Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding.

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.

Hemostatic mechanism of Jianpi Yiqi Shexue decoction in treatment of immune thrombocytopenia.

OBJECTIVE: To explore the early hemostatic mechanism of Jianpi Yiqi Shexue decoction (, JYSD) in treating immune thrombocytopathy (ITP), based on the functional homeostasis of brain-intestine axis and blood neurotransmitter METHODS: Non-drug treatment cases: Healthy volunteers were selected as normal control group and compared with patients with dysfunctional uterine bleeding, gastrointestinal tumors with bleeding and ITP, to detect the changes of blood 5-hydroxytryptamine (5-HT), ß-endorphin (ß-EP), vasoactive intestinal peptide (VIP) and compare the changes of blood neuro-transmitters in patients with different disease symptoms. Drug treatment cases: According to the randomized controlled multicenter clinical trial, 272 ITP patients were randomly divided into three groups: treatment group (JYSD) combined group (JYSD + Prednisone) control group (Prednisone). The changes of blood neuro-transmitter (5-HT, ß-EP, VIP) before and after treatment were detected on the basis of peripheral blood platelet (PLT) and grade score. RESULTS: Non-drug treatment cases: compared with the normal control group, the 5-HT level was higher, and the VIP and ß-EP levels were both lower in the ITP group (P < 0.001), and the 5-HT, VIP and ß-EP levels in the Gastrointestinal tumors with bleeding group were also lower compared with the normal control group (P < 0.05, 0.001). Drug treatment cases: The PLT grading scores of the combination group and the control group after treatment were lower than that before treatment (P < 0.05, 0.001). The PLT grading score of the 3 groups were compared in pairs after treatment: the combination group was the lowest among the 3 groups, which was better than the treatment group, but no better than the control group (vs the treatment group, P = 0.005, vs the control group, P = 0.709). The statistical results of full analysis set (FAS) and per protocol set (PPS) were consistent. The bleeding symptom scores of the treatment and combination groups began to drop 7 d after treatment, and kept dropping 14 d after treatment until the end of the study (P < 0.05). On the other hand, the control group started to show favorable results 14 d after treatment (P < 0.05). The FAS and PPS analysis results were consistent. In the control group, the 5-HT level was higher and VIP level was lower after treatment, compared with those before treatment (P < 0.05, 0.001). The ß-EP levels were both increased in the treatment and combination group after treatment, compared with those before treatment (P < 0.05). After treatment, the ß-EP levels in the treatment and control groups were significantly lower compared with the combination groups (P < 0.05). After treatment, compared with the control group, the VIP levels in the treatment and combination groups were up-regulated, and the differences were statistically significant by rank sum test (P < 0.01), and by t-test (P = 0.0002, 0.0001). CONCLUSIONS: The prednisone tablet is better than the JYSD in increasing the level of PLT, while prednisone tablet combined with JYSD has more advantages in improving patients' peripheral blood PLT levels. However, in improving the bleeding time of ITP patients, the combination of the two drugs was significantly delayed compared with the single usage, showing the characteristics and advantages of traditional Chinese medicine. JYSD can regulate the neurotransmitter level of ITP patients through the function of the brain-gut axis, mobilize 5-HT in the blood of ITP patients to promote the contraction of blood vessels and smooth muscles, and activate the coagulation mechanism are the early hemostatic mechanisms of JYSD. Up-regulate the levels of ß-EP and balancing VIP levels may be an important part of the immune mechanism of JYSD for regulating ITP patients.

Antibacterial polyurethane foams with quaternized-chitosan as a chain extender for nasal packing and hemostasis.

Endoscopic surgery is an effective and common clinical practice for chronic sinusitis. Nasal packing materials are applied in nasal surgery to prevent hemorrhage and promote wound healing. In this study, a degradable polyurethane foam dressing is successfully developed as a promising nasal packing material with good biocompatibility and antibacterial capability. Specifically, quaternized chitosan (QCS) serves as the crosslinker instead of polyols to offer polyurethane foam (PUF-QCS) antibacterial capability. The PUF-QCS2.0 % (with 2.0 wt% QCS) exhibits satisfactory liquid absorption capacity (19.4 g/g), high compressive strengths at both wet (14.5 kPa) and dry states (7.7 kPa), and a good degradation rate (8.3 %) within 7 days. Meanwhile, PUF-QCS2.0 % retains long-term antibacterial activity for 7 days and kills 97.3 % of S. aureus and 91.8 % of E. coli within 6 hours in antibacterial testing. Furthermore, PUF-QCS2.0 % demonstrates a positive hemostatic response in the rabbit nasal septum mucosa trauma model by reducing hemostatic time over 50.0 % and decreasing blood loss up to 76.1 % compared to the commercial PVA nasal packing sponge. Importantly, PUF-QCS also exhibits a significant antibacterial activity in nasal cavity. This nasal packing material has advantages in post-surgery bleeding control and infection prevention. STATEMENT OF SIGNIFICANCE: The performance of a nasal packing sponge requires good mechanical properties, fast and high liquid absorption rate, effective degradability and strong antibacterial activity. These features are helpful for improving the postoperative recovery and patient healing. However, integrating these into a single polyurethane foam is a challenge. In this study, quaternized chitosan (QCS) is synthesized and used as a chain extender and antibacterial agent in preparing a degradable polyurethane foam (PUF-QCS) dressing. PUF-QCS undergoes partial degradation and exhibits effective broad-spectrum antibacterial activity in 7 days. The reduction of postoperative bleeding and infection observed in the animal experiment further demonstrates that the PUF-QCS developed here outperforms the existing commercial nasal packing materials.

Cascade encapsulation of antimicrobial peptides, exosomes and antibiotics in fibrin-gel for first-aid hemostasis and infected wound healing.

Wounding is one of the most common healthcare problems. Bioactive hydrogels have attracted much attention in first-aid hemostasis and wound healing due to their excellent biocompatibility, antibacterial properties, and pro-healing bioactivity. However, their applications are limited by inadequate mechanical properties. In this study, we first prepared edible rose-derived exosome-like nanoparticles (ELNs) and used them to encapsulate antimicrobial peptides (AMP), abbreviated as ELNs(AMP). ELNs(AMP) showed superior intracellular antibacterial activity, 2.5 times greater than AMP, in in vitro cell infection assays. We then prepared and tested an FDA-approved fibrin-gel of fibrinogen and thrombin encapsulating ELNs(AMP) and novobiocin sodium salt (NB) (ELNs(AMP)/NB-fibrin-gels). The fibrin gel showed a sustained release of ELNs(AMP) and NB over the eight days of testing. After spraying onto the skin, the formulation underwent in situ gelation and developed a stable patch with excellent hemostatic performance in a mouse liver injury model with hemostasis in 31 s, only 35.6 % of the PBS group. The fibrin gel exhibited pro-wound healing properties in the mouse-infected skin defect model. The thickness of granulation tissue and collagen of the ELNs(AMP)/NB-fibrin-gels group was 4.00, 6.32 times greater than that of the PBS group. In addition, the ELNs(AMP)/NB-fibrin-gels reduced inflammation (decreased mRNA levels of TNF-α, IL-1ß, IL6, MCP1, and CXCL1) at the wound sites and demonstrated a biocompatible and biosafe profile. Thus, we have developed a hydrogel system with excellent hemostatic, antibacterial, and pro-wound healing properties, which may be a candidate for next-generation tissue regeneration with a wide clinical application for first-aid hemostasis and infected wound healing.

A macroporous composite sponge with high water absorbency and active coagulation mechanism for traumatic hemostasis and anti-infection.

The development of a composite sponge with high water absorbency and active coagulation mechanism for traumatic hemostasis and anti-infection remains a challenge. Herein, we developed a composite sponge using gelation, swelling, and freeze-drying methods based on quaternized chitosan, succinimidyl-modified F127, and bioactive glass. The sponge exhibited macroporous structure, high porosity, and water absorbency. When exposed to blood, it strongly interacted with blood cells, promoting their adhesion, aggregation, and activation. Moreover, it activated the intrinsic coagulation pathway. The sponge/powder demonstrated superior hemostatic capacity to commercial gauze, gelatin sponge, Yunnan Baiyao, and chitosan hemostatic powder in rat tail amputation, liver superficial injury, liver resection, and liver semi-perforation wound models. The sponge also presented robust anti-infection activity against methicillin-resistantStaphylococcus aureusandEscherichia coli. Additionally, the sponge showed low cytotoxicity, hemolysis activity, inflammation response, and systemic toxicity, demonstrating its favorable biocompatibility.

Coagulating blood into adhesive gel by hybrid powder based on oppositely charged polysaccharide/tannic acid-modified mesoporous bioactive glass.

Hemostatic powder is widely utilized in emergency situations to control bleeding due to its ability to work well on wounds with irregular shapes, ease of application, and long-term stability. However, traditional powder often suffers from limited tissue adhesion and insufficient support for blood clot formation, leaving it susceptible to displacement by the flow of blood. This study introduces a hemostatic powder composed of tannic modified mesoporous bioactive glass (TMBG), cationic quaternized chitosan (QCS), and anionic hyaluronic acid modified with catechol group (HADA). The resulting TMBG/QCS/HADA based hemostatic powder (TMQH) rapidly absorbs plasma, concentrating blood coagulation factors. Simultaneously, the water-soluble QCS and HADA interact to form a 3D network structure, which can be strengthened by crosslinking with TMBG. This network effectively captures clustered blood coagulation factors, leading to a strong and adhesive thrombus that resists disruption from blood flow. TMQH exhibits superior efficacy in promoting hemostasis compared to Celox™ both in rat arterial injuries and non-compressible liver puncture wounds. TMQH demonstrates excellent antibacterial activity, cytocompatibility, and blood compatibility. These outstanding superiorities in blood clotting capability, wet tissue adhesion, antibacterial activity, safety for living organisms, ease of application, and long-term stability, make TMQH highly suitable for emergency hemostasis.

Self-healing, antioxidant, and antibacterial Bletilla striata polysaccharide-tannic acid dual dynamic crosslinked hydrogels for tissue adhesion and rapid hemostasis.

Biomaterials capable of achieving effective sealing and hemostasis at moist wounds are in high demand in the clinical management of acute hemorrhage. Bletilla striata polysaccharide (BSP), a natural polysaccharide renowned for its hemostatic properties, holds promising applications in biomedical fields. In this study, a dual-dynamic-bonds crosslinked hydrogel was synthesized via a facile one-pot method utilizing poly(vinyl alcohol) (PVA)-borax as a matrix system, followed by the incorporation of BSP and tannic acid (TA). Chemical borate ester bonds formed around borax, coupled with multiple physical hydrogen bonds between BSP and other components, enhanced the mechanical properties and rapid self-healing capabilities. The catechol moieties in TA endowed the hydrogel with excellent adhesive strength of 30.2 kPa on the surface of wet tissues and facilitated easy removal without residue. Benefiting from the synergistic effect of TA and the preservation of the intrinsic properties of BSP, the hydrogel exhibited outstanding biocompatibility, antibacterial, and antioxidant properties. Moreover, it effectively halted acute bleeding within 31.3 s, resulting in blood loss of 15.6 % of that of the untreated group. As a superior hemostatic adhesive, the hydrogel in this study is poised to offer a novel solution for addressing future acute hemorrhage, wound healing, and other biomedical applications.

A macromolecular cross-linked alginate aerogel with excellent concentrating effect for rapid hemostasis.

Alginate-based materials present promising potential for emergency hemostasis due to their excellent properties, such as procoagulant capability, biocompatibility, low immunogenicity, and cost-effectiveness. However, the inherent deficiencies in water solubility and mechanical strength pose a threat to hemostatic efficiency. Here, we innovatively developed a macromolecular cross-linked alginate aerogel based on norbornene- and thiol-functionalized alginates through a combined thiol-ene cross-linking/freeze-drying process. The resulting aerogel features an interconnected macroporous structure with remarkable water-uptake capacity (approximately 9000 % in weight ratio), contributing to efficient blood absorption, while the enhanced mechanical strength of the aerogel ensures stability and durability during the hemostatic process. Comprehensive hemostasis-relevant assays demonstrated that the aerogel possessed outstanding coagulation capability, which is attributed to the synergistic impacts on concentrating effect, platelet enrichment, and intrinsic coagulation pathway. Upon application to in vivo uncontrolled hemorrhage models of tail amputation and hepatic injury, the aerogel demonstrated significantly superior performance compared to commercial alginate hemostatic agent, yielding reductions in clotting time and blood loss of up to 80 % and 85 %, respectively. Collectively, our work illustrated that the alginate porous aerogel overcomes the deficiencies of alginate materials while exhibiting exceptional performance in hemorrhage, rendering it an appealing candidate for rapid hemostasis.

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review).

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low­density lipoprotein­cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti­PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.

Chitosan/starch based unoxidized tannic acid modified microparticles for rapid hemostasis with broad spectrum antibacterial activity.

The development of a rapid hemostat through a facile method with co-existing antibacterial activity and minimum erythrocyte lysis property stands as a major requirement in the field of hemostasis. Herein, a series of novel microparticle hemostats were synthesized using chitosan, different hydrothermally-treated starches, and cross-linked with tannic acid (TA) simultaneously in an unoxidized environment via ionotropic gelation method. Hemostats' comparative functional properties, such as adjustable antibacterial and erythrocyte compatibility upon various starch additions were evaluated. The in vivo hemostatic study revealed that the developed hemostats for mouse liver laceration and rat tail amputation had clotting times (13 s and 38 s, respectively) and blood loss (51 mg and 62 mg, respectively) similar to those of Celox™. The erythrocyte adhesion test suggested that erythrocyte distortion can be lowered by modifying the antibacterial hemostats with different starches. The broad-spectrum antibacterial efficacy of the hemostats remained intact against S. aureus (>90 %), E. coli (>80 %), and P. mirabilis bacteria upon starch modification. They also demonstrated high hemocompatibility (<3 % hemolysis ratio), moderate cell viability (>81 %), in vivo biodegradation, and angiogenesis indicating adequate biocompatibility and wound healing. The developed hemostats hold significant promise to be employed as rapid hemostatic agents for preventing major bleeding and bacterial infection in emergencies.

Protamine-grafted carboxymethyl chitosan based hydrogel with adhesive and long-term antibacterial properties for hemostasis and skin wound healing.

In this study, we developed a tissue-adhesive and long-term antibacterial hydrogel consisting of protamine (PRTM) grafted carboxymethyl chitosan (CMC) (PCMC), catechol groups modified CMC (DCMC), and oxidized hyaluronic acid (OHA), named DCMC-OHA-PCMC. According to the antibacterial experiments, the PCMC-treated groups showed obvious and long-lasting inhibition zones against E. coli (and S. aureus), and the corresponding diameters varied from 10.1 mm (and 15.3 mm) on day 1 to 9.8 mm (and 15.3 mm) on day 7. The DCMC-OHA-PCMC hydrogel treated groups also exhibited durable antibacterial ability against E. coli (and S. aureus), and the antibacterial rates changed from 99.3 ± 0.21 % (and 99.6 ± 0.36 %) on day 1 to 76.2 ± 1.74 % (and 84.2 ± 1.11 %) on day 5. Apart from good mechanical and tissue adhesion properties, the hydrogel had excellent hemostatic ability mainly because of the grafted positive-charged PRTM. As the animal assay results showed, the hydrogel was conducive to promoting the deposition of new collagen (0.84 ± 0.03), the regeneration of epidermis (98.91 ± 6.99 µm) and wound closure in the process of wound repairing. In conclusion, the presented outcomes underline the prospective potential of the multifunctional CMC-based hydrogel for applications in wound dressings.

Dragon's Blood-Loaded Mesoporous Silica Nanoparticles for Rapid Hemostasis and Antibacterial Activity.

Dragon's blood (DB) is a traditional Chinese medicine (TCM) with hemostatic effects and antibacterial properties. However, it is still challenging to use for rapid hemostasis because of its insolubility. In this study, different amounts of DB were loaded on mesoporous silica nanoparticles (MSNs) to prepare a series of DB-MSN composites (5DB-MSN, 10DB-MSN, and 20DB-MSN). DB-MSN could quickly release DB and activate the intrinsic blood coagulation cascade simultaneously by DB and MSN. Hemostasis tests demonstrated that DB-MSN showed superior hemostatic effects than either DB or MSNs alone, and 10DB-MSN exhibited the best hemostatic effect. In addition, the antibacterial activities of DB-MSN against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) improved with the increase in DB. Furthermore, the hemolysis assay and cytocompatibility assay demonstrated that all DB-MSNs exhibited excellent biocompatibility. Based on these results, 10DB-MSN is expected to have potential applications for emergency hemostatic and antibacterial treatment in pre-hospital trauma.

The study of double-network carboxymethyl chitosan/sodium alginate based cryogels for rapid hemostasis in noncompressible hemorrhage.

Developing an injectable hemostatic dressing with shape recovery and high blood absorption ratio for rapid hemostasis in noncompressible hemorrhage maintains a critical clinical challenge. Here, double-network cryogels based on carboxymethyl chitosan, sodium alginate, and methacrylated sodium alginate were prepared by covalent crosslinking and physical crosslinking, and named carboxymethyl chitosan/methacrylated sodium alginate (CM) cryogels. Covalent crosslinking was achieved by methacrylated sodium alginate in the freeze casting process, while physical crosslinking was realized by electrostatic interaction between the amino group of carboxymethyl chitosan and the carboxyl group of sodium alginate. CM cryogels exhibited large water swelling ratios (8167 ± 1062 %), fast blood absorption speed (2974 ± 669 % in 15 s), excellent compressive strength (over 160 kPa for CM100) and shape recovery performance. Compared with gauze and commercial gelatin sponge, better hemostatic capacities were demonstrated for CM cryogel with the minimum blood loss of 40.0 ± 8.9 mg and the lowest hemostasis time of 5.0 ± 2.0 s at hemostasis of rat liver. Made of natural polysaccharides with biocompatibility, hemocompatibility, and cytocompatibility, the CM cryogels exhibit shape recovery and high blood absorption rate, making them promising to be used as an injectable hemostatic dressing for rapid hemostasis in noncompressible hemorrhage.

Enhanced physiochemical, antibacterial, and hemostatic performance of collagen-quaternized chitosan-graphene oxide sponges for promoting infectious wound healing.

Bacteria-infected wound healing has attracted widespread attention in biomedical engineering. Wound dressing is a potential strategy for repairing infectious wounds. However, the development of wound dressing with appropriate physiochemical, antibacterial, and hemostatic properties, remains challenging. Hence, there is a motivation to develop new synthetic dressings to improve bacteria-infected wound healing. Here, we fabricate a biocompatible sponge through the covalent crosslinking of collagen (Col), quaternized chitosan (QCS), and graphene oxide (GO). The resulting Col-QCS-GO sponge shows an elastic modulus of 1.93-fold higher than Col sponge due to enhanced crosslinking degree by GO incorporation. Moreover, the fabricated Col-QCS-GO sponge shows favorable porosity (84.30 ± 3.12 %), water absorption / retention (2658.0 ± 113.4 % / 1114.0 ± 65.7 %), and hemostasis capacities (blood loss <50.0 mg). Furthermore, the antibacterial property of the Col-QCS-GO sponge under near-infrared (NIR) irradiation is significantly enhanced (the inhibition rates are 99.9 % for S. aureus and 99.9 % for E. coli) due to the inherent antibacterial properties of QCS and the photothermal antibacterial capabilities of GO. Finally, the Col-QCS-GO+NIR sponge exhibits the lowest percentage of wound area (9.05 ± 1.42 %) at day 14 compared to the control group (31.61 ± 1.76 %). This study provides new insights for developing innovative sponges for bacteria-infected wound healing.

Sodium alginate/carboxycellulose/polydopamine composite microspheres for rapid hemostasis of deep irregular wounds.

Hemostasis of deep irregular wounds is a severe problem in clinical practice. The development of rapid-acting hemostatic agents for deep and irregular wound is urgently needed. Here, sodium alginate/carboxycellulose/polydopamine (SA/CNF/PDA) microspheres was prepared by reverse emulsification and crosslinking with Ca2+, and SA/CNF/PDA composite hemostatic microspheres with porous structure were obtained by freeze-drying. SA/CNF/PDA composite hemostatic microspheres exhibited excellent porosity and water absorption which could rapidly absorb blood on the wound surface. Moreover, SA/CNF/PDA composite microspheres demonstrated remarkable hemostatic capabilities both in vitro and in vivo. It exhibited strong hemostatic performance in models of mouse tail-break and liver damage. Especially in liver injury model, it was completely hemostatic in 95 s, and blood loss (19.3 mg). The hemostatic efficacy of the SA/CNF/PDA composite microspheres was amplified through the stimulation of both exogenous and endogenous coagulation pathways. Therefore, SA/CNF/PDA composite hemostatic microspheres are suitable for rapid hemostasis of deep irregular wounds which are potential rapid hemostatic material for surgical application.

The hemostatic performance and mechanism of palygorskite with structural regulate by oxalic acid gradient leaching.

Palygorskite (Pal) is a naturally available one-dimensional clay mineral, featuring rod-shaped morphology, nanoporous structure, permanent negative charges as well as abundant surface hydroxyl groups, exhibiting promising potential as a natural hemostatic material. In this study, the hemostatic performance and mechanisms of Pal were systematically investigated based on the structural regulate induced by oxalic acid (OA) gradient leaching from perspectives of structure, surface attributes and ion release.In vitroandin vivohemostasis evaluation showed that Pal with OA leaching for 1 h exhibited a superior blood procoagulant effect compared with the raw Pal as well as the others leached for prolonging time. This phenomenon might be ascribed to the synergistic effect of the intact nanorod-like morphology, the increase in the surface negative charge, the release of metal ions (Fe3+and Mg2+), and the improved blood affinity, which promoted the intrinsic coagulation pathway, the fibrinogenesis and the adhesion of blood cells, thereby accelerating the formation of robust blood clots. This work is expected to provide experimental and theoretical basis for the construction of hemostatic biomaterials based on clay minerals.

Multihydrogen Bond Modulated Polyzwitterionic Removable Adhesive Hydrogel with Antibacterial and Hemostatic Function for Wound Healing.

Wound management is a major challenge worldwide, placing a huge financial burden on the government of every nation. Wound dressings that can protect wounds, accelerate healing, prevent infection, and avoid secondary damage continue to be a major focus of research in the health care and clinical communities. Herein, a novel zwitterionic polymer (LST) hydrogel incorporated with [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (SBMA), mussel-inspired N-[tris(hydroxymethyl)methyl] acrylamide (THMA), and lithium magnesium salt was prepared for functional wound dressings. The incorporation of the THMA monomer containing three hydroxyl groups gives the hydrogel suitable adhesion properties (∼6.0 KPa). This allows the LST zwitterionic hydrogels to bind well to the skin, which not only protects the wound and ensures its therapeutic efficacy but also allows for painless removal and reduced patient pain. Zwitterionic sulfobetaine units of SBMA provide antimicrobial and mechanical properties. The chemical structure and microscopic morphology of LST zwitterionic hydrogels were systematically studied, along with their swelling ratio, adhesion, and mechanical properties. The results showed that the LST zwitterionic hydrogels had a uniform and compact porous structure with the highest swelling and mechanical strain of 1607% and 1068.74%, respectively. The antibacterial rate of LST zwitterionic hydrogels was as high as 99.49%, and the hemostatic effect was about 1.5 times that of the commercial gelatin hemostatic sponges group. In further studies, a full-thickness mouse skin model was selected to evaluate the wound healing performance. Wounds covered by LST zwitterionic hydrogels had a complete epithelial reformation and new connective tissue, and its vascular regenerative capacity was increased to about 2.4 times that of the commercial group, and the wound could completely heal within 12-13 days. This study provides significant advances in the design and construction of multifunctional zwitterionic hydrogel adhesives and wound dressings.

Development of an efficient hemostatic material based on cuttlefish ink nanoparticles loaded in cuttlebone biocomposite.

Traumatic hemorrhage is one of the main causes of mortality in civilian and military accidents. This study aimed to evaluate the effectiveness of cuttlefish bone (cuttlebone, CB) and CB loaded with cuttlefish ink (CB-CFI) nanoparticles for hemorrhage control. CB and CB-CFI were prepared and characterized using different methods. The hemostasis behavior of constructed biocomposites was investigated in vitro and in vivo using a rat model. Results showed that CFI nanoparticles (NPs) are uniformly dispersed throughout the CB surface. CB-CFI10 (10 mg CFI in 1.0 g of CB) showed the best blood clotting performance in both in vitro and in vivo tests. In vitro findings revealed that the blood clotting time of CB, CFI, and CB-CFI10 was found to be 275.4 ± 12.4 s, 229.9 ± 19.9 s, and 144.0 ± 17.5 s, respectively. The bleeding time in rat liver injury treated with CB, CFI, and CB-CFI10 was 158.1 ± 9.2 s, 114.0 ± 5.7 s, and 46.8 ± 2.7 s, respectively. CB-CFI10 composite resulted in more reduction of aPTT (11.31 ± 1.51 s) in comparison with CB (17.34 ± 2.12 s) and CFI (16.79 ± 1.46 s) (p < 0.05). Furthermore, CB and CB-CFI10 exhibited excellent hemocompatibility. The CB and CB-CFI did not show any cytotoxicity on human foreskin fibroblast (HFF) cells. The CB-CFI has a negative surface charge and may activate coagulation factors through direct contact with their components, including CaCO3, chitin, and CFI-NPs with blood. Thus, the superior hemostatic potential, low cost, abundant, simple, and time-saving preparation process make CB-CFI a very favorable hemostatic material for traumatic bleeding control in clinical applications.

Advances of biological macromolecules hemostatic materials: A review.

Achieving hemostasis is a necessary intervention to rapidly and effectively control bleeding. Conventional hemostatic materials currently used in clinical practice may aggravate the damage at the bleeding site due to factors such as poor adhesion and poor adaptation. Compared to most traditional hemostatic materials, polymer-based hemostatic materials have better biocompatibility and offer several advantages. They provide a more effective method of stopping bleeding and avoiding additional damage to the body in case of excessive blood loss. Various hemostatic materials with greater functionality have been developed in recent years for different organs using diverse design strategies. This article reviews the latest advances in the development of polymeric hemostatic materials. We introduce the coagulation cascade reaction after bleeding and then discuss the hemostatic mechanisms and advantages and disadvantages of various polymer materials, including natural, synthetic, and composite polymer hemostatic materials. We further focus on the design strategies, properties, and characterization of hemostatic materials, along with their applications in different organs. Finally, challenges and prospects for the application of hemostatic polymeric materials are summarized and discussed. We believe that this review can provide a reference for related research on hemostatic materials, contributing to the further development of polymer hemostatic materials.

Nanofibrous composite from chitosan-casein polyelectrolyte complex for rapid hemostasis in rat models in vivo.

Bleeding causes ∼5.8 million deaths globally; half of the patients die if rapid hemostasis is not achieved. Here, we report a chitosan-casein (CC)-based nanofibrous polyelectrolyte complex (PEC) that could clot blood within 10 s in the rat femoral artery model in vivo. The nanofiber formation by self-assembly was also optimized for process parameters (concentration, mixing ratio, pH, and ultrasonication). Results showed that increasing the concentration of chitosan from 10 % to 90 % in the formulation increased the productivity (r = 0.99) of PECs but led to increased blood clotting time (r = 0.90) due to an increase in zeta potential (r = 0.98), fiber diameter (r = 0.93), and decreased surface porosity (r = -0.99), absorption capacity (r = -0.99). The pH also influenced the zeta potential of PEC, with an optimized pH of 8.0 ± 0.1 yielding clear nanofibers. Sonication improved the segregation of nanofibers by promoting water removal. The optimized PECs containing chitosan and casein in the ratio of 30:70 (CC30) at a pH of 8.0 and dehydration under sonication could clot the blood within 9 ± 2 s in vitro and 9 ± 2 s in rat femoral artery puncture model. The CC30 formulation did not cause any irritation or corrosion on rat skin. Histopathology and immunohistochemistry of various organs showed that CC30 was biocompatible and non-immunogenic under in vivo conditions.