Spatiotemporally Controlled Release of Etamsylate from Bioinspired Peptide-Functionalized Nanoparticles Arrests Bleeding Rapidly and Improves Clot Stability in a Rabbit Internal Hemorrhage Model.

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.

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.

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.

Potential novel role of the human amniotic membrane as a sustainable hemostat.

OBJECTIVES: Acute hemorrhage can cause significant morbidity and mortality arising from trauma, bleeding disorders, surgical procedures, or obstetric complications. Surgical hemostasis methods may fail to stop acute bleeding due to the complex bleeding dynamics of each bleeding type. Therefore, developing safe and effective topical hemostatic agents remains crucial. The human amniotic membrane (hAM) has established clinical evidence of effectiveness in promoting wound healing and tissue regeneration. Despite its unique biological and immunologic properties and its structural composition of established hemostatic elements, the hemostatic role of hAM has not been yet explored. The present study aimed to investigate this potential role and to describe the development protocol and characterization of hAM-derived topical hemostat. METHODS: Surface electron microscope (SEM) imaging and Fourier transform infrared (FTIR) spectroscopy were used for characterization, and mouse models with induced peritoneal and tail wound bleeding were employed to evaluate the hemostatic effectiveness using physiological studies, in comparison to a chitosan-based combat-scale hemostat. RESULTS: The hAM hemostat showed a distinctive composition by SEM and FTIR. Applying equal masses of the hAM hemostat, the commercial hemostat, or a combination reduced peritoneal wound bleeding time to averages of 108.4, 86.2, and 76.8 s, respectively, compared to the control group (300 s). Tail wound bleeding times were similarly reduced with no significant difference between the hAM and the commercial hemostat (P values = 0.29, 0.34 in peritoneal and tail wounds, respectively). Neither hemostat affected coagulation time. CONCLUSION: This study describes a simple cost-effective preparation protocol for a hAM-based hemostatic agent. The long-recognized safety, sustainability, and immunotolerance advantages of hAM can establish superiority over commercial hemostats with reported safety concerns. Robust research validation in larger-scale bleeding models is required for wider applications and severe bleeding types.

Degradation-controlled tissue extracellular sponge for rapid hemostasis and wound repair after kidney injury.

Patients diagnosed with T1a cancer undergo partial nephrectomy to remove the tumors. In the process of removing the tumors, loss of kidney volume is inevitable, and current surgical methods focus solely on hemostasis and wound closure. Here, we developed an implantable form of decellularized extracellular matrix sponge to target both hemostasis and wound healing at the lesion site. A porous form of kidney decellularized matrix was achieved by fabricating a chemically cross-linked cryogel followed by lyophilization. The prepared kidney decellularized extracellular matrix sponge (kdES) was then characterized for features relevant to a hemostasis as well as a biocompatible and degradable biomaterial. Finally, histological evaluations were made after implantation in rat kidney incision model. Both gelatin sponge and kdES displayed excellent hemocompatibility and biocompatibility. However, after a 4-week observation period, kdES exhibited more favorable wound healing results at the lesion site. This suggests a promising potential for kdES as a supportive material in facilitating wound closure during partial nephrectomy surgery. KdES not only achieved rapid hemostasis for managing renal hemorrhage that is comparable to commercial hemostatic sponges, but also demonstrated superior wound healing outcomes.

An architecturally rational hemostat for rapid stopping of massive bleeding on anticoagulation therapy.

Hemostatic devices are critical for managing emergent severe bleeding. With the increased use of anticoagulant therapy, there is a need for next-generation hemostats. We rationalized that a hemostat with an architecture designed to increase contact with blood, and engineered from a material that activates a distinct and undrugged coagulation pathway can address the emerging need. Inspired by lung alveolar architecture, here, we describe the engineering of a next-generation single-phase chitosan hemostat with a tortuous spherical microporous design that enables rapid blood absorption and concentrated platelets and fibrin microthrombi in localized regions, a phenomenon less observed with other classical hemostats without structural optimization. The interaction between blood components and the porous hemostat was further amplified based on the charged surface of chitosan. Contrary to the dogma that chitosan does not directly affect physiological clotting mechanism, the hemostat induced coagulation via a direct activation of platelet Toll-like receptor 2. Our engineered porous hemostat effectively stopped the bleeding from murine liver wounds, swine liver and carotid artery injuries, and the human radial artery puncture site within a few minutes with significantly reduced blood loss, even under the anticoagulant treatment. The integration of engineering design principles with an understanding of the molecular mechanisms can lead to hemostats with improved functions to address emerging medical needs.

Quaternized chitosan/oxidized bacterial cellulose cryogels with shape recovery for noncompressible hemorrhage and wound healing.

Management of noncompressible torso hemorrhage is an urgent clinical requirement, desiring biomaterials with rapid hemostasis, anti-infection and excellent resilient properties. In this research, we have prepared a highly resilient cryogel with both hemostatic and antibacterial effects by chemical crosslinking and electrostatic interaction. The network structure crosslinked by quaternized chitosan and genipin was interspersed with oxidized bacterial cellulose after lyophilization. The as-prepared cryogel can quickly return to the original volume when soaking in water or blood. The appropriately sized pores in the cryogel help to absorb blood cells and further activate coagulation, while the quaternary ammonium salt groups on quaternized chitosan inhibit bacterial infections. Both cell and animal experiments showed that the cryogel was hypotoxic and could promote the regeneration of wound tissue. This research provides a new pathway for the preparation of double crosslinking cryogels and offers effective and safe biomaterials for the emergent bleeding management of incompressible wounds.

A 3D-Printed Cuttlefish Bone Elastomeric Sponge Rapidly Controlling Noncompressible Hemorrhage.

Developing a self-expanding hemostatic sponge with high blood absorption and rapid shape recovery for noncompressible hemorrhage remains a challenge. In this study, a 3D-printed cuttlefish bone elastomeric sponge (CBES) is fabricated, which combined ordered channels and porous structures, presented tunable mechanical strength, and shape memory potentials. The incorporation of cuttlefish bone powder (CBp) plays key roles in concentrating blood components, promoting aggregation of red blood cells and platelets, and activating platelets, which makes CBES show enhanced hemostatic performance compared with commercial gelatin sponges in vivo. Moreover, CBES promotes more histiocytic infiltration and neovascularization in the early stage of degradation than gelatin sponges, which is conducive to the regeneration and repair of injured tissue. To conclude, CBp loaded 3D-printed elastomeric sponges can promote coagulation, present the potential to guide tissue healing, and broaden the hemostatic application of traditional Chinese medicine.

Porosity controlled soya protein isolate-polyethylene oxide multifunctional dual membranes as smart wound dressings.

Multifunctional membranes S7P0.7, S7P3.0, and dual membranes composed of soya protein isolate (SPI) and polyethylene oxide (PEO) were produced for wound dressing applications. The internal structure of the membranes was confirmed by scanning electron microscopy (SEM) to be homogeneous and coarser with a porous-like network. S7P3.0 showed the tensile strength of 0.78 ± 0.04 MPa. In the absence of antibiotics, the dual membrane (combination of S7P0.7 and S7P3.0) exhibited potential antibacterial activity against Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) bacteria. Hemolysis quantitative data presented in the image demonstrates that all samples exhibited hemolysis levels below 5 %. Dual membrane showed 77.93 ± 9.5 % blood uptake which reflects its absorption capacity. The combination of S7P0.7 and S7P3.0 influenced the dual membrane's antibacterial, biocompatibility, and good hemolytic potentials. The dual membranes' promising histology features after implantation suggest they could be used as wound dressings.

Safety and Hemostatic Effectiveness of SURGICEL® Powder in Mild and Moderate Intraoperative Bleeding.

This postmarket clinical study evaluated the safety and effectiveness of the novel adjunctive topical hemostat SURGICEL® Powder (SURGICEL®-P), a powdered form of oxidized regenerated cellulose. In a prospective, open-label, single-arm multicenter trial, adult surgical subjects with mild-to-moderate bleeding for which conventional hemostatic methods were impractical/ineffective were treated with SURGICEL®-P. Descriptive analyses included hemostatic success rate at 3, 5, and 10 min, rebleeding and thromboembolic events, SURGICEL®-P-related serious adverse events requiring surgical intervention, and SURGICEL®-P ease of use (questionnaire). In 8 centers, 103 subjects were enrolled with a median (range) age of 64.0 (33.0-88.0) years. Surgeries were open (53.4%) or laparoscopic/thoracoscopic (46.6%) and mostly urological (37.9%) and abdominal (32.0%) procedures. Bleeding sites included various tissue types, with a median (range) surface area of 4 (0.02-72.0) cm2. Hemostatic success rates were 77.7%, 87.4%, and 92.2% at 3, 5, and 10 min, respectively. In 7 subjects (6.8%), investigators reverted to standard of care. No safety signals were identified. Two deaths occurred with causes unrelated to SURGICEL®-P. Investigators favorably evaluated the ease of use of the SURGICEL®-P device. SURGICEL®-P is safe and effective in controlling mild-to-moderate bleeding in a broad range of surgical procedures. The trial was registered at https://clinicaltrials.gov as NCT03762200.

The effects of Ankaferd hemostat on preventing oral mucositis in colorectal cancer patients receiving chemotherapy.

INTRODUCTION: New agents are introduced each day to be used in the prevention and treatment of mucositis in cancer treatment. One of those agents is the Ankaferd hemostat. Ankaferd hemostat has pleiotropic effects and anti-infective characteristics in tissue healing. METHODS: The study was designed as a randomized controlled experimental study. The sample of the study comprised a total of 66 patients (33 patients in the Ankaferd hemostat group and 33 patients in the sodium bicarbonate group) with colorectal cancer who received FOLFOX combination chemotherapy treatment in the first cycle of chemotherapy to prevent mucositis. Participants who met the criteria were randomly assigned to the groups. Before the patient received chemotherapy, ECOG performance score and Oral Mucositis Grading Scale were applied on the 7th day and 15th day. The Ankaferd hemostat group brushed teeth at least twice a day for 2 min and gargled with Ankaferd hemostat twice for 2 min for 2 weeks. The sodium bicarbonate group brushed teeth at least 2 min a day and gargled with sodium bicarbonate 4 times for 2 min for 2 weeks. The Consolidated Standards of Reporting Trials diagram was used to illustrate the randomization of patients. RESULTS: When the Ankaferd hemostat group is compared with the sodium bicarbonate group, there is a significant difference in favor of the Ankaferd hemostat group in the mucositis grade on the 7th day and 15th day after chemotherapy (p < 0.05). In the binary logistic regression analysis, among the factors affecting the formation of mucositis on the 7th day, only neutrophil and thyroid-stimulating hormone (TSH) were included in the model, while only the TSH variable is statistically significant. CONCLUSIONS: It was determined that Ankaferd hemostat is effective in preventing oral mucositis due to chemotherapy in adult patients diagnosed with colorectal cancer. In addition, it has been suggested to conduct new studies on the effectiveness of Ankaferd hemostat in the prevention of mucositis in different groups. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (ID: NCT05438771, Date: 25.06.2022).

A polymer-based systemic hemostat for managing uncontrolled bleeding.

Uncontrolled bleeding is a life-threatening emergency that requires immediate intervention. Currently available on-site bleeding interventions largely rely on the use of tourniquets, pressure dressing, and other topical hemostatic agents, which can only treat bleeding injuries that are known, accessible, and potentially compressible. Synthetic hemostats that are stable at room temperature, easy to carry, field-usable, and able to stop internal bleeding at multiple or unknown sources, are still lacking. We recently developed a hemostatic agent via polymer peptide interfusion (HAPPI), which can selectively bind to activated platelets and injury sites after intravascular administration. Here we report that HAPPI is highly effective in treating multiple lethal traumatic bleeding conditions in normal as well as hemophilia models via either systemic administration or topical application. In a rat liver traumatic model, intravenous injection of HAPPI resulted in a significant decrease in blood loss and a four-fold reduction in mortality rate within 2 h after injury. When applied topically on liver punch biopsy wounds in heparinized rats, HAPPI achieved a 73% of reduction in blood loss and a five-fold increase in survival rate. HAPPI also exhibited hemostatic efficacy in hemophilia A mice by reducing blood loss. Further, HAPPI worked synergistically with rFVIIa to induce immediate hemostasis and 95% reduction in total blood loss compared to the saline-treated group in hemophelia mice models. These results demonstrate that HAPPI is a promising field-usable hemostatic agent for a broad range of different hemorrhagic conditions.

Polymer nanomaterials for use as adjuvant surgical tools.

Materials employed in the treatment of conditions encountered in surgical and clinical practice frequently face barriers in translation to application. Shortcomings can be generalized through their reduced mechanical stability, difficulty in handling, and inability to conform or adhere to complex tissue surfaces. To overcome an amalgam of challenges, research has sought the utilization of polymer-derived nanomaterials deposited in various fashions and formulations to improve the application and outcomes of surgical and clinical interventions. Clinically prevalent applications include topical wound dressings, tissue adhesives, surgical sealants, hemostats, and adhesion barriers, all of which have displayed the potential to act as superior alternatives to current materials used in surgical procedures. In this review, emphasis will be placed not only on applications, but also on various design strategies employed in fabrication. This review is designed to provide a broad and thought-provoking understanding of nanomaterials as adjuvant tools for the assisted treatment of pathologies prevalent in surgery. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery.

Nano cellulose-laden alginate/chitosan sponge with enhanced biological and hemostatic behavior.

Present study describes about hybrid hemostat developed with alginate (Alg), chitosan (Chito) and TEMPO-oxidized nanofibrillar cellulose (TOCNF) via lyophilization. All samples were analyzed under scanning electron microscopy (SEM) to determine their microstructure, size, and distribution of pores. Cell viability and proliferation of the scaffolds tested using fibroblast type L929 cells, showed it to be an excellent medium for cell generation. Blood coagulation started in ∼7.5 min, and most of the fibrin network formation took place in the Alg-Chito-TOCNF sponge, making it a suitable hemostatic material.

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

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

The use of sealing hemostat patch (HEMOPATCH®) in laparotomic myomectomy: a prospective case-control study.

PURPOSE: Uterine myomas are the most common gynecological disease. In these cases, a myomectomy is performed traditionally laparotomically. However, alternatives have been widely used, including laparoscopic, endoscopic, and robotic surgery. During these techniques, diffuse parenchymatous bleeding remains one of the main intraoperative and postoperative complications and sometimes requires unplanned hysterectomies. Recently, hemostatic agents and sealants have been used to prevent excessive blood loss during surgical repair. METHODS: We propose a prospective case-control study on the use of a sealing hemostat patch (HEMOPATCH®) on uterine sutures in laparotomic myomectomy. In the period between July 2016 and April 2017, 46 patients with symptomatic uterine fibromatosis underwent surgery. They were divided into two groups of 23 patients, with different treatments in the hemostatic phase of oozing bleeding. HEMOPATCH® is applied in group A, and spray electrocoagulation is applied in group B. RESULTS: In group A, we achieve faster hemostasis (p < 0.05), than in group B. We report a significantly lower C-reactive protein value on the second and third days after surgery for group A compared to group B. CONCLUSIONS: HEMOPATCH®, during laparotomic myomectomy, is a valid alternative solution for obtaining rapid hemostasis and consequently intraoperative and postoperative bleeding. Furthermore, we suggest that a lower inflammatory peritoneal state is probably correlated with the barrier effect of the patch on the suture.

Silk composite interfacial layer eliminates rebleeding with chitosan-based hemostats.

Chitosan foams are among the approved hemostats for pre-hospital hemorrhagic control but suffer from drawbacks related to mucoadhesiveness and rebleeding. Herein, we have developed a designer bilayered hemostatic foam consisting of a bioactive layer composed of silica particles (≈300 nm) and silk fibroin to serve as the tissue interfacing component on a chitosan foam. The foam composition was optimized based on the in vitro clotting behavior and cytocompatibility of individual components. In vivo analysis in a rat model demonstrated that the developed hemostat could achieve rapid clotting (31 ± 4 s), similar to a chitosan-based hemostat, but the former had significantly lower blood loss. Notably, removal of the bilayered hemostat prevented rebleeding, unlike the chitosan foam, which was associated with markedly higher incidences of rebleeding (50 %) and left behind material residue. Thus, the designer bilayered foam presented here is a potent inducer of blood clotting whilst affording easy removal with minimal rebleeding.

Tissue adhesive hemostatic microneedle arrays for rapid hemorrhage treatment.

Blood loss by hemorrhaging wounds accounts for over one-third of ∼5 million trauma fatalities worldwide every year. If not controlled in a timely manner, exsanguination can take lives within a few minutes. Developing new biomaterials that are easy to use by non-expert patients and promote rapid blood coagulation is an unmet medical need. Here, biocompatible, and biodegradable microneedle arrays (MNAs) based on gelatin methacryloyl (GelMA) biomaterial hybridized with silicate nanoplatelets (SNs) are developed for hemorrhage control. The SNs render the MNAs hemostatic, while the needle-shaped structure increases the contact area with blood, synergistically accelerating the clotting time from 11.5 min to 1.3 min in vitro. The engineered MNAs reduce bleeding by ∼92% compared with the untreated injury group in a rat liver bleeding model. SN-containing MNAs outperform the hemostatic effect of needle-free patches and a commercial hemostat in vivo via combining micro- and nanoengineered features. Furthermore, the tissue adhesive properties and mechanical interlocking support the suitability of MNAs for wound closure applications. These hemostatic MNAs may enable rapid hemorrhage control, particularly for patients in developing countries or remote areas with limited or no immediate access to hospitals.

A Comparative Study of the Resorption and Immune Response for Two Starch-Based Hemostat Powders.

INTRODUCTION: Powder hemostats are valuable adjuncts to minimize intraoperative and postoperative complications. In addition to promotion of rapid coagulation, resorption, and biocompatibility are desirable attributes. Plant starch-based polysaccharide hemostat powders are effective and widely used hemostatic agents, however their source and/or processing can affect characteristics such as in vivo degradability. For example, Arista is a purified/hydrolyzed starch powder that is rapidly resorbed in vivo; whereas PerClot shows slow resorption and preservation of a crystalline form. MATERIALS AND METHODS: In the present study, we compared the cellular response to the hemostatic agents PerClot and Arista both in vitro and in vivo, and used potato starch and urinary bladder extracellular matrix (UBM-ECM) as high crystallinity/slowly resorbable and prohealing controls, respectively. RESULTS: All test articles and their degradation products were cytocompatible in vitro as measured by cell viability and metabolic activity of bone-marrow macrophages. PerClot induced a stronger proinflammatory, M1-like macrophage response in vitro (P < 0.001) than Arista, likely due to differences in source composition. Histologic examination of the in vivo surgical site showed the almost complete degradation of Arista after 12 h (day 0), whereas both PerClot and potato starch were still present at 28 d with crystals identifiable with polarized light microscopy and periodic acid Schiff (PAS) staining. Macrophage phenotype in vivo showed no differences between PerClot and Arista. Collagen deposition and mononuclear cell accumulation consistent with an early foreign body response were present around PerClot and potato starch crystals, whereas no such cell or connective tissue deposition was noted at the site of Arista or UBM-ECM placement.

Use of absorbable hemostat bolster for prevention of donor renal artery kinking in kidney transplant.

Transplant renal artery stenosis due to mechanical kinking is a rare but significant complication in kidney transplantation that can lead to graft dysfunction due to graft hypoperfusion, delayed graft function, or even global kidney infarction. When detected during surgery, re-anastomosis is usually performed after re-clamping, which inevitably prolongs the warm ischemia time, and increases the possibility of primary graft non-function. In this report, we describe a novel, noninvasive surgical technique whereby the donor renal artery is padded with absorbable hemostatic material (i.e., Surgicel) bolster, placed below the middle third of the renal artery in recipients who were found to have mechanical kinking during the implantation procedure. The bolster technique was used in 12 kidney transplant recipients who were found to have kinking of the donor artery during the primary surgery. After pillowing the renal artery with absorbable hemostatic bolster, no residual kinking was observed intra-operatively, and good allograft perfusion was confirmed with no Doppler ultrasound evidence of renal artery stenosis confirmed at 1 week, 1 month, and 1 year after transplantation.