these limitations, we synthesized multifunctional hydrogels using carboxymethyl chitosan (CMCS) and unzipped carbon nanotubes (f-CNTs) as strain sensor via a one-pot strategy. The polar groups in CMCS and f-CNTs enhance the properties of the hydrogels through different interactions. The hydrogels show superior printability with a uniformity factor (U) of 0.996 ± 0.049, close to 1. The f-CNTs-assisted hydrogels showed improved storage modulus (8.8 × 105 Pa) than the pure polymer hydrogel. The hydrogels adequately adhered to different surfaces, including human skin, plastic, plastic/glass interfaces, and printed polymers. The hydrogels demonstrated rapid self-healing and good conductivity. The biocompatibility of the hydrogels was assessed using human fibroblast cells. No adverse effects were observed with hydrogels, showing their biocompatibility. Furthermore, hydrogels exhibited antibacterial potential against Escherichia coli. The developed hydrogel exhibited unidirectional motion and complex letter recognition potential with a strain sensitivity of 2.4 at 210 % strain. The developed hydrogels could explore developing wearable electronic devices for detecting human motion.

Recent advances and biomedical application of 3D printed nanocellulose-based adhesive hydrogels: A review.

Nanocellulose-based tissue adhesives show promise for achieving rapid hemostasis and effective wound healing. Conventional methods, such as sutures and staples, have limitations, prompting the exploration of bioadhesives for direct wound adhesion and minimal tissue damage. Nanocellulose, a hydrolysis product of cellulose, exhibits superior biocompatibility and multifunctional properties, gaining interest as a base material for bioadhesive development. This study explores the potential of nanocellulose-based adhesives for hemostasis and wound healing using 3D printing techniques. Nanocellulose enables the creation of biodegradable adhesives with minimal adverse effects and opens avenues for advanced wound healing and complex tissue regeneration, such as skin, blood vessels, lungs, cartilage, and muscle. This study reviews recent trends in various nanocellulose-based 3D printed hydrogel patches for tissue engineering applications. The review also introduces various types of nanocellulose and their synthesis, surface modification, and bioadhesive fabrication techniques via 3D printing for smart wound healing.

Synthesis and reactivity of N-heterocyclic carbene (NHC)-supported heavier nitrile ylides.

The synthesis and isolation of stable heavier analogues of nitrile ylide as N-heterocyclic carbene (NHC) adducts of phosphasilenyl-tetrylene [(NHC)(TerAr)Si(H)PE14(TerAr)] (E14 = Ge 1, Sn 2; TerAr = 2,6-Mes2C6H3, NHC = IMe4) are reported. The delocalized Si-P-E14 π-conjugation was examined experimentally and computationally. Interestingly, the germanium derivative 1 exhibits a 1,3-dipolar nature, leading to an unprecedented [3 + 2] cycloaddition with benzaldehyde, resulting in unique heterocycles containing four heteroatoms from group 14, 15, and 16. Further exploiting the nucleophilicity of germanium, activation of the P-P bond of P4 was achieved, leading to a [(NHC)(phosphasilenyl germapolyphide)] complex. Moreover, the [3 + 2] cycloaddition and the σ-bond activation by 1 resemble the characteristics of the classic nitrile ylide.

Manufacturing 3D Biomimetic Tissue: A Strategy Involving the Integration of Electrospun Nanofibers with a 3D-Printed Framework for Enhanced Tissue Regeneration.

3D printing and electrospinning are versatile techniques employed to produce 3D structures, such as scaffolds and ultrathin fibers, facilitating the creation of a cellular microenvironment in vitro. These two approaches operate on distinct working principles and utilize different polymeric materials to generate the desired structure. This review provides an extensive overview of these techniques and their potential roles in biomedical applications. Despite their potential role in fabricating complex structures, each technique has its own limitations. Electrospun fibers may have ambiguous geometry, while 3D-printed constructs may exhibit poor resolution with limited mechanical complexity. Consequently, the integration of electrospinning and 3D-printing methods may be explored to maximize the benefits and overcome the individual limitations of these techniques. This review highlights recent advancements in combined techniques for generating structures with controlled porosities on the micro-nano scale, leading to improved mechanical structural integrity. Collectively, these techniques also allow the fabrication of nature-inspired structures, contributing to a paradigm shift in research and technology. Finally, the review concludes by examining the advantages, disadvantages, and future outlooks of existing technologies in addressing challenges and exploring potential opportunities.

Extracellular Matrix-Bioinspired Anisotropic Topographical Cues of Electrospun Nanofibers: A Strategy of Wound Healing through Macrophage Polarization.

The skin serves as the body's outermost barrier and is the largest organ, providing protection not only to the body but also to various internal organs. Owing to continuous exposure to various external factors, it is susceptible to damage that can range from simple to severe, including serious types of wounds such as burns or chronic wounds. Macrophages play a crucial role in the entire wound-healing process and contribute significantly to skin regeneration. Initially, M1 macrophages infiltrate to phagocytose bacteria, debris, and dead cells in fresh wounds. As tissue repair is activated, M2 macrophages are promoted, reducing inflammation and facilitating restoration of the dermis and epidermis to regenerate the tissue. This suggests that extracellular matrix (ECM) promotes cell adhesion, proliferation, migrationand macrophage polarization. Among the numerous strategies, electrospinning is a versatile technique for obtaining ECM-mimicking structures with anisotropic and isotropic topologies of micro/nanofibers. Various electrospun biomaterials influence macrophage polarization based on their isotropic or anisotropic topologies. Moreover, these fibers possess a high surface-area-to-volume ratio, promoting the effective exchange of vital nutrients and oxygen, which are crucial for cell viability and tissue regeneration. Micro/nanofibers with diverse physical and chemical properties can be tailored to polarize macrophages toward skin regeneration and wound healing, depending on specific requirements. This review describes the significance of micro/nanostructures for activating macrophages and promoting wound healing.

Photoexcitation of Distinct Divalent Palladium Complexes in Cross-Coupling Amination Under Air.

The development of metal complexes that function as both photocatalyst and cross-coupling catalyst remains a challenging research topic. So far, progress has been shown in palladium(0) excited-state transition metal catalysis for the construction of carbon-carbon bonds where the oxidative addition of alkyl/aryl halides to zero-valent palladium (Pd0 ) is achievable at room temperature. In contrast, the analogous process with divalent palladium (PdII ) is uphill and endothermic. For the first time, we report that divalent palladium can act as a light-absorbing species that undergoes double excitation to realize carbon-nitrogen (C-N) cross-couplings under air. Differently substituted aryl halides can be applied in the mild, and selective cross-coupling amination using palladium acetate as both photocatalyst and cross-coupling catalyst at room temperature. Density functional theory studies supported by mechanistic investigations provide insight into the reaction mechanism.

Stimuli-Responsive 3D Printable Conductive Hydrogel: A Step toward Regulating Macrophage Polarization and Wound Healing.

Conductive hydrogels (CHs) are promising alternatives for electrical stimulation of cells and tissues in biomedical engineering. Wound healing and immunomodulation are complex processes that involve multiple cell types and signaling pathways. 3D printable conductive hydrogels have emerged as an innovative approach to promote wound healing and modulate immune responses. CHs can facilitate electrical and mechanical stimuli, which can be beneficial for altering cellular metabolism and enhancing the efficiency of the delivery of therapeutic molecules. This review summarizes the recent advances in 3D printable conductive hydrogels for wound healing and their effect on macrophage polarization. This report also discusses the properties of various conductive materials that can be used to fabricate hydrogels to stimulate immune responses. Furthermore, this review highlights the challenges and limitations of using 3D printable CHs for future material discovery. Overall, 3D printable conductive hydrogels hold excellent potential for accelerating wound healing and immune responses, which can lead to the development of new therapeutic strategies for skin and immune-related diseases.

A Review on Electroactive Polymer-Metal Composites: Development and Applications for Tissue Regeneration.

Electroactive polymer-metal composites (EAPMCs) have gained significant attention in tissue engineering owing to their exceptional mechanical and electrical properties. EAPMCs develop by combining an electroactive polymer matrix and a conductive metal. The design considerations include choosing an appropriate metal that provides mechanical strength and electrical conductivity and selecting an electroactive polymer that displays biocompatibility and electrical responsiveness. Interface engineering and surface modification techniques are also crucial for enhancing the adhesion and biocompatibility of composites. The potential of EAPMC-based tissue engineering revolves around its ability to promote cellular responses, such as cell adhesion, proliferation, and differentiation, through electrical stimulation. The electrical properties of these composites can be used to mimic natural electrical signals within tissues and organs, thereby aiding tissue regeneration. Furthermore, the mechanical characteristics of the metallic components provide structural reinforcement and can be modified to align with the distinct demands of various tissues. EAPMCs have extraordinary potential as regenerative biomaterials owing to their ability to promote beneficial effects in numerous electrically responsive cells. This study emphasizes the characteristics and applications of EAPMCs in tissue engineering.

Polyphenolic Carbon Quantum Dots with Intrinsic Reactive Oxygen Species Amplification for Two-Photon Bioimaging and In Vivo Tumor Therapy.

Recent studies indicate that mitochondrial dysfunctions and DNA damage have a critical influence on cell survival, which is considered one of the therapeutic targets for cancer therapy. In this study, we demonstrated a comparative study of the effect of polyphenolic carbon quantum dots (CQDs) on in vitro and in vivo antitumor efficacy. Dual emissive (green and yellow) shape specific polyphenolic CQDs (G-CQDs and Y-CQDs) were synthesized from easily available nontoxic precursors (phloroglucinol), and the antitumor property of the as-synthesized probe was investigated as compared to round-shaped blue emissive CQDs (B-CQDs) derived from well-reported precursor citric acid and urea. The B-CQDs had a nuclei-targeting property, and G-CQDs and Y-CQDs had mitochondria-targeting properties. We have found that the polyphenol containing CQDs (at a dose of 100 µg mL-1) specifically attack mitochondria by excess accumulation, altering the metabolism, inhibiting branching pattern, imbalanced Bax/Bcl-2 homeostasis, and ultimately generating oxidative stress levels, leading to oxidative stress-induced cell death in cancer cells in vitro. We show that G-CQDs are the main cause of oxidative stress in cancer cells because of their ability to produce sufficient •OH- and 1O2 radicals, evidenced by electron paramagnetic resonance spectroscopy and a terephthalic acid test. Moreover, the near-infrared absorption properties of the CQDs were exhibited in two-photon (TP) emission, which was utilized for TP cellular imaging of cancer cells without photobleaching. The in vivo antitumor test further discloses that intratumoral injection of G-CQDs can significantly augment the treatment efficacy of subcutaneous tumors without any adverse effects on BalB/c nude mice. We believe that shape-specific polyphenolic CQD-based nanotheranostic agents have a potential role in tumor therapy, thus proving an insight on treatment of malignant cancers.

Immediate responses to ambient light in vivo reveal distinct subpopulations of suprachiasmatic VIP neurons.

The circadian rhythm pacemaker, the suprachiasmatic nucleus (SCN), mediates light entrainment via vasoactive intestinal peptide (VIP) neurons (SCNVIP). Yet, how these neurons uniquely respond and connect to intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin (Opn4) has not been determined functionally in freely behaving animals. To address this, we first used monosynaptic tracing from SCNVIP neurons in mice and identified two SCNVIP subpopulations. Second, we recorded calcium changes in response to ambient light, at both bulk and single-cell levels, and found two unique activity patterns in response to high- and low-intensity blue light. The activity patterns of both subpopulations could be manipulated by application of an Opn4 antagonist. These results suggest that the two SCNVIP subpopulations connect to two types of Opn4-expressing ipRGCs, likely M1 and M2, but only one is responsive to red light. These findings have important implications for our basic understanding of non-image-forming circadian light processing.

Trackable and highly fluorescent nanocellulose-based printable bio-resins for image-guided tissue regeneration.

Dynamic tracking of cell migration during tissue regeneration remains challenging owing to imaging techniques that require sophisticated devices, are often lethal to healthy tissues. Herein, we developed a 3D printable non-invasive polymeric hydrogel based on 2,2,6,6-(tetramethylpiperidin-1-yl) oxyl (TEMPO)-oxidized nanocellulose (T-CNCs) and carbon dots (CDs) for the dynamic tracking of cells. The as-prepared T-CNC@CDs were used to fabricate a liquid bio-resin containing gelatin methacryloyl (GelMA) and polyethylene glycol diacrylate (GPCD) for digital light processing (DLP) bioprinting. The shear-thinning properties of the GPCD bio-resin were further improved by the addition of T-CNC@CDs, allowing high-resolution 3D printing and bioprinting of human cells with higher cytocompatibility (viability ∼95 %). The elastic modulus of the printed GPCD hydrogel was found to be ∼13 ± 4.2 kPa, which is ideal for soft tissue engineering. The as-fabricated hydrogel scaffold exhibited tunable structural color property owing to the addition of T-CNC@CDs. Owing to the unique fluorescent property of T-CNC@CDs, the human skin cells could be tracked within the GPCD hydrogel up to 30 days post-printing. Therefore, we anticipate that GPCD bio-resin can be used for 3D bioprinting with high structural stability, dynamic tractability, and tunable mechanical stiffness for image-guided tissue regeneration.

The mechanism of visible light-induced C-C cross-coupling by Csp3-H bond activation.

Csp3-C cross-coupling by activating Csp3-H bonds is a dream reaction for the chemical community, and visible light-induced transition metal-catalysis under mild reaction conditions is considered a powerful tool to achieve it. Advancement of this research area is still in its infancy because of the chemical and technical complexity of this catalysis. Mechanistic studies illuminating the operative reaction pathways can rationalize the increasing amount of experimental catalysis data and provide the knowledge allowing faster and rational advances in the field. This goal requires complementary experimental and theoretical mechanistic studies, as each of them is unfit to clarify the operative mechanisms alone. In this tutorial review we summarize representative experimental and computational mechanistic studies, highlighting weaknesses, strengths, and synergies between the two approaches.

Unraveling the potential of 3D bioprinted immunomodulatory materials for regulating macrophage polarization: State-of-the-art in bone and associated tissue regeneration.

Macrophage-assisted immunomodulation is an alternative strategy in tissue engineering, wherein the interplay between pro-inflammatory and anti-inflammatory macrophage cells and body cells determines the fate of healing or inflammation. Although several reports have demonstrated that tissue regeneration depends on spatial and temporal regulation of the biophysical or biochemical microenvironment of the biomaterial, the underlying molecular mechanism behind immunomodulation is still under consideration for developing immunomodulatory scaffolds. Currently, most fabricated immunomodulatory platforms reported in the literature show regenerative capabilities of a particular tissue, for example, endogenous tissue (e.g., bone, muscle, heart, kidney, and lungs) or exogenous tissue (e.g., skin and eye). In this review, we briefly introduced the necessity of the 3D immunomodulatory scaffolds and nanomaterials, focusing on material properties and their interaction with macrophages for general readers. This review also provides a comprehensive summary of macrophage origin and taxonomy, their diverse functions, and various signal transduction pathways during biomaterial-macrophage interaction, which is particularly helpful for material scientists and clinicians for developing next-generation immunomodulatory scaffolds. From a clinical standpoint, we briefly discussed the role of 3D biomaterial scaffolds and/or nanomaterial composites for macrophage-assisted tissue engineering with a special focus on bone and associated tissues. Finally, a summary with expert opinion is presented to address the challenges and future necessity of 3D bioprinted immunomodulatory materials for tissue engineering.

TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo.

The role of TREM2 in Alzheimer's disease (AD) is not fully understood. Previous studies investigating the effect of TREM2 deletion on tauopathy mouse models without the contribution of b-amyloid have focused only on tau overexpression models. Herein, we investigated the effects of TREM2 deficiency on tau spreading using a mouse model in which endogenous tau is seeded to produce AD-like tau features. We found that Trem2-/- mice exhibit attenuated tau pathology in multiple brain regions concomitant with a decreased microglial density. The neuroinflammatory profile in TREM2-deficient mice did not induce an activated inflammatory response to tau pathology. These findings suggest that reduced TREM2 signaling may alter the response of microglia to pathological tau aggregates, impairing their activation and decreasing their capacity to contribute to tau spreading. However, caution should be exercised when targeting TREM2 as a therapeutic entry point for AD until its involvement in tau aggregation and propagation is better understood.

Nanocellulose-assisted 3D-printable, transparent, bio-adhesive, conductive, and biocompatible hydrogels as sensors and moist electric generators.

Transparent hydrogels have found increasing applications in wearable electronics, printable devices, and tissue engineering. Integrating desired properties, such as conductivity, mechanical strength, biocompatibility, and sensitivity, in one hydrogel remains challenging. To address these challenges, multifunctional hydrogels of methacrylate chitosan, spherical nanocellulose, and ß-glucan with distinct physicochemical characteristics were combined to develop multifunctional composite hydrogels. The nanocellulose facilitated the self-assembly of the hydrogel. The hydrogels exhibited good printability and adhesiveness. Compared with the pure methacrylated chitosan hydrogel, the composite hydrogels exhibited improved viscoelasticity, shape memory, and conductivity. The biocompatibility of the composite hydrogels was monitored using human bone marrow-derived stem cells. Their motion-sensing potential was analyzed on different parts of the human body. The composite hydrogels also possessed temperature-responsiveness and moisture-sensing abilities. These results suggest that the developed composite hydrogels demonstrate excellent potential to fabricate 3D-printable devices for sensing and moist electric generator applications.

A 3D Bioprinted Nanoengineered Hydrogel with Photoactivated Drug Delivery for Tumor Apoptosis and Simultaneous Bone Regeneration via Macrophage Immunomodulation.

One of the significant challenges in bone tissue engineering (BTE) is the healing of traumatic tissue defects owing to the recruitment of local infection and delayed angiogenesis. Herein, a 3D printable multi-functional hydrogel composing polyphenolic carbon quantum dots (CQDs, 100 µg mL-1 ) and gelatin methacryloyl (GelMA, 12 wt%) is reported for robust angiogenesis, bone regeneration and anti-tumor therapy. The CQDs are synthesized from a plant-inspired bioactive molecule, 1, 3, 5-trihydroxybenzene. The 3D printed GelMA-CQDs hydrogels display typical shear-thinning behavior with excellent printability. The fabricated hydrogel displayed M2 polarization of macrophage (Raw 264.7) cells via enhancing anti-inflammatory genes (e.g., IL-4 and IL10), and induced angiogenesis and osteogenesis of human bone mesenchymal stem cells (hBMSCs). The bioprinted hBMSCs are able to produce vessel-like structures after 14 d of incubation. Furthermore, the 3D printed hydrogel scaffolds also show remarkable near infra-red (NIR) responsive properties under 808 nm NIR light (1.0 W cm-2 ) irradiation with controlled release of antitumor drugs (≈49%) at pH 6.5, and thereby killing the osteosarcoma cells. Therefore, it is anticipated that the tissue regeneration and healing ability with therapeutic potential of the GelMA-CQDs scaffolds may provide a promising alternative for traumatic tissue regeneration via augmenting angiogenesis and accelerated immunomodulation.

Multifunctional 3D platforms for rapid hemostasis and wound healing: Structural and functional prospects at biointerfaces.

354Fabrication of multifunctional hemostats is indispensable against chronic blood loss and accelerated wound healing. Various hemostatic materials that aid wound repair or rapid tissue regeneration has been developed in the last 5 years. This review provides an overview of the three-dimensional (3D) hemostatic platforms designed through the latest technologies like electrospinning, 3D printing, and lithography, solely or in combination, for application in rapid wound healing. We critically discuss the pivotal role of micro/nano-3D topography and biomaterial properties in mediating rapid blood clots and healing at the hemostat-biointerface. We also highlight the advantages and limitations of the designed 3D hemostats. We anticipate that this review will guide the fabrication of smart hemostats of the future for tissue engineering applications.

Cellulose nanocrystals vs. cellulose nanospheres: A comparative study of cytotoxicity and macrophage polarization potential.

Nanocellulose application has been increasing owing to its appealing physicochemical properties. Monitoring of the crystallinity, surface topography, and reactivity of this high-aspect-ratio nanomaterial is crucial for efficient tissue engineering. Controlling macrophage polarization phenotype remains a challenge in regenerative medicine and tissue engineering. Herein, we monitored the effects of shape-regulated (rod and spherical) nanocellulose on the macrophage modulatory potential of RAW 246.7 cells in vitro. Spherical nanocellulose (s-NC) exhibited higher thermal stability and biocompatibility than rod nanocellulose. Macrophage polarization was profoundly affected by nanocellulose topography and incubation period. M2 polarization was observed in vitro after 1 day of treatment with s-NC, followed by M1 polarization after treatment for longer periods. Transcriptome analysis similarly revealed that M1 polarization was dominant after 1 day h of incubation with both nanocellulose types. These findings demonstrate that macrophage polarization can be controlled by selecting suitable nanocellulose shape and incubation time for desired applications.