Recent research advances in polysaccharide-based hemostatic materials: A review.

Massive bleeding resulting from civil and martial accidents can often lead to shock or even death, highlighting the critical need for the development of rapid and efficient hemostatic materials. While various types of hemostatic materials are currently utilized in clinical practice, they often come with limitations such as poor biocompatibility, toxicity, and biodegradability. Polysaccharides, such as alginate (AG), chitosan (CS), cellulose, starch, hyaluronic acid (HA), and dextran, have exhibit excellent biocompatibility and in vivo biodegradability. Their degradation products are non-toxic to surrounding tissues and can be absorbed by the body. As a result, polysaccharides have been extensively utilized in the development of hemostatic materials and have gained significant attention in the field of in vivo hemostasis. This review offers an overview of the different forms, hemostatic mechanisms, and specific applications of polysaccharides. Additionally, it discusses the future opportunities and challenges associated with polysaccharide-based hemostats.

PAA-PU Janus Hydrogels Stabilized by Janus Particles and its Interfacial Performance During Hemostatic Processing.

Hydrogel is a very promising dressing for hemostasis and wound healing due to its good adhesion and long-term moist environment. However, secondary injury caused by tissue adhesion due to homogeneous hydrogel cannot be ignored. The obvious interface existing in Janus hydrogel will weaken its asymmetric function. Here, a hierarchical adhesive polyacrylic acid-polyurushiol water-oil Janus hydrogel (JPs@PAA-PU) without adhesive layer is fabricated by one-pot method in the stabilization of polystyrene@silica-siliver Janus particles (JPs). The morphological structure, mechanical properties, anisotropic chemical composition, and adhesion performance, in vivo, and in vitro hemostatic properties of Janus hydrogel are investigated. Result shows that the obtained Janus hydrogel possesses obvious compartmentalization in microstructure, functional groups, and chemical elements. Janus hydrogel is provided with asymmetric interfacial toughness with top 52.45 ± 2.29 Kpa and bottom 7.04 ± 0.88 Kpa on porcine liver. The adhesion properties of PAA side to tissue, red blood cells and platelets, promoting effect of PU side on coagulation cascade reaction and its physical battier endow Janus hydrogel with shorter hemostatic time and less blood loss than control group. It also exhibits excellent antibacterial effects against Escherichia coli and Staphylococcus aureus (>90%). Janus hydrogel possesses biosafety, providing safety guarantee for clinical applications in the future.

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.

Ferried Albumin-Inspired Bioadhesive With Dynamic Interfacial Bonds for Emergency Rescue.

Emergency prehospital wound closure and hemorrhage control are the first priorities for life-saving. Majority of bioadhesives form bonds with tissues through irreversible cross-linking, and the remobilization of misalignment may cause severe secondary damage to tissues. Therefore, developing an adhesive that can quickly and tolerably adhere to traumatized dynamic tissue or organ surfaces in emergency situations is a major challenge. Inspired by the structure of human serum albumin (HSA), a branched polymer with multitentacled sulfhydryl is synthesized, then, an instant and fault-tolerant tough wet-tissue adhesion (IFA) hydrogel is prepared. Adhesive application time is just 5 s (interfacial toughness of ≈580 J m-2), and favorable tissue-adhesion is maintained after ten cycles. IFA hydrogel shows unchangeable adhesive performance after 1 month of storage based on the internal oxidation-reduction mechanism. It not only can efficiently seal various organs but also achieves effective hemostasis in models of the rat femoral artery and rabbit-ear artery. This work also proposes an effective strategy for controllable adhesion, enabling the production of asymmetric adhesives with on-demand detachment. Importantly, IFA hydrogel has sound antioxidation, antibacterial property, hemocompatibility, and cytocompatibility. Hence, the HSA-inspired bioadhesive emerges as a promising first-aid supply for human-machine interface-based health management and non-invasive wound closure.

Cohering Plasma into Adhesive Gel by Natural Biopolymer-Nanoparticle Hybrid Powder for Efficient Hemostasis and Wound Healing.

Hemostatic powder is commonly used in emergency bleeding control due to its suitability for irregularly shaped wounds, ease of use, and stable storage. However, traditional powder often has limited tissue adhesion and weak thrombus support, which makes it vulnerable to displacement by blood flow. Herein, we have developed a tricomponent hemostatic powder (MQS) composed of mesoporous bioactive glass nanoparticle (MBG), positively charged quaternized chitosan (QCS), and negatively charged catechol-modified alginate (SADA). Upon application to the wound, MBG with its high specific surface area quickly absorbs plasma, concentrating the blood coagulation factor. Simultaneously, the water-soluble QCS and SADA interact with each other and form a net, which can be further cross-linked by MBG. This network efficiently binds and entraps clustered blood coagulation factors, ultimately resulting in the formation of a durable and robust thrombus. Furthermore, the formed net adheres to the injury site, offering protection against thrombus disruption caused by the bloodstream. Benefiting from the synergistic effect of these three components, MQS demonstrates superior hemostatic performance compared to commercial hemostatic powders like Celox in both arterial injuries and noncompressible liver puncture wounds. Furthermore, MQS can effectively accelerate wound healing. In addition, MQS exhibits excellent antibacterial activity, cytocompatibility, and hemocompatibility. These advantages of MQS, including strong blood clotting, wet tissue adherence, antibacterial activity, wound healing ability, biosafety, ease of use, and stable storage, make it a promising hemostatic agent for emergency situations.

Polysaccharides based rapid self-crosslinking and wet tissue adhesive hemostatic powders for effective hemostasis.

Hemostatic powders with flexible shape are widely used for the noncompressible and inaccessible hemorrhage wounds. However, current hemostatic powders display poor wet tissue adhesion and fragile mechanical strength of the powder-supported blood clots, leading to compromised hemostasis efficacy. Herein, a bi-component of carboxymethyl chitosan (CMCS) and aldehyde-modified hyaluronic acid grafted with catechol groups (COHA) was designed. Upon absorption of blood, the bi-component powders (CMCS-COHA) spontaneously self-crosslinks into an adhesive hydrogel within 10 s, tightly adhering to wound tissue to form a pressure-resistant physical barrier. During gelation, the hydrogel matrix captures and locks the blood cells/platelets to generate a robust thrombus in the bleeding sites. Compared with traditional hemostatic powder Celox™, CMCS-COHA displays superior blood coagulation and hemostatic performance. More importantly, CMCS-COHA has inherent cytocompatibility and hemocompatibility. These prominent advantages in rapid and effective hemostasis, adaptability to fit irregulate defective wound, easy preservation, facile usage, and bio-safety, make CMCS-COHA a promising hemostatic in emergency situations.

Mussel Foot Protein Inspired Tape-Type Adhesive with Water-Responsive, High Conformal, Tough, and On-Demand Detachable Adhesion to Wet Tissue.

Wet adhesion is highly demanded in noninvasive wound closure, tissue repair, and biomedical devices, but it is still a big challenge for developing biosafe and tough wet bioadhesives due to low or even nonadhesion in the wet state for conventional adhesives. Inspired by the wet-adhesion-contributing factors of mussel foot proteins, a water-responsive dry robust tissue adhesive PAGU tape is made with thickness of <0.5 mm through fast UV-initiated copolymerization of acrylic acid (AA), gelatin (Gel), and hexadecenyl-1,2-catechol (UH). The tape shows strong cohesive mechanical properties and strong interfacial adhesion bonds. Upon application onto wet tissue, the adhesive tape can conform to the tissue, quickly dry tissue surface through absorbing surface/interfacial water and then allows formation of interfacial bonding with a high interfacial toughness of ≈818 J m-2 . Furthermore, it can be readily detached by treating with aq. urea solution. A highly efficient avenue is provided here for producing conformable, tough, and easy detachable wet bioadhesive tapes.

Robust but On-Demand Detachable Wet Tissue Adhesive Hydrogel Enhanced with Modified Tannic Acid.

Adhesives with robust but readily detachable wet tissue adhesion are of great significance for wound closure. Polyelectrolyte complex adhesive (PECA) is an important wet tissue adhesive. However, its relatively weak cohesive and adhesive strength cannot satisfy clinical applications. Herein, modified tannic acid (mTA) with a catechol group, a long alkyl hydrophobic chain, and a phenyl group was prepared first, and then, it was mixed with acrylic acid (AA) and polyethylenimine (PEI), followed by UV photopolymerization to make a wet tissue adhesive hydrogel with tough cohesion and adhesion strength. The hydrogel has a strong wet tissue interfacial toughness of ∼1552 J/m2, good mechanical properties (∼7220 kPa cohesive strength, ∼873% strain, and ∼33,370 kJ/m3 toughness), and a bursting pressure of ∼1575 mmHg on wet porcine skin. The hydrogel can realize quick and effective adhesion to various wet biological tissues including porcine skin, liver, kidney, and heart and can be changed easily with triggering urea solution to avoid tissue damage or uncomfortable pain to the patient. This biosafe adhesive hydrogel is very promising for wound closure and may provide new ideas for the design of robust wet tissue adhesives.

Tough and On-Demand Detachable Wet Tissue Adhesive Hydrogel Made from Catechol Derivatives with a Long Aliphatic Side Chain.

Wet adhesion is critical in cases of wound closure, but it is usually deterred by the hydration layer on tissues. Inspired by dopamine-mediated underwater adhesion in mussel foot proteins, wet tissue adhesives containing catechol with 2-3 carbons side chains are reported mostly. To make wet adhesion of this type of adhesives much tougher, catechol derivatives with a long aliphatic side chain (≈10 atoms length) are synthesized. Then, a series of strong wet tissue adhesive hydrogels are prepared through photoinduced copolymerization of acrylic acid with synthetic monomers. The adhesive hydrogel has a high cohesion strength, that is, tensile strength and strain, and toughness of ≈1800 kPa, ≈540%, and ≈4100 kJ m-3 , respectively. Its interfacial toughness on wet and underwater porcine skin is respectively ≈1300 and ≈1100 J m-2 , and its adhesion strength to wet porcine skin is ≈153 kPa. These values are much higher than those of dopamine-based adhesives in the same conditions, demonstrating that the long aliphatic side chain on catechol can greatly improve the wet tissue-adhesion. Additionally, the tough interfacial adhesion can be broken on demand with 5 wt.% aqueous urea solution. This adhesive hydrogel is highly promising in safe wound closure.

Biosynthesis and polyketide oxidation of Monascus red pigments in an integrated fermentation system with microparticles and surfactants.

Monascus red pigments are widely used in the food industry, mainly as intracellular red pigments. The low yields of extracellular red pigments (ERPs) make them unsuitable for large-scale industrial production. Herein, a novel integrated fermentation system (IFS) consisting of sodium starch octenyl succinate and Triton X-100 was explored for increasing yield, resulting in an ERP yield of 126.7 U/mL, 82.6% higher production than controls (69.4 U/mL). Major ERP components in control fermentations were monascopyridine A and monascopyridine B, but dehydro derivatives, rubropunctamine and monascorubramine, predominated in the test fermentations, presumably due to polyketide oxidation induced by Triton X-100. Improvement of hyphal morphology, membrane permeability, respiratory activity, and gene expression for red pigment biosynthesis is likely to be critical to increase yield and change the compositions. This study provides an effective strategy to accelerate the biosynthesis and secretion of Monascus pigments.

Efficient, biosafe and tissue adhesive hemostatic cotton gauze with controlled balance of hydrophilicity and hydrophobicity.

Cotton gauze is a widely used topical hemostatic material for bleeding control, but its high blood absorption capacity tends to cause extra blood loss. Therefore, development of rapid hemostatic cotton gauze with less blood loss is of great significance. Here, we develop an efficient hemostatic cotton gauze whose surface is slightly modified with a catechol compound which features a flexible long hydrophobic alkyl chain terminated with a catechol group. Its hemostatic performance in animal injuries is superior to standard cotton gauze and Combat GauzeTM. Its biosafety is similar to cotton gauze and rebleeding hardly occurs when the gauze is removed. Here, we show its hemostatic capability is attributable to the rapid formation of big and thick primary erythrocyte clots, due to its effective controlling of blood movement through blocking effect from tissue adhesion by catechol, blood wicking in cotton, and the hydrophobic effect from long alkyl chains.

Mussel foot protein inspired tough tissue-selective underwater adhesive hydrogel.

Mussel foot proteins (Mfps) show strong adhesion to underwater substrates, making mussels tightly cling to reefs to withstand the sea current. Therefore, Mfps-inspired tissue adhesives have aroused much research interest, but tough underwater biological tissue adhesion is still a great challenge. Herein, we report a tough and reversible wet tissue-selective adhesive hydrogel made of poly(acrylic acid-co-catechol) and chitosan (CS). It provides negatively charged -COO-, positively charged -NH3+, catechol group and hydrophobic alkyl chain, resemble amino acids, catechol and hydrophobic units in Mfps. Due to the covalent/electrostatic attraction/π-π/cationic-π/hydrogen bonding, in addition to the hydrophobic interaction from the long hydrophobic alkyl chain of the catechol derivative, the hydrogel has a high cohesion strength and toughness, i.e., tensile stress, fracture strain and fracture toughness of ∼0.57 MPa, 2510% and 6620 J m-2, respectively. As a tissue adhesive, its adhesion bonding to the porcine skin surface is so strong that its adhesion strength is almost equal to the tearing strength of the hydrogel. The 180-degree peeling adhesion energy of the hydrogel to blood-wetted porcine skin is notably ∼1010 J m-2. It can tightly and seamlessly adhere to the porcine small intestine, and has a bursting pressure of up to 520 mmHg. The hydrogel can be handily debonded from the porcine skin surface in the presence of aqueous solution at pH 8.0, and its adhesiveness is reversible for at least 20 cycles. It is supposed that the synergistic interactions of the adhesive catechol group, displacement of water on the wet skin surface by the positively charged -NH3+ groups of CS and the water-repelling potential of the hydrophobic unit of the catechol derivative, the protection of the catechol group from oxidation into a less adhesive quinone group, and the energy dissipation capacity of the mechanically tough hydrogel contribute to the strong and repeatable wet tissue adhesion.

Tough polyacrylamide-tannic acid-kaolin adhesive hydrogels for quick hemostatic application.

Adhesive hydrogels for wet and dynamic tissues are important for biomedical applications in order to withstand cyclic loading such as in the case of hemorrhaging control on the curved skins and heart tissues. However, the fabrication of hydrogels with strong mechanical properties, high adhesion strength, and hemostatic efficiency remains a big challenge. Inspired by the great adhesive behavior of mussels and Arion subfuscus, novel adhesive and hemostatic polyacrylamide-tannic acid-kaolin (PAAm-TA-KA) hydrogels were reported in this work. The hydrogels displayed high strength and toughness due to their physical and chemical crosslinking structures. The abundant catechol groups on tannic acid endow the hydrogels with strong and durable adhesion strength of up to 500 kPa on porcine skin. When applied onto human skin, the hydrogels could be easily peeled off without leaving any remains and causing any damages. The kaolin nanoparticles incorporated in the PAAm-TA-KA hydrogels not only served as a physical crosslinking agent, but an activator of the blood clotting factor FXII for accelerating the formation of thrombus. The strong tissue adhesion and blood coagulant potential of the PAAm-TA-KA hydrogels imparted them high hemostatic efficiency. The free-standing, adhesive, tough, cytocompatible, and hemostatic hydrogels are highly promising for traumatic bleeding control materials.

Porous chitosan microspheres as microcarriers for 3D cell culture.

Highly porous chitosan microspheres (CSM) were prepared through emulsion-based thermally induced phase separation (TIPS) without using toxic crosslinkers and chemical porogenic agents other than ice. The CSM had an average diameter of ∼150 µm with interconnected pores varying from 20∼50 µm in size. Due to their excellent biocompatibility and unique porous structure, high-performance hepatocyte culture in three-dimensional (3D) space was achieved using the CSM as microcarriers, as cell growth also took place within the internal pores of the CSM, besides their external surface, and multidirectional cell-cell interactions were observed. Enhanced cellular activity and functions were obtained with the CSM microcarriers as compared with 2D cell culture. It is believed that these CSM microcarriers provide a promising platform for 3D cell culture in vitro.

Comparative Analysis of Gene Expression Profiles of Human Dental Fluorosis and Kashin-Beck Disease.

To explore the pathologies of Kashin-Beck disease (KBD) and KBD accompanied with dental fluorosis (DF), we conducted a comparative analysis of gene expression profiles. 12 subjects were recruited, including 4 KBD patients, 4 patients with KBD and DF and 4 healthy subjects. Genome-wide expression profiles from their peripheral blood mononuclear cells were evaluated by customized oligonucleotide microarray. R programming software was used for the microarray data analysis followed by functional enrichment analysis through KOBAS. Several potential biomarkers were identified, and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used for their validation. In this study, 28 genes and 8 genes were found to be up- and down-regulated respectively in KBD patients compared with health subjects. In patients with KBD and DF, we obtained 10 up-regulated and 3 down-regulated genes compared with health controls. Strikingly, no differential expression gene (DEG) was identified between the two groups of patients. A total of 10 overlaps (DUSP2, KLRF1, SRP19, KLRC3, CD69, SIK1, ITGA4, ID3, HSPA1A, GPR18) were obtained between DEGs of patients with KBD and patients with KBD and DF. They play important roles in metabolism, differentiation, apoptosis and bone-development. The relative abundance of 8 DEGs, i.e. FCRL6, KLRC3, CXCR4, CD93, CLK1, GPR18, SRP19 and KLRF1, were further confirmed by qRT-PCR analysis.

Highly sensitive and selective sensor for sunset yellow based on molecularly imprinted polydopamine-coated multi-walled carbon nanotubes.

Polydopamine (PDA) can be formed by monomeric self-polymerization in water. This convenient behavior was exploited to prepare a molecularly imprinted polymer (MIP) layer on the surface of multi-walled carbon nanotubes (MWCNTs) with sunset yellow (SY) as a template molecule. The prepared nanocomposites were characterized, and their electrochemical behavior towards SY was investigated. Under the optimized conditions, a glassy carbon electrode modified with the imprinted nanocomposite showed a highly selective and ultrasensitive electrochemical response to SY compared with the performance of control electrodes and previously reported electrochemical sensors for SY. The improved behavior of the developed sensor can be attributed to its superficial highly matched imprinted cavities on the excellent electrocatalytic matrix of MWCNTs and the electronic barrier of the non-imprinted PDA to outside molecules. The fabricated sensor expressed a linear relationship to SY concentrations from 2.2nM to 4.64µM with a detection limit of 1.4nM (S/N = 3). The sensor also exhibited excellent selectivity for SY over its structural analogs, good stability, and adequate reproducibility. The prepared sensor was successfully used to detect SY in real spiked samples. This methodology has potential application value and may be readily adapted to design other PDA-based MIP sensors.

Fabrication of porous chitosan membranes composed of nanofibers by low temperature thermally induced phase separation, and their adsorption behavior for Cu2.

Low temperature thermally induced phase separation (LT-TIPS) of chitosan solution was developed to fabricate porous chitosan membranes (p-CSMs), which were composed of short nanofibers with diameter of 40-60nm. Compared to the conventional acetic acid/water solvent, a mixed solvent of acetic acid/ethanol/water was used to prepare chitosan solution. The effect of solvent composition, quenching temperature and time, and coagulant on the p-CSM morphology were systematically explored. The optimum conditions for fabricating p-CSM was to quench 2% chitosan/2% acetic acid in water/ethanol (70/30) at -20°C for 12h, followed by coagulating in 1% Na2CO3 in water/ethanol (50/50). The p-CSM was an effective adsorbent for Cu2+ and had a Langmuir adsorption capacity of 2.57mmol/g, which is close to the adsorption capacity of natural and electrospun chitosan nanofibers. The p-CSM maintained 90% adsorption efficiency for Cu2+ even after six cycles.

Novel imidazole fluorescent poly(ionic liquid) nanoparticles for selective and sensitive determination of pyrogallol.

This paper reports novel imidazole fluorescent poly(ionic liquid) nanoparticles (FPILNs) of poly(1-[(4-methyphenyl)methyl]-3-vinyl-imidazolium bromide (poly([MVI]Br) for selective and sensitive determination of pyrogallol. An imidazole ionic liquid of 1-[(4-methyphenyl)methyl]-3-vinyl-imidazolium bromide ([MVI]Br) was synthesized and used as the only monomer to obtain poly([MVI]Br) possessing phenyl fluorophores using a radical polymerization technique. The obtained poly([MVI]Br) can form nanoparticles in water. Scanning electron microscopy and dynamic light scattering results revealed majority of poly([MVI]Br) FPILNs with diameters ranging from 40 to 400nm. Although [MVI]Br showed weak fluorescence intensity, poly([MVI]Br) FPILNs exhibited strong fluorescence intensity with a quantum yield of 0.192, which is attributed to the presence of significant number of phenyl fluorophores and rigid construction. The selective and sensitive determination of pyrogallol was achieved through fluorescence quenching of poly([MVI]Br) FPILNs, and the quenching was attributed to the oxidation of poly([MVI]Br) FPILNs by O2˙¯ produced by pyrogallol autoxidation. The poly([MVI]Br) FPILNs-based sensor demonstrated a good linear relationship between the extent of fluorescence quenching and the concentration of pyrogallol in a range of 0.05 - 10.0µM, achieving a detection limit of 0.01µM. Furthermore, the poly([MVI]Br) FPILNs-based assay detected pyrogallol in environmental water samples, suggesting its potential to be applied for practical purposes.

Electrochemical Molecular Imprinted Sensors Based on Electrospun Nanofiber and Determination of Ascorbic Acid.

In this study, electrochemical molecularly imprinted sensors were fabricated and used for the determination of ascorbic acid (AA). Nanofiber membranes of cellulose acetate (CA)/multi-walled carbon nanotubes (MWCNTs)/polyvinylpyrrolidone (PVP) (CA/MWCNTs/PVP) were prepared by electrospinning technique. After being transferred to a glass carbon electrode (GC), the nanofiber interface was further polymerized with pyrrole through electrochemical cyclic voltammetry (CV) technique. Meanwhile, target molecules (such as AA) were embedded into the polypyrrole through the hydrogen bond. The effects of monomer concentration (pyrrole), the number of scan cycles and scan rates of polymerization were optimized. Differential pulse voltammetry (DPV) tests indicated that the oxidation current of AA (the selected target) were higher than that of the structural analogues, which illustrated the selective recognition of AA by molecularly imprinted sensors. Simultaneously, the molecularly imprinted sensors had larger oxidation current of AA than non-imprinted sensors in the processes of rebinding. The electrochemical measurements showed that the molecularly imprinted sensors demonstrated good identification behavior for the detection of AA with a linear range of 10.0 - 1000 µM, a low detection limit down to 3 µM (S/N = 3), and a recovery rate range from 94.0 to 108.8%. Therefore, the electrochemical molecularly imprinted sensors can be used for the recognition and detection of AA without any time-consuming elution. The method presented here demonstrates the great potential for electrospun nanofibers and MWCNTs to construct electrochemical sensors.