Ionic Crosslinking Research Articles

Double Cross-linked Methacrylated Carboxymethyl Pea Starch Cryogels with Highly Compressive Elasticity and Hemostatic Function.

As an abundant renewable natural material, starch has attracted unprecedented interest in the biomedical field. Carboxylated starch particles have been investigated for topical hemostasis, but the powder may not provide physical protection or support for wounds. Here, we prepared macroporous cryogel sponges of methacrylated carboxymethyl starch (CM-ST-MA) containing a covalent and a calcium ionic double network. The second ionic cross-linking network enhanced the compressive strength and toughness dramatically but reduced the swelling ratios. Cryogels and sponges exhibited excellent compressive elasticity at low Ca2+ concentrations (0.01 M). Cryogels became more plastic and dry sponges became rigid and brittle at high Ca2+ concentrations. The cryogels have outstanding wet-thermal stability but are still degradable via enzymatic hydrolysis. All CM-ST-MA sponges showed excellent biocompatibility, hemocompatibility, and outstanding hemostasis in in vitro assays. In the in vivo mouse tail amputation model, both CM-ST-MA cryogels without or with Ca2+ (0.01 M) reduced the blood loss and bleeding time significantly.

Double-Dynamic-Bond Cross-Linked Hydrogel Adhesive with Cohesion-Adhesion Enhancement for Emergency Tissue Closure and Infected Wound Healing.

The hydrogel adhesives with strong tissue adhesion and biological characteristics adhm202404447are urgently needed for injury sealing and tissue repair. However, the negative correlation between tissue adhesion and the mechanical strength poses a challenge for their practical application. Herein, a bio-inspired cohesive enhancement strategy is developed to prepare the hydrogel adhesive with simultaneously enhanced mechanical strength and tissue adhesion. The double cross-linked network is achieved through the cooperation between polyacrylic acid grafted with N-hydroxy succinimide crosslinked by tannic acid and cohesion-enhanced ion crosslinking of sodium alginate and Ca2+. Such a unique structure endows the resultant hydrogel adhesive with excellent tissue adhesion strength and mechanical strength. The hydrogel adhesive is capable of sealing various organs in vitro, and exhibits satisfactory on-demand removability, antibacterial, and antioxidant properties. As a proof of concept, the hydrogel adhesive not only effectively halts non-compressible hemorrhages of beating heart and femoral artery injury models in rats, but also accelerates the healing of infected wound by inhibiting bacteria and reducing inflammation. Overall, this advanced hydrogel adhesive is promising as an emergency rescue adhesive that enables robust tissue closure, timely controlling bleeding, and promoting damaged tissue healing.

A bioactive Hydrogel Patch Accelerates Revascularization in Ischemic Lesions for Tissue Repair

Abstract Background Magnesium ions play crucial roles in maintaining cellular functions. Research has shown that Mg2+ can promote angiogenesis, indicating its potential for treating cardiovascular ischemic diseases. However, conventional intravenous or oral administration of Mg2+ presents several challenges, including the risk of systemic side effects, diminished bioavailability, and a lack of targeted delivery mechanisms. In this study, we designed a Mg2+-releasing adhesive tissue patch (MgAP) that enables the dural release of Mg2+ ions. Methods A novel Mg2+-releasing adhesive patch (MgAP) was developed on the basis of ionic crosslinking. Fourier transform infrared spectroscopy confirmed the chemical structure, whereas rheological analysis demonstrated stable mechanical properties and adaptability to dynamic loads. Sustained Mg2+ release was quantified over 7 days by inductively coupled plasma–mass spectrometry. In a rat acute myocardial infarction model, we performed echocardiography and strain analysis to assess cardiac function and histological staining to evaluate adverse remodeling. We also verified the proangiogenic effect through in vitro tube formation and in vivo immunofluorescence assays. Furthermore, transcriptomics and Western blotting were performed to explore the underlying mechanism. Additional assessments were also carried out in a rat model of lower limb ischemia. Results Compared with intravenous administration of magnesium chloride, MgAP application effectively improved cardiac function and reduced adverse remodeling in the myocardial infarction rat model. The left ventricular ejection fraction increased by 20.3 ± 6.6%, and the cardiac radial strain improved by 27.4 ± 4.1%. The cardiac fibrosis area and cell apoptosis rate decreased by 10.9 ± 1.2% and 32.1 ± 5.5%, respectively. RNA sequencing analysis also highlighted the upregulation of genes related to cardiac electrophysiological properties, structural and functional intercellular connections, and revascularization. The increased gap junction protein expression and restored local blood supply could contribute to the cardiac repair process posttreatment. The proangiogenic effect of MgAP was also observed in the rat limb ischemia model. Conclusions The above results revealed the convincing vascular regeneration effect of an ion therapy-based hydrogel, which enabled the local delivery of Mg2+ to the targeted ischemic tissue, aiding in cardiac and lower limb repair. This study presents a novel strategy and highlights its potential for use across various ischemic conditions.

Influence of Electrostatic Interactions on the Self-Assembly of Charged Peptides.

Peptides can be designed to self-assemble into predefined supramolecular nanostructures, which are then employed as biomaterials in a range of applications, including tissue engineering, drug delivery, and vaccination. However, current self-assembling peptide (SAP) hydrogels exhibit inadequate self-healing capacities and necessitate the use of sophisticated printing apparatus, rendering them unsuitable for 3D printing under physiological conditions. Here, we report a precisely designed charged peptide, Z5, with the object of investigating the impact of electrostatic interactions on the self-assembly and the rheological properties of the resulting hydrogels. This peptide displays salt-triggered self-assembly resulting in the formation of a nanofiber network with a high β-sheet content. The peptide self-assembly and the hydrogel properties can be modified according to the ionic environment. It is noteworthy that the Z5 hydrogel in normal saline (NS) shows exceptional self-healing properties, demonstrating the ability to recover its initial strength in seconds after the removal of shear force, thus rendering it an acceptable material for printing. In contrast, the strong salt shielding effect and the ionic cross-linking of Z5 hydrogels in PBS result in the bundling of peptide nanofibers, which impedes the recovery of the initial strength post-destruction. Furthermore, incorporating materials with varied charging properties into Z5 hydrogels can alter the electrostatic interactions among peptide nanofibers, further modulating the rheological properties and the printability of SAP hydrogels.

Strong and Fireproof Regenerated Wood via a Combined Phosphorylation-Surface Nanofibrillation and Ionic Cross-Linking Strategy.

To reduce the environmental impact of plastics, an increasing number of high-performance sustainable materials have emerged. Among them, wood-based high-performance structural materials have gained growing attention due to their outstanding mechanical and thermal properties. Here, we introduce phosphate groups onto the wood veneers for surface nanofibrillation, effectively altering both the molecular structure and surface morphology of wood, which enhances the interactions between wood veneers and endows the wood with excellent fire resistance properties. With these phosphorylated wood-based building blocks, "chemical welding" structural materials (CWSMs) obtained through chemical cross-linking exhibit excellent mechanical properties. The flexural strength of CWSM reaches 225 MPa, and the modulus reaches 16 GPa, surpassing those of various types of natural wood. At the same time, phosphorylation has endowed CWSM with excellent fire resistance, with a limiting oxygen index reaching 49%, making it completely noncombustible. More importantly, as a biomass-based structural material, CWSM exhibits mechanical, thermal, and fire resistance properties and degradability far superior to those of traditional petroleum-based plastics, making it an ideal candidate for plastic replacement.

Effects of Calcium Chloride Crosslinking Solution Concentration on the Long-Term Cell Viability of 16HBE14o- Human Bronchial Cells Embedded in Alginate-Based Hydrogels.

In this preliminary study, the long-term effects of calcium chloride crosslinking concentration on viability of 16HBE14o- human bronchial epithelial cells embedded in alginate-extracellular matrix (ECM) or alginate-methylcellulose-ECM hydrogels have been investigated. There is currently a limited understanding regarding the effects of crosslinking solution concentration on lung epithelial cells embedded in hydrogel. Furthermore, the effects of calcium chloride concentration in crosslinking solutions on other cell types have not been reported regarding whether the addition of viscosity and stiffness tuning agents such as methylcellulose will alter the responses of cells to changes in calcium chloride concentration in crosslinking solutions. While there were no significant effects of calcium chloride concentration on cell viability in alginate-ECM hydrogels, there is a decrease in cell viability in alginate-methylcellulose-ECM hydrogels crosslinked with 300 mM calcium chloride crosslinking solution. These findings have implications in the maintenance of 16HBE14o- 3D cultures with respect to the gelation of alginate with high concentrations of ionic crosslinking solution.

Designing & optimisation of dual Ca2+ and SO4 2– ionic cross-linked sericin/pectin microbeads using response surface methodology for colon-specific delivery

Ulcerative colitis, a chronic inflammatory condition of the colon, requires precise and targeted treatment, and polysaccharides, with their pH responsiveness and biodegradability, offer an innovative approach for colon-specific drug delivery. This study aims to develop a highly precise drug delivery system with enhanced therapeutic and targeting efficiency for ulcerative colitis, focusing on the preparation, optimisation, and evaluation of dual cross-linked mesalamine-loaded sericin-pectin (DCLSPs) micro-beads. These beads utilise the pH-responsive and microflora biodegradability properties of polysaccharides for targeted colon delivery, employing the Response Surface Methodology. Formulated via the ionotropic gelation method with divalent cross-linking ions (Ca2+ and SO4 2–), the DCLSPs were optimised using a Box-Behnken design to assess the impact of the varying drug, pectin, and sericin polymer proportions. The DCLSPs were evaluated for entrapment efficiency, thermal behaviour, surface morphology, water uptake, swelling, and in-vitro drug release. Results indicated that spherical beads were successfully developed, with encapsulation efficiency ranging from 65.1% to 95.5%, drug loading between 32.5% and 49.9%, bead sizes of 0.75 mm to 0.92 mm, and degrees of swelling from 0.92 to 1.82. Drug release was controlled by both diffusion and swelling mechanisms, as supported by the Higuchi and Korsmeyer-Peppas models. The optimised formulation demonstrated high drug encapsulation efficiency, pH-responsive swelling, and strong adhesion to the colon, ensuring extended retention at the targeted site. Additionally, the incorporation of sericin enhanced the accuracy of Gaussian fitting for particle size distribution. Overall, the dual cross-linked sericin-pectin beads show potential as mucoadhesive carriers for delivering drugs specifically to the colon.

Modified natural polymers as additives in high-temperature drilling fluids: A review.

Drilling fluids are often referred to as the "blood" of the drilling process, as they play a crucial role in determining both the efficiency and safety of drilling operations. Natural polymers, derived from renewable sources, such as cellulose, lignin, chitosan, xanthan gum, and starch, offer inherent advantages such as sustainability, biodegradability, and environmentally-friendliness when used as additives in drilling fluids. However, the inherent properties of natural polymers are adversely affected by thermal degradation due to their low heat resistance under harsh drilling conditions, where temperatures can exceed 150°C. To address these challenges, various modification techniques, including free radical polymerization, esterification, etherification, silanization, hydroxymethylation, and ionic crosslinking, have been employed. This paper provides an overview of recent advances in the application of modified natural polymers as additives in water-based drilling fluids (WBDFs) under high-temperature drilling conditions. It begins by discussing the degradation mechanisms of natural polymers at high temperatures, followed by a review of the techniques used for their modification. Subsequently, the application of modified natural polymers as rheological and fluid loss additives in high-temperature WBDFs is briefly presented. Finally, the challenges, environmental impacts, and future considerations for the use of modified polymers are outlined to guide future development of environmentally friendly, high-performance WBDFs.

Protein-polyelectrolyte complexation: effects of sterically repulsive groups, macromolecular architecture and hierarchical assembly.

Self-assembly of proteins and polyelectrolytes in aqueous solutions is a promising approach for the development of advanced biotherapeutics and engineering efficient biotechnological processes. Synthetic polyions containing sterically repulsive ethylene oxide moieties are especially attractive as protein modifying agents, as they can potentially induce a PEGylation-like stabilizing effect without the need for complex covalent binding reactions. In this study, we investigated the protein-binding properties of anionic polyelectrolytes based on an inorganic polyphosphazene backbone, with ethylene oxide groups incorporated into both grafted and linear macromolecular topologies. The study was conducted in aqueous solutions using isothermal titration calorimetry, dynamic light scattering, and cryogenic electron microscopy to analyze the samples in their vitrified state. Our findings revealed that the stability of the resulting protein-polyion complexes and the thermodynamic profiles of these interactions were influenced by the molecular architecture of the polyions. Furthermore, the formation of hierarchical assemblies of polyions, through ionic crosslinking into nanogels, rapidly reduced or eliminated the ability of the polyelectrolyte to bind proteins. The comprehensive analysis, combining thermodynamic, spectroscopy and direct visualization techniques, provides valuable insights into the multivalent charge-charge interactions that are critical for the development of successful non-covalent protein modification methods.

Highly compressible lamellar graphene/cellulose/sodium alginate aerogel via bidirectional freeze-drying for flexible pressure sensor.

Graphene exhibits exceptional electrical properties, and aerogels made from it demonstrate high sensitivity when used in sensors. However, traditional graphene aerogels have poor biocompatibility and sustainability, posing potential environmental and health risks. Moreover, the stacking of their internal structures results in low compressive strength and fatigue resistance, which limits their further applications. In this study, green and sustainable cellulose nanofibers/sodium alginate/reduced graphene oxide aerogels (BCSRA) were synthesized, featuring a well-defined lamellar structure and a fiber cross-linked network, employing techniques such as bidirectional freeze-drying, ionic cross-linking, and thermal annealing. The unique internal architecture of BCSRA results in a compressive strength of up to 64.55 kPa at 70 % compression deformation and an extremely low density of merely 7.21 mg/cm3. Furthermore, BCSRA displays outstanding fatigue resistance, maintaining 82.17 % of its stress after 100 compression cycles at 70 % compressive strain and 86.99 % after 1000 cycles at 50 % compressive strain. Remarkably, when utilized as a flexible pressure sensor, BCSRA achieves a sensitivity of 5.71 kPa-1 and endures over 2200 cycles at 40 % compression, all while ensuring consistent electrical signal output. These properties underscore its significant potential for application in wearable flexible pressure sensors, capable of detecting various human movements.

Fabrication of phospholipid polymer-modified alginate hydrogels for bioartificial pancreas.

The bioartificial pancreas, composed of a semi-permeable hydrogel encapsulating insulin-secreting cells, has attracted attention as a treatment for type 1 diabetes. In this study, we developed phospholipid polymer-modified alginate hydrogel beads that encapsulated spheroids of the pancreatic beta cell line MIN6. The hydrogel beads were composed of methacrylated alginic acid, which enabled both ionic and covalent cross-linking, resulting in a hydrogel that was more stable than conventional alginate hydrogels. Furthermore, modification of biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers suppressed protein adsorption to the hydrogel beads. Hydrogel beads encapsulating MIN6 spheroids maintained the cell viability and insulin secretion ability in response to glucose levels invitro. Allogenic transplantation of gel beads lowered blood glucose levels in diabetic mice for 30 days, whereas gel beads without MPC polymer modification failed to regulate blood glucose levels. These results indicate that MPC polymer modification of hydrogels provides a new strategy for the fabrication of functional bioartificial pancreas and transplantable biomaterials for cell therapies.

Preparation of chitosan/HMX energy-containing microspheres with stable combustion performance by an environmentally friendly process based on ionic cross-linking mechanism

Preparation of chitosan/HMX energy-containing microspheres with stable combustion performance by an environmentally friendly process based on ionic cross-linking mechanism

Improved electrochemical performance of graphene oxide via copper ions cross-linking and plasma functionalization

Improved electrochemical performance of graphene oxide via copper ions cross-linking and plasma functionalization

Multi-performance sodium alginate-based composite films for sensing and electromagnetic shielding.

As science and technology progress swiftly, the demand for high-performance composite films designed to shield against electromagnetic interference (EMI) and for strain sensing applications has significantly increased, making these films essential components for the future generation of smart wearable electronics. However, designing and developing multifunctional flexible composite films remains a considerable challenge. This study employed vacuum-assisted filtration techniques combined with calcium ion cross-linking to create multifunctional MXene/sodium alginate/liquid metal (MSL) composite films exhibiting exceptional EMI shielding and strain sensing capabilities. The mechanical strength of the MSL composite films was optimized by implementing continuous hydrogen bonding and ionic interactions among MXene, sodium alginate, liquid metal (LM), and calcium ions, resulting in a tensile strength of 71.71 MPa. The composite film exhibits excellent electromagnetic absorption properties, resulting in an exceptional EMI shielding efficacy of 50.61 dB and a specific shielding effectiveness value of 7563 dB·cm2·g-1. This is due to the heterogeneous interface between MXene and LM nanoparticles. Furthermore, the composite film exhibits favorable electrothermal and photothermal conversion capabilities. The film can be a flexible sensor to detect human motion, contingent on the conductive network between MXene and LM. This research illustrates the potential of multifunctional MSL composite films for EMI shielding and human motion monitoring, offering a promising pathway for creating adaptable wearable electronics in challenging electromagnetic conditions.

Natrium Alginate and Graphene Nanoplatelets-Based Efficient Material for Resveratrol Delivery.

In this study, alginate-based composite beads were developed for the delivery of resveratrol, a compound with therapeutic potential. Two formulations were prepared: one with sodium alginate and resveratrol (AR) and another incorporating graphene nanoplatelets (AGR) to improve drug release control. The beads were formed by exploiting alginate's ability to gel via ionic cross-linking. For the AGR formulation, sodium alginate was dissolved in water, and graphene was dispersed in isopropyl alcohol to achieve smaller flakes. Resveratrol was dissolved in an ethanol/water mixture and added to the graphene dispersion; the resulting solution was mixed with the alginate one. For the AR formulation, the resveratrol solution was mixed directly with the alginate solution. Both formulations were introduced into a calcium chloride solution to form the beads. The release of resveratrol was studied in phosphate-buffered saline at different pH values. Results showed that the presence of graphene in the AGR sample increased drug release, particularly at pH 6.8, indicating a pH-driven release mechanism. Kinetic analysis revealed that the Higuchi model best describes the release mechanism. Finally, cytotoxicity tests showed the biocompatibility of the system in normal human cells. These findings suggest that graphene-enhanced alginate matrices have significant potential for controlled drug delivery applications.

Progress in Research on Metal Ion Crosslinking Alginate-Based Gels.

Alginate is an important natural biopolymer and metal ion-induced gelation is one of its most significant functional properties. Alginate-based hydrogels crosslinked with metal ions are commonly utilized in the food, biomedical, tissue engineering, and environment fields. The process of metal ion-induced alginate gelation has been the subject of thorough research over the last few decades. This review aims to summarize the mechanisms of alginate hydrogels induced by different cations (primarily including Ca2+, Ba2+, Cu2+, Sr2+, Fe2+/Fe3+, and Al3+). Metal ion-induced alginate gelation shows different preferences for α-L-guluronic acid (G), β-D-mannuronic acid (M), and GM blocks. Some metal ions can also selectively bind to the carboxyl groups of guluronic acid. The properties and applications of these alginate-based hydrogels are also discussed. The primary objective of this review is to provide useful information for exploring the practical applications of alginate.

Cell Membrane- and Extracellular Vesicle-Coated Chitosan Methacrylate-Tripolyphosphate Nanoparticles for RNA Delivery.

mRNA-based vaccines against the COVID-19 pandemic have propelled the use of nucleic acids for drug delivery. Conventional lipid-based carriers, such as liposomes and nanolipogels, effectively encapsulate and deliver RNA but are hindered by issues such as premature burst release and immunogenicity. To address these challenges, cell membrane-coated nanoparticles offer a promising alternative. We developed a novel nanoparticle system using chitosan methacrylate-tripolyphosphate (CMATPP), which capitalizes on interactions involving membrane proteins at biointerfaces. Ionic crosslinking between chitosan methacrylate and tripolyphosphate facilitates the formation of nanoparticles amenable to coating with red blood cell (RBC) membranes, extracellular vesicles (EVs), and cell-derived nanovesicles (CDNs). Coating CMATPP nanoparticles with RBC membranes effectively mitigated the initial burst release of encapsulated small interfering RNA (siRNA), sustaining controlled release while preserving membrane proteins. This concept was extended to EVs, where CMATPP nanoparticles and CDNs were incorporated into a microfluidic device and subjected to electroporation to create hybrid CDN-CMATPP nanoparticles. Our findings demonstrate that CMATPP nanoparticles are a robust siRNA delivery system with suppressed burst release and enhanced membrane properties conferred by cell or vesicle membranes. Furthermore, the adaptation of the CDN-CMATPP nanoparticle formation in a microfluidic device suggests its potential for personalized therapies using diverse cell sources and increased throughput via automation. This study underscores the versatility and efficacy of CMATPP nanoparticles in RNA delivery, offering a pathway towards advanced therapeutic strategies that utilize biomimetic principles and microfluidic technologies.

Air-Drying for Rapid Manufacture of Flexible Aramid Nanofiber Aerogel Fibers with Robust Mechanical Properties and Thermal Insulation in Harsh Environments.

Aerogel fibers uniting characteristics of both aerogels (lightweight and porosity) and fibers (flexibility and wearability) exhibit a great potential for the production of the next generation of thermal protection textiles; still, the complex drying procedures and mechanical brittleness remain the main obstacles toward further exploitation. Herein, flexible and robust aramid nanofiber aerogel fibers (ANAFs) are scalably prepared by continuous wet-spinning coupled with fast air-drying. This synthesis involves calcium ions (Ca2⁺) cross-linking and solvent displacement by low surface tension solvents, to enhance skeleton strength and reduce the capillary force during evaporation, respectively, thus minimizing shrinkage to 29.0% and maximizing specific surface area to 225.0m2g-1 for ANAF. Surprisingly, the air-dried ANAF showed excellent tensile strength (13.5MPa) and toughness (7.0MJm-3), allowing their easy weaving into the textile without damage. Importantly, the ANAF textile with a skin-core porous structure exhibited low thermal conductivity (≈38.5mWm-1K-1) and excellent thermal insulation ability in the wide temperature range (-196 to 400°C). Besides, the aramid molecular structure, as well as Ca2⁺ cross-linking, endowed the ANAF with high thermal stability and flame retardancy. Consequently, the robust ANAF with a fast-air-drying method is promising for thermal protection in extreme environments, such as in spacesuits.

Injectable Self-Healing and Anti-Dissolving Low-Molecular-Weight Hydrogels Enabled by Ionic Cross-Linking for Cell Encapsulation.

Injectable behavior is often observed in polymer-based hydrogels yet is rarely achieved in low-molecular-weight hydrogels (LMWHs), the realization of which may boost the development of new soft materials for biomedical applications. Here, we report on injectable self-healing and antidissolving LMWHs that are formed through a simple ionic cross-linking strategy, showing a fundamental application for the encapsulation of living cells. The LMWHs are formed by simply mixing Ca2+ with negatively charged supramolecular polymers. Surprisingly, the resultant hydrogels are capable of rapidly self-healing within seconds after damage, showing an unexpected injectable function. When the hydrogel is injected into an aqueous medium, continuous macroscopic hydrogel fibers can be produced. Interestingly, the hydrogel can remain intact in the aqueous medium, showing impressive antidissolving behavior which is less observed in other LMWHs. Furthermore, the hydrogel is demonstrated to be nontoxic and can be used as a cytocompatible scaffold for living cells. This work may open an avenue toward injectable and antidissolving LMWHs for the ever-expanding list of applications in biotherapy and bioprinting.

Intelligent Generic High-Throughput Oscillatory Shear Technology Fabricates Programmable Microrobots for Real-Time Visual Guidance During Embolization.

Microrobots for endovascular embolization face challenges in precise delivery within dynamic blood vessels. Here, an intelligent generic high-throughput oscillatory shear technology (iGHOST) is proposed to fabricate diversely programmable, multifunctional microrobots capable of real-time visual guidance for in vivo endovascular embolization. Leveraging machine learning (ML), key synthesis parameters affecting the success and sphericity of the microrobots are identified. Therefore, the ML-optimized iGHOST enables continuous production of uniform microrobots with programmable sizes (400-1000µm) at an ultrahigh rate exceeding 240mLh-1 by oscillatory segmenting fluid into droplets before ionic cross-linking, and without requiring purification. Particularly, the iGHOST-fabricated magnetically responsive lipiodol-calcium alginate (MagLiCA) microrobots are highly distinguishable under X-ray imaging, which allows for precise navigation in fluid flows of up to 4mLmin-1 and accurate embolization in liver and kidney blood vessels, thus addressing the current issues. Crucially, MagLiCA microrobots possess drug-loading capabilities, enabling simultaneous embolization and site-specific treatment. The iGHOST process is an intelligent, rapid, and green manufacturing method, which can produce size-controllable, multifunctional microrobots with the potential for precise drug delivery and treatment under real-time imaging across various medical applications.