RESUMEN
Uncontrolled non-compressible hemorrhage, which is often accompanied by coagulopathy, is a major cause of mortality following traumatic injuries in civilian and military populations. In this study, coagulopathy-independent injectable catechol-modified chitosan (CS-HCA) hemostatic materials featuring rapid shape recovery were fabricated by combining controlled sodium tripolyphosphate-crosslinking with hydrocaffeic acid (HCA) grafting. CS-HCA exhibited robust mechanical strength and rapid blood-triggered shape recovery. Furthermore, CS-HCA demonstrated superior blood-clotting ability, enhanced blood cell adhesion and activation, and greater protein adsorption than commercial hemostatic gauze and Celox. CS-HCA showed enhanced procoagulant and hemostatic capacities in a lethal liver-perforation wound model in rabbits, particularly in heparinized rabbits. CS-HCA is suitable for mass manufacturing and shows promise as a clinically translatable hemostat.
Asunto(s)
Catecoles , Quitosano , Hemorragia , Hemostáticos , Quitosano/química , Quitosano/farmacología , Animales , Conejos , Catecoles/química , Catecoles/farmacología , Hemorragia/tratamiento farmacológico , Hemostáticos/química , Hemostáticos/farmacología , Coagulación Sanguínea/efectos de los fármacos , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacología , Masculino , Materiales Inteligentes/química , InyeccionesRESUMEN
Uncontrolled hemorrhage stands as the primary cause of potentially preventable deaths following traumatic injuries in both civilian and military populations. Addressing this critical medical need requires the development of a hemostatic material with rapid hemostatic performance and biosafety. This work describes the engineering of a chitosan-based cryogel construct using thermo-assisted cross-linking with α-ketoglutaric acid after freeze-drying. The resulting cryogel exhibited a highly interconnected macro-porous structure with low thermal conductivity, exceptional mechanical properties, and great fluid absorption capacity. Notably, assessments using rabbit whole blood in vitro, as well as rat liver volume defect and femoral artery injury models simulating severe bleeding, showed the remarkable hemostatic performance of the chitosan cryogel. Among the cryogel variants with different chitosan molecular weights, the 150 kDa one demonstrated superior hemostatic efficacy, reducing blood loss and hemostasis time by approximately 73 % and 63 % in the hepatic model, and by around 60 % and 68 %, in the femoral artery model. Additionally, comprehensive in vitro and in vivo evaluations underscored the good biocompatibility of the chitosan cryogel. Taken together, these results strongly indicate that the designed chitosan cryogel configuration holds significant potential as a safe and rapid hemostatic material for managing severe hemorrhage.
Asunto(s)
Quitosano , Criogeles , Hemorragia , Hemostáticos , Quitosano/química , Quitosano/farmacología , Criogeles/química , Animales , Conejos , Hemorragia/terapia , Hemorragia/tratamiento farmacológico , Hemostáticos/química , Hemostáticos/farmacología , Ratas , Masculino , Ratas Sprague-Dawley , Arteria Femoral/lesiones , Porosidad , Hígado/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Reactivos de Enlaces Cruzados/química , Hemostasis/efectos de los fármacosRESUMEN
Biopolymer aerogel is a new type of material with potential applications in the biomedical field. Silk fibroin is of particular interest as a raw material with good biocompatibility and degradable. However, the low mechanical strength and small specific surface area of silk fibroin aerogels limit its further development. Herein, a fast water absorption, highly specific surface area and mechanically strong of aerogels were prepared using low crystal silk fibroin nanofibers (SNF), sol-gel process, solvent exchange and supercritical carbon dioxide (CO2) drying method. The resulting Aero-Sc displayed highly specific surface area (251 m2/g), porosity (97.6 %) and water absorption capacity (1200 %). Furthermore, with rapid water absorption and stronger erythrocyte adhesion, the Aero-Sc showed highly effective hemostasis in vitro. In vivo, animal experiments on rat liver hemorrhage model confirmed that SNF aerogels have a less blood loss (312 ± 29 mg) and faster hemostatic time (92 ± 13 s) than commercially gelatin sponge (p < 0.05). The unique properties of silk fibroin nanofibers aerogel developed in this study has great potential to be a safe and effective hemostatic medical device.
Asunto(s)
Fibroínas , Geles , Hemostasis , Nanofibras , Nanofibras/química , Animales , Ratas , Fibroínas/química , Fibroínas/farmacología , Hemostasis/efectos de los fármacos , Geles/química , Porosidad , Hemorragia/tratamiento farmacológico , Fenómenos Mecánicos , Hemostáticos/química , Hemostáticos/farmacología , Propiedades de Superficie , Agua/química , Masculino , Bombyx/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacologíaRESUMEN
Inherited bleeding disorders such as Glanzmann thrombasthenia (GT) lack prophylactic treatment options. As a result, serious bleeding episodes are treated acutely with blood product transfusions or frequent, repeated intravenous administration of recombinant activated coagulation factor VII (rFVIIa). Here we describe HMB-001, a bispecific antibody designed to bind and accumulate endogenous FVIIa and deliver it to sites of vascular injury by targeting it to the TREM (triggering receptor expressed on myeloid cells)-like transcript-1 (TLT-1) receptor that is selectively expressed on activated platelets. In healthy nonhuman primates, HMB-001 prolonged the half-life of endogenous FVIIa, resulting in its accumulation. Mouse bleeding studies confirmed antibody-mediated potentiation of FVIIa hemostatic activity by TLT-1 targeting. In ex vivo models of GT, HMB-001 localized FVIIa on activated platelets and potentiated fibrin-dependent platelet aggregation. Taken together, these results indicate that HMB-001 has the potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.
Asunto(s)
Anticuerpos Biespecíficos , Animales , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/inmunología , Humanos , Factor VIIa , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos , Plaquetas/inmunología , Ratones , Modelos Animales de Enfermedad , Hemorragia/prevención & control , Hemorragia/tratamiento farmacológico , Agregación Plaquetaria/efectos de los fármacos , Trombastenia/tratamiento farmacológico , Trombastenia/inmunología , Ratones Endogámicos C57BL , Femenino , Masculino , Macaca fascicularis , Activación Plaquetaria/efectos de los fármacosRESUMEN
Developing an effective and user-friendly hemostatic agent is highly desired in the treatment of hemorrhage. Inspired by the natural nanostructure and abundant hydroxyl groups of cellulose and clay minerals, we designed an aerogel (HNTs/TOCNs) composed of halloysite nanotubes (HNTs) and TEMPO-oxidized cellulose nanofibers (TOCNs) with a hierarchical porous structure for the treatment of bleeding, using a simple and environmentally friendly self-assembly method. TOCNs formed a three-dimensional porous scaffold with excellent water-holding capacity. The incorporation of HNTs enhanced the hemostatic efficiency and mechanical properties of the 3D framework. The large interlayer spaces and wide channels within the HNTs/TOCNs aerogel provided rapid passage for blood, facilitating blood concentration and offering ample room for interactions between the HNTs/TOCNs aerogel and platelets, erythrocytes, and coagulation factors, thereby promoting hemostasis. Benefiting from the natural hemostatic properties and well-designed structure, the HNTs/TOCNs aerogel displayed excellent hemostatic performance both in vitro and in vivo. Notably, the hemostatic time of HNTs/TOCNs-2 was only 74 ± 8 s, which is approximately 50 % shorter than the blank control (151 ± 20 s) in liver femoral artery injury model. This design of an HNTs/TOCNs aerogel presents a unique opportunity to enhance hemostatic efficacy by synergizing the advantages of natural materials.
Asunto(s)
Celulosa , Arcilla , Hemostasis , Nanofibras , Nanofibras/química , Porosidad , Animales , Hemostasis/efectos de los fármacos , Arcilla/química , Celulosa/química , Geles/química , Hemostáticos/química , Hemostáticos/farmacología , Ratas , Hemorragia/tratamiento farmacológico , Masculino , Nanotubos/química , Óxidos N-Cíclicos/química , RatonesRESUMEN
The development of efficient hemostatic materials is crucial for achieving rapid hemorrhage control and effective wound healing. Inorganic polyphosphate (polyP) is recognized as an effective modulator of the blood coagulation process. However, the specific effect of polyP chain length on coagulation is not yet fully understood. Furthermore, calcium ions (Ca2+) are essential for the coagulation process, promoting multiple enzyme-catalyzed reactions within the coagulation cascade. Hence, calcium ion-coupled polyphosphate powders with three different degrees of polymerization (CaPP-n, n = 20, 50, and 1500) are synthesized by an ion-exchange reaction. CaPP exhibits a crystalline phase at a low polymerization degree and transitions to an amorphous phase as the polymerization degree increases. Notably, the addition of Ca2+ enhances the wettability of polyP, and CaPP promotes hemostasis, with varying degrees of effectiveness related to chain length. CaPP-50 exhibits the most promising hemostatic performance, with the lowest blood clotting index (BCI, 12.1 ± 0.7%) and the shortest clotting time (302.0 ± 10.5 s). By combining Ca2+ with polyP of medium-chain length, CaPP-50 demonstrates an enhanced ability to accelerate the adhesion and activation of blood cells, initiate the intrinsic coagulation cascade, and form a stable blood clot, outperforming both CaPP-20 and CaPP-1500. The hemostatic efficacy of CaPP-50 is further validated using rat liver bleeding and femoral artery puncture models. CaPP-50 is proven to possess hemostatic properties comparable to those of commercial calcium-based zeolite hemostatic powder and superior to kaolin. In addition, CaPP-50 exhibits excellent biocompatibility and long-term storage stability. These results suggest that CaPP-50 has significant clinical and commercial potential as an active inorganic hemostatic agent for rapid control of bleeding.
Asunto(s)
Calcio , Hemorragia , Polimerizacion , Polifosfatos , Animales , Polifosfatos/química , Polifosfatos/farmacología , Calcio/química , Ratas , Hemorragia/prevención & control , Hemorragia/tratamiento farmacológico , Hemostáticos/química , Hemostáticos/farmacología , Coagulación Sanguínea/efectos de los fármacos , Ratas Sprague-Dawley , Masculino , Hemostasis/efectos de los fármacos , Iones/químicaRESUMEN
The study focuses on developing a bioactive shape memory sponge to address the urgent demand for short-term rapid hemostasis and long-term wound healing in noncompressible hemorrhage cases. A composite sponge was created by spontaneously generating pores and double cross-linking under mild conditions using biomimetic collagen fibril (BCF) and oxidized alginate (OA) as natural backbone, combined with an inert calcium source (Ca) from CaCO3-GDL slow gelation mechanism. The optimized BCF/OACa (5/5) sponge efficiently absorbed blood after compression and recovered to its original state within 11.2 ± 1.3 s, achieving physical hemostatic mechanism. The composite sponge accelerated physiological coagulation by promoting platelet adhesion and activation through BCF, as well as enhancing endogenous and exogenous hemostatic pathways by Ca2+. Compared to commercial PVA expanding hemostatic sponge, the composite sponge reduced bleeding volume and shortened hemostasis time in rat liver injury pick and perforation wound models. Additionally, it stimulated fibroblast migration and differentiation, thus promoting wound healing. It is biodegradable with low inflammatory response and promotes granulation tissue regeneration. In conclusion, this biocomposite sponge provides multiple hemostatic pathways and biochemical support for wound healing, is biologically safe and easy to fabricate, process and use, with significant potential for clinical translation and application.
Asunto(s)
Alginatos , Materiales Biomiméticos , Colágeno , Hemorragia , Hemostáticos , Cicatrización de Heridas , Alginatos/química , Alginatos/farmacología , Animales , Cicatrización de Heridas/efectos de los fármacos , Colágeno/química , Ratas , Hemorragia/tratamiento farmacológico , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Hemostáticos/farmacología , Hemostáticos/química , Masculino , Ratas Sprague-Dawley , Hemostasis/efectos de los fármacos , Oxidación-Reducción , Adhesividad Plaquetaria/efectos de los fármacosRESUMEN
The key to saving lives is to achieve instant and effective sealing hemostasis in the event of emergency bleeding. Herein, a plant oil-based EMTA/Zn2+ bioadhesive is prepared by a facile reaction of epoxidized soybean oil (ESO) with methacrylic acid (MAA) and tannic acid (TA), followed by the addition of zinc ions for coordination with TA. The EMTA/Zn2+ bioadhesive can be rapidly cured in situ at the wound site through photo-cross-linking under ultraviolet (UV) light-emitting diode (LED) irradiation within 30 s, achieving ultrastrong wet-tissue adhesion performance of 92.4 and 51.8 kPa to porcine skin and aortic skin after 7 days underwater, respectively. Especially, the EMTA/Zn2+ bioadhesive exhibits outstanding sealing performance in vitro with the high burst pressure of 525 mmHg (70 kPa) and 337.5 mmHg (45 kPa) to porcine skin and aortic skin, respectively. Moreover, the EMTA/Zn2+ bioadhesive not only has outstanding hemocompatibility and good biodegradability but also exhibits excellent cytocompatibility and antibacterial properties. Notably, the EMTA/Zn2+ bioadhesive has remarkable instant sealing hemostatic ability for hemorrhaging liver in vivo. Therefore, the prepared plant oil-based EMTA/Zn2+ bioadhesive can serve as a charming alternative candidate for instant sealing hemostasis in clinical applications, especially in traumatic internal organs and arterial bleeding.
Asunto(s)
Hemostasis , Animales , Porcinos , Hemostasis/efectos de los fármacos , Aceites de Plantas/química , Aceites de Plantas/farmacología , Hemostáticos/química , Hemostáticos/farmacología , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Zinc/química , Zinc/farmacología , Ratones , Humanos , Hemorragia/tratamiento farmacológico , Piel/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Taninos/química , Taninos/farmacología , Metacrilatos/química , Metacrilatos/farmacologíaRESUMEN
Achieving rapid clotting and clot stability are important unmet goals of clinical management of noncompressible hemorrhage. This study reports the development of a spatiotemporally controlled release system of an antihemorrhagic drug, etamsylate, in the management of internal hemorrhage. Gly-Arg-Gly-Asp-Ser (GRGDS) peptide-functionalized chitosan nanoparticles, with high affinity to bind with the GPIIa/IIIb receptor of activated platelets, were loaded with the drug etamsylate (etamsylate-loaded GRGDS peptide-functionalized chitosan nanoparticles; EGCSNP). Peptide conjugation was confirmed by LCMS, and the delivery system was characterized by DLS, SEM, XRD, and FTIR. In vitro study exhibited 90% drug release till 48 h fitting into the Weibull model. Plasma recalcification time and prothrombin time tests of GRGDS-functionalized nanoparticles proved that clot formation was 1.5 times faster than nonfunctionalized chitosan nanoparticles. The whole blood clotting time was increased by 2.5 times over clot formed under nonfunctionalized chitosan nanoparticles. Furthermore, the application of rheometric analysis revealed a 1.2 times stiffer clot over chitosan nanoparticles. In an in vivo liver laceration rabbit model, EGCSNP spatially localized at the internal injury site within 5 min of intravenous administration, and no rebleeding was recorded up to 3 h. The animals survived for 3 weeks after the injury, indicating the strong potential of the system for the management of noncompressible hemorrhage.
Asunto(s)
Coagulación Sanguínea , Quitosano , Modelos Animales de Enfermedad , Hemorragia , Nanopartículas , Animales , Conejos , Nanopartículas/química , Quitosano/química , Hemorragia/tratamiento farmacológico , Coagulación Sanguínea/efectos de los fármacos , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/química , Masculino , Péptidos/química , Péptidos/farmacología , Péptidos/uso terapéuticoRESUMEN
Gauze or bandages are commonly used to effectively control bleeding during trauma and surgery. However, conventional treatment methods can sometimes lead to secondary damages. In recent years, there has been increased interest in developing adhesive hemostatic hydrogels as a safer alternative for achieving hemostasis. Methylcellulose (MC) is a well-known thermo-sensitive polymer with excellent biocompatibility that is capable of forming a hydrogel through physical crosslinking owing to its inherent thermo-reversible properties. However, the poor mechanical properties of the MC hydrogel comprising a single crosslinked network (SN) limit its application as a hemostatic material. To address this issue, we incorporated a chitosan-gallol (CS-GA) conjugate, which has the ability to form chemical crosslinks through self-crosslinking reactions under specific pH conditions, into the MC hydrogel to reinforce the MC hydrogel network. The resulting MC/CS-GA hydrogel with a dual-crosslinked network (DN), involving both physical and chemical crosslinks, exhibited synergistic effects of the two types of crosslinks. Thus, compared with those of the SN hydrogel, the composite DN hydrogel exhibited significantly enhanced mechanical strength and tissue adhesive properties. Moreover, the DN hydrogel presented excellent biological activity in vitro. Additionally, in rat hepatic hemorrhage models, the DN hydrogel exhibited high hemostatic efficiency, showcasing its multifunctional capabilities.
Asunto(s)
Quitosano , Hemostáticos , Hidrogeles , Metilcelulosa , Temperatura , Adhesivos Tisulares , Hidrogeles/química , Hidrogeles/farmacología , Quitosano/química , Animales , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Concentración de Iones de Hidrógeno , Hemostáticos/química , Hemostáticos/farmacología , Ratas , Metilcelulosa/química , Hemorragia/tratamiento farmacológico , Ratas Sprague-Dawley , Masculino , Reactivos de Enlaces Cruzados/química , HumanosRESUMEN
Acute hemorrhage is a major cause of death in many emergency cases. Although many hemostatic materials have been studied in recent years, it is still necessary to develop new hemostatic materials with remarkable efficiency, biosafety, convenient preparation, low cost, and good biodegradability. In this work, novel chitosan (CS)/ß-glycerophosphate (ß-GP) composite porous microsphere with a uniform size of 210.00 ± 2.14 µm was fabricated through water-in-water (W/W) emulsion via microencapsulation, which can avoid the use of toxic crosslink chemicals and organic solvents to achieve facile and efficient preparation of microspheres. ß-GP could promote the formation of microspheres by enhancing the hydrogen-bonding interaction between CS chains, which contributed to the macro-porous structure. Owing to their large pore size (6.0 µm) and high specific surface area (37.8 m2/g), the CS/ß-GP microspheres could absorb water quickly and adsorb protein, red blood cells, and platelets through electrostatic forces to promote blood coagulation. Furthermore, the CS/ß-GP microspheres achieved a significantly shortened hemostatic time (45 s) and reduced blood loss (0.03 g) in a rat liver injury model. Rat tail amputation test also showed a satisfactory hemostatic effect. Overall, the green and porous CS/ß-GP microspheres can be used as a facile and topical rapid hemostatic material.
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Quitosano , Emulsiones , Glicerofosfatos , Hemostáticos , Microesferas , Agua , Quitosano/química , Hemostáticos/química , Hemostáticos/farmacología , Animales , Porosidad , Emulsiones/química , Ratas , Agua/química , Glicerofosfatos/química , Hemorragia/tratamiento farmacológico , Hemorragia/prevención & control , Masculino , Ratas Sprague-DawleyRESUMEN
In our search for a biocompatible composite hemostatic dressing, we focused on the design of a novel biomaterial composed of two natural biological components, collagen and sodium alginate (SA), cross-linked using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) and oxidized sodium alginate (OSA). We conducted a series of tests to evaluate the physicochemical properties, acute systemic toxicity, skin irritation, intradermal reaction, sensitization, cytotoxicity, and in vivo femoral artery hemorrhage model. The results demonstrated the excellent biocompatibility of the collagen/sodium alginate (C/SA)-based dressings before and after crosslinking. Specifically, the femoral artery hemorrhage model revealed a significantly shortened hemostasis time of 132.5 ± 12.82 s for the EDC/NHS cross-linked dressings compared to the gauze in the blank group (hemostasis time of 251.43 ± 10.69 s). These findings indicated that C/SA-based dressings exhibited both good biocompatibility and a significant hemostatic effect, making them suitable for biomedical applications.
Asunto(s)
Alginatos , Vendajes , Colágeno , Hemostáticos , Alginatos/química , Alginatos/farmacología , Animales , Colágeno/química , Colágeno/farmacología , Hemostáticos/química , Hemostáticos/farmacología , Ratones , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ensayo de Materiales , Hemorragia/tratamiento farmacológico , Masculino , Ratas , Hemostasis/efectos de los fármacos , Arteria FemoralRESUMEN
Developing a hemostatic material suitable for rapid hemostasis remains a challenge. This study presents a novel aminated gelatin sponge cross-linked with dialdehyde starch, exhibiting excellent biocompatibility and hemostatic ability. This aminated gelatin sponge features hydrophilic surface and rich porous structure with a porosity of up to 80 %. The results show that the aminated gelatin sponges exhibit superior liquid absorption capacity and can absorb up to 30-50 times their own mass of simulated body fluid within 5 min. Compared with the commercial gelatin hemostatic sponge and non-aminated gelatin hemostatic sponge, the aminated gelatin hemostatic sponge can accelerate the hemostatic process through electrostatic interactions, demonstrating superior hemostatic performance in both in vitro and in vivo hemostasis tests. The aminated gelatin sponge can effectively control the hemostatic time within 80 s in the in vivo rat femoral artery injury model, significantly outperforming both commercial and non-aminated gelatin sponges. In addition, the aminated gelatin sponge also exhibits good biocompatibility and certain antibacterial properties. The proposed aminated gelatin sponge has very good application prospects for the management of massive hemorrhage.
Asunto(s)
Materiales Biocompatibles , Gelatina , Hemostáticos , Almidón , Animales , Almidón/química , Almidón/farmacología , Almidón/análogos & derivados , Ratas , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Hemostáticos/química , Hemostáticos/farmacología , Gelatina/química , Gelatina/farmacología , Masculino , Porosidad , Ratas Sprague-Dawley , Hemorragia/tratamiento farmacológico , Hemostasis/efectos de los fármacos , Esponja de Gelatina Absorbible/química , Esponja de Gelatina Absorbible/farmacología , Reactivos de Enlaces Cruzados/química , Arteria Femoral/efectos de los fármacos , HumanosRESUMEN
Rapid and safe hemostasis is crucial for the survival of bleeding patients in prehospital care. It is urgent to develop high performance hemostatic material to control the massive hemorrhage in the military field and accidental trauma. In this work, an efficient protein hemostat of thrombin was immobilized onto commercial gauze, which was mediated by self-polymerization and anchoring of tannic acid (TA). Through TA treatment, the efficient immobilization of thrombin was achieved, preserving both the biological activity of thrombin and the physical properties of the dressing, including absorbency, breathability, and mechanical performance. Moreover, in the presence of TA coating and thrombin, Gau@TA/Thr could obviously shortened clotting time and enriched blood components such as plasma proteins, platelets, and red blood cells, thereby exhibiting an enhanced in vitro coagulation effect. In SD rat liver volume defect and artery transection hemorrhage models, Gau@TA/Thr still had outstanding hemostatic performance. Besides, the Gau@TA/Thr gauze had inherent antibacterial property and demonstrated excellent biocompatibility. All results suggested that Gau@TA/Thr would be a potential candidate for treating uncontrollable hemorrhage in prehospital care.
Asunto(s)
Vendajes , Coagulación Sanguínea , Hemorragia , Hemostáticos , Taninos , Trombina , Taninos/química , Taninos/farmacología , Animales , Hemorragia/tratamiento farmacológico , Trombina/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Ratas , Hemostáticos/farmacología , Hemostáticos/química , Ratas Sprague-Dawley , Masculino , Antiinfecciosos/farmacología , Humanos , Proteínas Inmovilizadas/farmacología , Proteínas Inmovilizadas/química , Modelos Animales de Enfermedad , PolifenolesRESUMEN
Hyaluronic acid (HA), a major component of skin extracellular matrix, provides an excellent framework for hemostatic design; however, there still lacks HA materials tailored with superior mechanical properties to address non-compressible hemorrhages. Here, we present a solvent-free thermal approach for constructing a shape-memory HA sponge for this application. Following facile thermal incubation around 130 °C, HA underwent cross-linking via esterification with poly(acrylic acid) within the sponge pre-shaped through a prior freeze-drying process. The resulting sponge system exhibited extensively interconnected macropores with a high fluid absorption capacity, excellent shape-memory property, and robust mechanical elasticity. When introduced to whole blood in vitro, the HA sponges demonstrated remarkable hemostatic properties, yielding a shorter coagulation time and lower blood clotting index compared to the commercial gelatin sponge (GS). Furthermore, in vivo hemostatic studies involving two non-compressible hemorrhage models (rat liver volume defect injury or femoral artery injury) achieved a significant reduction of approximately 64% (or 56%) and 73% (or 70%) in bleeding time and blood loss, respectively, which also outperformed GS. Additionally, comprehensive in vitro and in vivo evaluations suggested the good biocompatibility and biodegradability of HA sponges. This study highlights the substantial potential for utilizing the designed HA sponges in massive bleeding management.
Asunto(s)
Hemorragia , Ácido Hialurónico , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Animales , Hemorragia/tratamiento farmacológico , Ratas , Hemostáticos/química , Hemostáticos/farmacología , Temperatura , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Coagulación Sanguínea/efectos de los fármacos , Masculino , Porosidad , Ratas Sprague-DawleyRESUMEN
Trauma is the leading cause of death for adults under the age of 44. Internal bleeding remains a significant challenge in medical emergencies, necessitating the development of effective hemostatic materials that could be administered by paramedics before a patient is in the hospital and treated by surgeons. In this study, we introduce a graphene oxide (GO)-based PEGylated synthetic hemostatic nanomaterial with an average size of 211 ± 83 nm designed to target internal bleeding by mimicking the role of fibrinogen. Functionalization of GO-g-PEG with peptides derived from the α-chain of fibrinogen, such as GRGDS, or the γ-chain of fibrinogen, such as HHLGGAKQAGDV:H12, was achieved with peptide loadings of 72 ± 6 and 68 ± 15 µM, respectively. In vitro studies with platelet-rich plasma (PRP) under confinement demonstrated aggregation enhancement of 39 and 24% for GO-g-PEG-GRGDS and GO-g-PEG-H12, respectively, compared to buffer, while adenosine diphosphate (ADP) alone induced a 5% aggregation. Compared to the same materials in the absence of ADP, GO-g-PEG-GRGDS achieved a 47% aggregation enhancement, while GO-g-PEG-H12 a 25% enhancement. This is particularly important for injectable hemostats and highlights the fact that our nanographene-based materials can only act as hemostats in the presence of agonists, reducing the possibility of unwanted clotting during circulation. Further studies on collagen-coated wells under dynamic flow revealed statistically significant augmentation of PRP fluorescence signal using GRGDS- or H12-coated GO-g-PEG compared to controls. Hemolysis studies showed <1% lysis of red blood cells (RBCs) at the highest PEGylated nanographene concentration. Finally, whole human blood coagulation studies reveal faster and more pronounced clotting using our nanohemostats vs PBS control from 3 min and below (blood is clotted with 10% CaCl2 within 4-5 min), with the biggest differences to be shown at 2 and 1 min. At 1 min, the clot weight was found to be â¼45% of that between 4 and 5 min, while no clot was formed in PBS-treated blood. Reduction of CaCl2 to 5 and 3%, or utilization of prostaglandin E1, an anticoagulant, still leads to clots but of smaller weight. The findings highlight the potential of our fibrinogen-mimic PEGylated nanographene as a promising non-hemolytic injectable scaffold for targeting internal bleeding, offering insights into its platelet aggregation capabilities under confinement and under dynamic flow as well as its pronounced coagulation abilities.
Asunto(s)
Fibrinógeno , Grafito , Hemostáticos , Grafito/química , Hemostáticos/química , Hemostáticos/farmacología , Humanos , Fibrinógeno/química , Fibrinógeno/metabolismo , Polietilenglicoles/química , Coagulación Sanguínea/efectos de los fármacos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Hemorragia/tratamiento farmacológicoRESUMEN
Uncontrolled bleeding and wound infections following severe trauma pose significant challenges for existing tissue adhesives, primarily due to their weak wet adhesion, slow adhesion formation, cytotoxicity concerns, and lack of antibacterial properties. Herein, an injectable hydrogel (denoted as ES gel) with rapid, robust adhesive sealing and inherent antibacterial activity based on ε-polylysine and a poly(ethylene glycol) derivative is developed. The engineered hydrogel exhibits rapid gelation behavior, high mechanical strength, strong adhesion to various tissues, and can sustain an ultrahigh burst pressure of 450 mmHg. It also presents excellent biocompatibility, biodegradability, antibacterial properties, and on-demand removability. Significantly improved hemostatic efficacy of ES gel compared to fibrin glue is demonstrated using various injury models in rats and rabbits. Remarkably, the adhesive hydrogel can effectively halt lethal non-compressible hemorrhages in visceral organs (liver, spleen, and heart) and femoral artery injury models in fully anticoagulated pigs. Furthermore, the hydrogel outperforms commercial products in sutureless wound closure and repair in the rat liver defect, skin incision, and infected full-thickness skin wound models. Overall, this study highlights the promising clinical applications of ES gel for managing uncontrolled hemorrhage, sutureless wound closure, and infected wound repair.
Asunto(s)
Antibacterianos , Hemostasis , Hidrogeles , Cicatrización de Heridas , Animales , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/uso terapéutico , Ratas , Conejos , Hemostasis/efectos de los fármacos , Presión , Polilisina/química , Polilisina/farmacología , Inyecciones , Porcinos , Polietilenglicoles/química , Hemorragia/tratamiento farmacológico , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ratas Sprague-Dawley , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Adhesivos Tisulares/uso terapéuticoRESUMEN
BACKGROUND: Sexual assault survivors may sustain vaginal trauma that requires intervention in the emergency department, or operating room. CASE REPORT: We describe the case of a 16-year-old female who was referred to the emergency department for evaluation of continued bleeding from a vaginal laceration following sexual assault 38 h prior. The bleeding limited the medical forensic medical examination, but she was hemodynamically stable. After the application of tranexamic acid (TXA)-soaked gauze, the patient's bleeding was controlled and the wound was able to be evaluated and the examination completed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: To our knowledge, this is the first case in the literature that describes the use of topical TXA in a patient to achieve hemostasis in a vaginal laceration sustained from sexual violence.
Asunto(s)
Administración Tópica , Antifibrinolíticos , Laceraciones , Ácido Tranexámico , Vagina , Humanos , Ácido Tranexámico/administración & dosificación , Ácido Tranexámico/uso terapéutico , Femenino , Adolescente , Laceraciones/complicaciones , Antifibrinolíticos/uso terapéutico , Antifibrinolíticos/administración & dosificación , Vagina/lesiones , Delitos Sexuales , Hemorragia/etiología , Hemorragia/tratamiento farmacológico , Servicio de Urgencia en HospitalRESUMEN
Fatal massive hemorrhage and diabetic wound healing are world widely challenging in surgical managements, and uncontrolled bleeding, chronic inflammation and damaged remodeling heavily hinder the whole healing processes. Considering hemostasis, inflammation and wound microenvironment cooperatively affect the healing progression, we design all-in-one beta-glucan (BG) hybrid hydrogels reinforced with laponite nanoclay that demonstrate tunable tissue adhesion, resistant vascular burst pressure and cooperative wound microenvironment regulation for arterial hemostasis and diabetic wound prohealing. Those hydrogels had honeycomb-like porous microstructure with average pore size of 7-19 µm, tissue adhesion strength of 18-46 kPa, and vascular burst pressure of 58-174 mmHg to achieve superior hemostasis in rat liver and femoral artery models. They could effectively scavenge reactive oxygen species, transform macrophages from proinflammatory M1 into prohealing M2, and shorten the inflammation duration via synergistic actions of BG and nitric oxide (NO). Single treatment of NO-releasing BG hybrid hydrogels attained complete closure of diabetic wounds within 14 days, orchestrated to accelerate the epithelization and dermis growth, and restored normal vascularization, achieving high performance healing with optimal collagen deposition and hair follicle regeneration. Consequently, this work opens up a new avenue to design all-in-one polysaccharide hydrogels for applications in massive bleeding hemostats and diabetic wound dressings.
Asunto(s)
Hemorragia , Hidrogeles , Cicatrización de Heridas , Animales , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Ratas , Hemorragia/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Masculino , Óxido Nítrico/metabolismo , beta-Glucanos/química , beta-Glucanos/farmacología , Ratones , Ratas Sprague-Dawley , Polisacáridos/farmacología , Polisacáridos/químicaRESUMEN
Severe bleeding from deep and irregular wounds poses a significant challenge in prehospital and surgical settings. To address this issue, we developed a novel chitosan-based hemostatic dressing with a magnetic targeting mechanism using Fe3O4, termed bovine serum albumin-modified Fe3O4 embedded in porous α-ketoglutaric acid/chitosan (BSA/Fe3O4@KA/CS). This dressing enhances hemostasis by magnetically guiding the agent to the wound site. In vitro, the hemostatic efficacy of BSA/Fe3O4@KA/CS is comparable to that of commercial chitosan (Celox™) and is not diminished by the modification. In vivo, BSA/Fe3O4@KA/CS demonstrated superior hemostatic performance and reduced blood loss compared to Celox™. The hemostatic mechanism of BSA/Fe3O4@KA/CS includes the concentration of solid blood components through water absorption, adherence to blood cells, and activation of the endogenous coagulation pathway. Magnetic field targeting is crucial in directing the dressing to deep hemorrhagic sites. Additionally, safety assessments have confirmed the biocompatibility and biodegradability of BSA/Fe3O4@KA/CS. In conclusion, we introduce a novel approach to modify chitosan using magnetic guidance for effective hemostasis, positioning BSA/Fe3O4@KA/CS as a promising candidate for managing various wounds.