Concave, NANO-perforated composite polysaccharide microparticles and method of preparation thereof

Abstract

A powder or other composition comprising non-spherical, concave microparticles comprising cross-linked starch or polysaccharides, such as plant polysaccharides, in combination with an alginate. Methods for making this powder and methods of using the powder for hemostasis.

Description

[0001] CONCAVE, NANO-PERFORATED COMPOSITE POLYSACCHARIDE MICROPARTICLES AND METHOD OF PREPARATION THEREOF

[0002] Reference to a Related Application

[0003] This application claims the benefit of priority to U. S. Provisional Application No. 63 / 729,904, filed December 9, 2024. The entire disclosure of U. S. Provisional Application No. 63 / 729,904, including any drawings or micrographs, is hereby incorporated by reference in its entirety to the extent permitted under application law and international rules. This application also claims priority to U. S. Provisional application corresponding to Obion 560808US, filed December 9, 2025, which is also incorporated by reference for all purposes.

[0004] Background of the invention

[0005] Field of the Disclosure

[0006] This disclosure pertains to the design of concave polysaccharide / starch microparticles, having better performances in medical applications, specifically in wound care and in hemostatics.

[0007] Description of the Related Art

[0008] Hemorrhage control in surgical settings is essential for successful procedures and minimizing complications. Hemostasis, the process of stopping blood flow from damaged vessels, is crucial for preventing post-surgical issues and fatalities. This natural bodily response involves clot formation through platelets and fibrin polymers [1]. Failure to achieve proper hemostasis can lead to severe blood loss, clotting factor deficiencies, platelet disorders, organ failure, and death. It is estimated that 35% of pre-hospital deaths and 40% of deaths within 24 hours of injury are due to severe bleeding and inability to achieve hemostasis [2]. Hemorrhagic shock during surgery is particularly dangerous, as it can lead to the loss of 25% or more of a patient's blood volume, necessitating immediate intervention [3,4],

[0009] Effective hemostasis relies on several factors, including bleeding intensity, location, visibility, and accessibility. Traditional methods such as direct compression and tourniquets are often used to control bleeding, particularly in the limbs. Other techniques include suturing and electrocoagulation, though these methods are limited to certain areas of the body.

[0010] Hemostatic agents, such as gelatin and collagen sponges, fibrin glues, and natural polysaccharide materials, are also used to control bleeding. Gelatin and collagen sponges, derived from animal tissue, help blood coagulation by triggering the body's natural clotting mechanisms. However, they present risks, such as slow absorption, anaphylaxis, delayed healing, and infection. These sponges are not ideal for narrow or difficult-to-reach surgical sites [5].

[0011] Fibrin glue, made from human plasma, is another hemostatic agent widely used in surgeries. It forms a stable fibrin polymer that supports clot formation and wound healing. While effective for deep wounds and coagulation disorders, fibrin glue is not suitable for all types of bleeding, especially arterial hemorrhages, and can be expensive. It also requires careful handling to avoid degradation and potential complications [6],

[0012] Natural polysaccharide or polymerized hemostatic materials, like starch-based products and chitosan, are gaining attention due to their biocompatibility. Chitosan, derived from crustacean shells, activates blood coagulation but cannot be degraded by human enzymes, limiting its use to topical applications. Starch-based products, like Arista® (absorbable hemostatic powder derived from purified potato starch as commercially available as of December 9, 2024), use microporous particles to absorb moisture and form a gel to seal wounds. However, these materials are not as effective for deep or profuse bleeding and pose challenges in production and application [5],

[0013] To address the issue of penetration, surgical powder was developed, claiming improved ability to penetrate tissues and bactericidal properties [7], This powder is designed in a rod shape and is made from regenerated oxidized cellulose. When it comes into contact with blood, Surgicel® powder creates a mildly acidic environment, which helps to reduce tissue pH, break down erythrocytes, and promote the formation of a viscous brown clot. This acidic environment also has antibacterial properties, particularly effective against certain bacteria. However, excessive use of Surgicel® near nerves should be avoided to prevent potential nerve damage due to its acidic properties.

[0014] When combined with other hemostatic agents, The acidic environment provided by Surgicel® 's can reduce the effectiveness of treatments with other combined hemostatic agents. Moreover, there are reports suggesting that Surgicel® may exacerbate local tissue inflammation and delay wound healing. This could lead to complications such as nerve compression, particularly in areas like bone cavities or intracranially, due to the absorption of blood and subsequent swelling [8], In addition, there have been several reports of adverse reactions related to oxidized regenerated cellulose. Notably, the rate of infections associated with oxidized regenerated cellulose is higher compared to natural biological polysaccharides. Although in vitro studies suggest that oxidized regenerated cellulose has bactericidal properties [7], several non-randomized clinical studies have reported postoperative complications such as hepatic or pelvic abscesses [9,10], infections, and bowel obstructions

[0011] , Although oxidized regenerated cellulose is believed to be absorbed within one to two weeks, there have been cases of persistent material remaining in the body for up to 15 months postoperatively

[0012] , Products with delayed absorption can act as a potential source of infection if not fully reabsorbed. Additionally, oxidized regenerated cellulose can trigger foreign-body reactions, leading to granulomas or abscesses [12, 13, 14]. These factors contribute to the high rates of adverse outcomes observed with oxidized regenerated cellulose [8],

[0015] In traumatic injuries or surgical procedures, achieving rapid and effective hemostasis is essential to saving lives. Absorbable hemostatic materials, particularly the newer in vivo absorbable variants, have shown potential promise in this regard. These materials may facilitate quick blood coagulation and are designed to be absorbed by the body within a short period.

[0016] Examples of these materials include collagen and microfibrous collagen, medical-grade hemostatic gelatin, oxidized cellulose and oxidized regenerated cellulose, cyanoacrylic tissue adhesives, and fibrin-based hemostatic agents. While effective in both animal studies and clinical settings, they are not without drawbacks. Collagen and gelatin, for instance, are derived from animal tissues, making them heterogeneous proteins that can trigger immune rejection or allergic reactions. Their slow absorption rates can also increase the risk of wound infections. Similarly, cellulose-based materials pose challenges due to the body's lack of specific enzymes to degrade them, leading to prolonged degradation times and potential infection risks.

[0017] Starch, a plant polysaccharide, presents an appealing alternative due to its affordability, widespread availability, and excellent biocompatibility and degradability. Recent years have seen growing interest in the development of starch-based products. However, current starch-based hemostatic materials have notable limitations. They typically lack antibacterial properties and rely on simple hemostatic mechanisms, which makes their performance inferior to materials like chitosan.

[0018] Several patents highlight advancements in polysaccharide-based hemostatic powders, including:

[0019] Arista® ™ (US 6,060,461A). Arista® AH is an absorbable hemostatic powder derived from purified plant starch using Microporous Polysaccharide Hemospheres (MPH®) technology. Upon contact with blood, the powder rapidly dehydrates it, accelerating clot formation within minutes, independent of the patient’s coagulation status. It is thrombin-free, biocompatible, non-pyrogenic, and absorbed by the body within 24 to 48 hours. However, its spherical microparticles lack nanopores and have limited adhesion, reducing their ability to penetrate blood effectively. As a result, the powder can be washed away by blood flow, which diminishes its effectiveness.

[0020] CN102406956A. This patent describes a method for producing starch-based hemostatic microspheres using emulsification and crosslinking. These microspheres demonstrate excellent biocompatibility and are specifically designed for surgical hemostasis. They have a significantly higher water absorption rate compared to existing materials, enhancing their hemostatic effect. Absorption rates recorded for this powder are 0.32, 0.133, and 0.083 over three consecutive 20- second intervals, outperforming Arista®, which achieved rates of 0.19, 0.033, and 0.025 in the same tests. Despite these improvements, the spherical microparticles still lack nanopores, limiting blood penetration and making them susceptible to being washed away by bleeding.

[0021] CN1043118707. This patent focuses on medical hemostatic starch microspheres made from pretreated potato starch and crosslinked with epichlorohydrin. The microspheres feature a three-dimensional network structure and wrinkled surfaces, increasing their surface area and absorption rates while reducing hemostasis time. Despite these benefits, the spherical microparticles suffer from the same limitations of poor adhesion and non-porous structures, reducing their efficacy at blood penetration and making them prone to being washed away by oozing blood.

[0022] US10076590B2. This patent covers chemically modified starch particles that enhance fluid absorption and adhesion to bleeding sites. Designed for surgical and emergency use, these particles are applied as powders, pastes, or incorporated into wound dressings. While effective in improving clotting efficiency, the particles remain non-porous and lack microporous surfaces, which limits their blood penetration and makes them prone to being washed away, reducing their effectiveness.

[0023] US20210100830A1 & W02020019880A1. These publications outline a starch-based hemostatic powder prepared by gelatinizing and modifying potato starch, followed by emulsification and crosslinking. The resulting powder absorbs fluids effectively and forms a gel-like barrier at bleeding sites, making it suitable for wound treatment and surgical applications. However, its maximum absorption capacity is 9.1 times its weight, with limited absorption kinetics of only 0.0078 ml / s in the first 20 seconds. This is attributed to the spherical morphology of the particles, which contrasts with the concave-shaped particles of Curaseal® powder. The unique structure of Curaseal® significantly enhances absorption kinetics, achieving 0.4 ml / s in the first 20 seconds. Further description of Curaseal® is available at incura-med.com / products / Curaseal® / (last accessed December 8, 2024; incorporated by reference).

[0024] Curaseal® ’s Plant-Based Technology Advances Bleeding Control and Wound Healing. Wound care and hemorrhage management are essential aspects of medical treatment, particularly in surgical procedures. Traditionally, these practices have relied on a combination of dressings, antibacterial agents, and antiseptics to prevent infection, promote healing, and control bleeding. However, the growing prevalence of antibiotic-resistant bacterial strains and the potential for antiseptics to damage healthy tissue have increasingly called the effectiveness of these conventional methods into question. As a result, there is a growing shift towards more advanced antimicrobial wound care solutions which are often enhanced with bioactive compounds.

[0025] Among InCurA’s ground-breaking products is Curaseal®, a 100 percent plant-based starch hemostatic powder designed to control bleeding effectively and rapidly. Unlike conventional hemostatic agents, Curaseal® employs a Nano-in-Microsphere technology, complemented by perforated microparticles that enable rapid blood clotting in seconds. This innovative structure ensures complete absorption by the body within 48 hours. Similarly, the starch porous microparticles feature a unique concave, red-blood-cell-like structure and nanopores on the surface, allowing for instant and complete blood penetration, setting it apart from existing products like Arista® (BD’s hemostatic powder) and SURGICEL® Powder (J& J) which only offer partial or no penetration; see The inventors surprisingly found that such a structure confers significant advantages to the innovative powder disclosed herein.

[0026] Besides, Curaseal® ’s versatility makes it suitable for a wide range of surgical applications, including vascular, urology, cardiothoracic, orthopedic, general, and plastic surgeries. Curaseal® is engineered to perform optimally in narrow and hard-to-reach surgical sites, providing the quickest blood clotting activity. This is achieved through three synergistic mechanisms: concentrating cellular and protein components for clot formation, amplifying thrombin formation to accelerate the coagulation cascade, and exhibiting antifibrinolytic activity to maintain a stable clot.

[0027] Curaseal® ’s starch microparticles are specifically designed for enhanced blood penetration and adhesion, which significantly improves its efficacy compared to other products on the market.

[0028] Additionally, by eliminating enzymes and animal products from the formulation, InCurA has managed to reduce production costs, allowing Curaseal® to be competitively priced and accessible to markets with critical needs, such as those in Africa.

[0029] Notwithstanding the products described above, despite that the global hemostatic market offers multiple products, big innovation gaps are still present demonstrating the need for highly biocompatible, biodegradable hemostatic agent that is suitable for narrow and hard two reach surgical site and has the capability to adhere to the bleeding site and of instant blood penetration and thus rapid blood clotting.

[0030] BRIEF DESCRIPTION OF THE DISCLOSURE

[0031] The present disclosure presents hemostatic powder that is made of microparticles of natural biological polysaccharides that have been conscientiously engineered as a concave structure resembling the RBCs, thus allowing better adhesion to the bleeding site. Additionally, the microparticles have been decorated with nano-pores thus allowing rapid fluid absorption from the blood and instant swelling (e.g. to 12X their shape) and thus instant blood penetration. The fast swelling capacity of engineered starch concave-nano pore-decorated microparticles allows the particles to display mechanical pressure to the bleeding site and the concentration of the clotting factors thus, allowing the fastest reported blood clotting activity. The present disclosure provides a hemostatic powder that is made of microparticles of natural biological polysaccharide that have been engineered into an inwardly dimpled concave, uni-concave, bi-concave, bi-concave discoid structure, or toroidal structure resembling red blood cells (RBCs) or in forms with increased surface area compared to many solid particles. These shapes are described in the electron micrographs of FIGS.

[0032] 1, 11 and 12. This structure allows better adhesion to a bleeding or wound site. This concave surface geometry distinguishes the disclosed microparticles from particles from spherical microparticles. Aggregates or clusters of the concave particles disclosed herein designated microberries can further increase the surface area and improve hemostatic functionality.

[0033] The current disclosure represents a breakthrough in introducing the first product to be made of starch, thus benefiting from its complete biocompatibility and fast biodegradability and at the same time attaining instant penetration of the blood allowing blood clotting in seconds due to the meticulous engineering of its microparticles as disclosed herein.

[0034] The current disclosure also introduces a two-step cost-efficient manufacturing process, instead of the five step enzymatic process that is currently utilized in manufacturing natural polysaccharide microparticles, thus eliminating the drawbacks of utilizing enzymes in the manufacturing.

[0035] The current disclosure sets itself apart by introducing a hemostatic powder composed of natural biological polysaccharide microparticles, uniquely designed with a concave shape resembling red blood cells (RBCs). This innovative structure significantly enhances adhesion to bleeding sites. Furthermore, the microparticles are engineered with nanopores on their surface, enabling rapid fluid absorption and swelling to ten times their original size. This ensures immediate blood penetration, leading to faster clot formation and improved hemostatic performance. A key and distinguishing aspect of the present disclosure is the use of starch as a primary material. Starch offers complete biocompatibility and biodegradability, addressing concerns associated with prolonged degradation times and potential complications seen with other materials. The manufacturing process, a two-step method, is cost-efficient and avoids the need for complex enzyme-based techniques.

[0036] Compared to existing products like Arista® AH, which lacks the capability for immediate blood penetration, or Surgicel®™ Powder, which has been linked to complications such as foreign body reactions, this invention delivers a superior solution to rapid and safe hemostasis. By combining rapid action, efficiency, safety, and affordability, it sets a new standard for hemostatic materials in both surgical and emergency applications.

[0037] The present disclosure relates to engineered hemostatic microparticles that is biocompatible, adhesive, biodegradable powder based on polysaccharide starch and sodium alginate that can be produced in an enzyme free simple reactions. One objective of the disclosure is to fabricate a non-spherical concave micro-particles that resembles the red blood cells and of a similar diameter of 6, 7, 8, 9, 10, 11,12, 13, 14 to 15 micrometer this is to achieve better blood surface tension penetration and better blood / bleeding site adhesion that was further enhanced by introducing scattered nano-pores to the surface of the microparticles ranging from 50, 100, 200, 300, 400 to 500 nm in diameter. These nanopores contribute to providing a biocompatible, fully blood penetrating hemostatic powder.

[0038] Embodiments of the disclosure shown herein allow the development of starch based porous concave micro-particles with internal porosity that reaches up to 10, 20, 30, 40, 50% or more of the total particle volume. That substantially enhanced both the absorption capacity that reaches up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 folds or more of the initial dry weight and the absorption kinetics that reaches up to 0.1, 0.2, 0.3, 0.4 ml / s or more, faster than commercially available hemostatic powders.

[0039] Another objective of the patent is to provide an enzyme free process for preparing polysaccharide based hemostatic powder. Preparation steps start with starch gelatinization followed by emulsion formation that is followed by microparticles fabrication / drying that encompass pore formation as well as formation of a concave structure.

[0040] Aspects of the disclosure include but not limited to the following embodiments.

[0041] One aspect of this disclosure is a powder comprising corn starch, sodium alginate, and a lipophilic surfactant that has a true density of no more than < 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, or < 3.0 g / mL and comprises pores ranging in average diameter 50, 100, 200, 300, 400, or >500 microns. These ingredients may be crosslinked with glutaraldehyde, epichorohydrine or another crosslinker.

[0042] The microparticles may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 to 10 wt. % starch, and 0.1, 0.2, 0.3, 0.4 to 0.5 wt. % alginate and 0.1, 0.15, 0.2, 0.25 to 0.3 wt. % lipophilic, and 0.1, 0.15, 0.2, 0.25 to 0.3 wt. % non-volatile triglyceride oil. In some embodiments, the microparticles may be in a foam composition instead of a powder.

[0043] In one embodiment, the microparticles comprise 3 wt. % corn starch, 0.5 wt. % sodium alginate, 0.25 wt. % span 80, and 0.25 wt. % a medium chain triglyceride oil, wherein each of these values may vary by ± 1, 2, 5, 10 or 20 wt.%.

[0044] In some embodiments, the solvent ratio for the emulsion preparation of the hydrocarbon oil and the aqueous in the range of 1:20, 1:10, 1:5, respectively.

[0045] In some embodiments, the powder absorbs at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or >15 -times its original dry weight in water or other liquid, such as blood, plasma, tissue fluid, CSF, saliva, mucous, urine, or other biological fluids.

[0046] The disclosed ranges described herein include both end points of the range, any subrange within the wider range, and any value falling within the range. Non-limited aspects of the disclosure also include the following specific embodiments of the disclosed products and methods.

[0047] A powder comprising non-spherical, concave microparticles, wherein the average diameter of the concave microparticles ranges from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 250, 30, to 35 pm, preferably from about 6 to 15 pm, and wherein said surface of the concave microparticles comprises nanopores having average diameters ranging from about 50, 60, 70, 80, 90, 100, 120, 140, 160, 180 to 200 nm.

[0048] The powder described above, wherein the non-spherical, concave nanoparticles comprise starch or polysaccharides, such as plant polysaccharides, which may be cross-linked; optionally in combination with an alginate.

[0049] The powder as described above, wherein the microparticles having a true density ranging from > 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 1.5, 2, to < 3.0 g / mL, bulk density of 0.4, 0.5, 0.6, 0.7, 0.8, to 0.9 gr / ml, angle of repose of 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 to 21 and a porosity of 10, 20, 30, 40, 50 to 60.

[0050] The powder as described above, wherein the microparticles having a true density of 1.357 g / ml, bulk density of 0.676 gr / ml, angle of repose of 15.90 and porosity of 50.18, wherein each of these values may vary by ± 1, 2, 5, 10, 15 or 20%.

[0051] The powder as described above, wherein the crosslinked starch is crosslinked corn starch or other cross-linked plant starch.

[0052] The powder as described above, wherein the crosslinked starch is crosslinked glutaraldehyde, epichlorohydrin, or another cross-linker.

[0053] The powder as described above that comprises 1, 2, 3, 4, 5,6, 7, 8, 9 to 10 wt.% of the crosslinked starch and 0.1, 0.2, 0.3, 0.4 to 0.5 wt.% of the alginate.

[0054] The powder as described above that comprises 1, 2, 3, 4, 5,6, 7, 8, 9 to 10 wt.% of crosslinked corn starch 0.1, 0.2, 0.3, 0.4 to 0.5 wt.% of sodium alginate.

[0055] The powder as described above, that further comprises a lipophilic surfactant and / or a nonvolatile triglyceride oil or medium-chain triglyceride oil.

[0056] The powder as described above, wherein an average diameter of the nanopores range in size from 50, 100, 200, 300, 400, to 500 nm.

[0057] The powder as described above, wherein the microparticles have an internal porosity ranging from 40, 45, 50, 55, to 60% of a total particle volume.

[0058] The powder as described above, wherein the starch is corn starch or potato starch and the alginate is sodium alginate, wherein the powder further comprises a lipophilic surfactant, wherein the powder has a true density of >0.1, 0.2, 0.5, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5 to < 3.0 g / ml; and wherein the pores range in average diameter from 50, 100, 200, 300, 400 to 500 microns.

[0059] The powder as described above, wherein the microparticles comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt% of the crosslinked starch,; 0.1, 0.2, 0.3, 0.4 to 0.5 wt. % of the alginate, 0.1, 0.15, 0.2, 0.25 to 0.3 wt. % of a lipophilic surfactant, and 0.1, 0.15, 0.2, 0.25 to 0.3 wt. % of a non-volatile triglyceride oil.

[0060] The powder as described above, that does not contain collagen and microfibrous collagen, medical-grade hemostatic gelatin, other animal components, oxidized cellulose, oxidized regenerated cellulose, a cyanoacrylic tissue adhesive, or a fibrin-based hemostatic agent.

[0061] The powder as described above, further comprising gelatin, thrombin, fibrinogen, oxidized cellulose, oxidized regenerated cellulose, a cyanoacrylic tissue adhesive, or a fibrin-based hemostatic or other hemostatic material.

[0062] The powder as described above, wherein the powder when dry has a capacity to absorb up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 to 15-times its weight in water, blood, plasma, tissue fluid, CSF, saliva, mucous, urine, or other biological fluid.

[0063] The powder as described above, wherein the powder when dry absorbs water, blood, plasma, tissue fluid, CSF, saliva, mucous, urine, or other biological fluid at a rate up to 0.1, 0.2, 0.3, 0.4 ml / s or more.

[0064] The powder as described above that is in a form suitable to induce hemostasis, control bleeding, promote tissue adhesion, or control fluid accumulation when applied to a tissue or wound.

[0065] A dressing, bandage, gauze, sponge, or sealant comprising the powder of at least one of specific embodiments described above. These may be formulated as products or in kits for private sale and use, commercial sale or use, medical or hospital use, military or other industrial use. These products and the microparticle compositions disclosed herein may be used as part of treatment protocols for military wounds involving severe extremity or junctional hemorrhage from blast and ballistic trauma and reduce morbidity or mortality from uncontrolled bleeding that requires rapid hemorrhage control. Such wounds commonly involve the extremities and junctional areas, such as the groin, axilla and neck from gunshot and blast injuries where arterial or venous bleeding can be rapidly fatal without immediate control. Similarly, these products may be used in civilian emergency care or in surgery or even during routine blood drawing procedures (e.g. as a bandage, patch or wrap or directly as a powder) to stem blood flow.

[0066] A composition comprising or formulated using the powder of any one of the specific embodiments described above. The composition of any of the embodiments disclosed herein that is formulated as a foam that comprises 3 wt. % corn starch, 0.5 wt. % sodium alginate, 0.25 wt. % Span 80 (sorbitan monooleate), and 0.25 wt. % medium chain triglyceride oil, wherein each of these values may vary by ± 1, 2, 5, 10 or 20 wt.%.

[0067] The composition comprising an aggregation of two or more microparticles of the specific embodiments above, wherein said aggregation has an average diameter 200, 300, 400 to 500 gm. In some embodiments of this composition comprise an aggregation of interparticle spaces with diameters ranging from about 50, 100, 150, 200, 250, 300, 350, 400, 450 to 500 nm or more.

[0068] The compositions described above in a form of a foam, particle, granule, flowable agent, spray, gel, or sealant.

[0069] A method for inducing hemostasis, controlling fluid accumulation, or inducing tissue adhesion comprising contacting a tissue or wound with the powder of any one of the above-described specific embodiments, which may be in a form of a dressing, bandage, gauze, sponge, or sealant. The method as disclosed above wherein the wound is a skin wound, an abrasion, puncture, laceration avulsion; bite wound; oral, buccal, gingival, or other dental wound; or bum, a surgical wound, an internal wound; an intracranial hemorrhage, subdural hemorrhage, epidural hematoma or other head injury; hemothorax, hemoperitoneum, splenic rupture, liver laceration or other chest or abdominal wound; a peptic ulcer, esophageal varices, gastritis, Mallory-Weiss tear, or other gastrointestinal bleeding; an aneurysm rupture, arteriovenous malformation, or other vascular condition; ectopic pregnancy rupture, postpartum hemorrhage, or other obstetric or gynecological condition; advanced stage cancer invading blood vessels or organs, or other cancer- or tumor-related condition; hemophilia, Von Willbrand disease, platelet disorder or other hematological disorder; or anticoagulant complication, antiplatelet drug-related bleeding or other medication-induced bleeding; or a dental wound.

[0070] The method disclosed above comprising applying the powder to a tissue or anatomical site to promote tissue adhesion, applying the powder to close a wound, applying the powder to promote adhesion of a skin graft or to guide tissue expansion in breast reconstruction or another reconstructive procedure; or applying the powder to or around a tom tendon, ligament or other fascia to facilitate repair or healing.

[0071] The methods as disclosed above, wherein the wound comprises non-variceal Upper Gastrointestinal Bleeding (NVUGIB).

[0072] The methods as disclosed above, comprising applying the powder to a tissue or anatomical site to control fluid accumulation.

[0073] A method for manufacturing the powder of the specific embodiments above comprising: (i) combining an aqueous crosslinked gelatinized starch or polysaccharide with an alginate and forming an o / w emulsion with an oil phase comprising a lipophilic surfactant and a triglyceride oil, and

[0074] (ii) spray drying the emulsion at a temperature and under other conditions suitable for forming said concave microparticles, thereby forming the powder of any one of embodiments described herein.

[0075] In some embodiments of this manufacturing method the spray drying is conducted with an emulsion and at a temperature sufficient to form said concave microparticles or microberries.

[0076] BRIEF DESCRIPTION OF THE DRAWINGS.

[0077] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing( s) will be provided by the Office upon request and payment of the necessary fee.

[0078] FIG. 1A-1D: Field emission scanning electron microscopy (FE-SEM) micrographs of the innovated starch-nano decorated microparticles. The micrographs display the meticulously engineered concave structure as well as die nanopores displayed at the surface of the concave starch Microparticles. Scale bars in lower left: (A) 10 um, (B) 10 um, (C) 2 um, (D) 10 um. Magnification (A): 999x, (B): 1.45 KX, (C): 3.77 KX and (D) 999x, respectively.

[0079] FIGS. 2A-2C: (A) Contact angle analysis for different products in comparison to Curaseal®. (B) Swelling capacity analysis for Curaseal® at different time intervals. (C) Weight loss for the Curaseal® powder during degradation test.

[0080] FIG. 3: Penetration test. The developed Curaseal-style concave-nano decorated microparticles were examined for their penetration capability upon contact with the blood and compared to the commercially available products; Arista® and Surgicel® powder.

[0081] FIG. 4: In vitro Assessment of Clotting Time. A comparison of Curaseal® ’s superior hemostatic efficacy as compared to Arista® and Surgicel® powder.

[0082] FIG. 5: Indirect Hemolysis Assay Assessment. Curaseal® ’s indirect hemolytic activity was compared to Arista®□and Surgicel®□powder as well as negative and positive controls, (a) Negative control, (b) Curaseal®□, (c) Surgicel®□, (d) Arista®□, and (e) Positive control. Optical Density at 540 nm. FIG. 6: In-direct hemolysis Assessment. A comparison of Curaseal® ’s minimal hemolytic activity as compared to Arista® and Surgicel® powder as well as the -ve and +ve controls.

[0083] FIG. 7: Direct Hemolysis Assessment. A comparison of Curaseal® ’s hemolytic activity in direct contact with the blood against Arista® and Surgicel® powder.

[0084] FIG. 8: In vitro Partial Thromboplastin Time (PTT) Test. Curaseal®’s ability to introduce clotting to PPP was assessed compared to Arista® and Surgicel® powder.

[0085] FIG. 9: Cytocompatibility of Curaseal®. Cell viability of L929 Cells was assessed Curaseal®, Arista® and Surgicel®, compared to the untreated negative control.

[0086] FIG. 10A: Curaseal® concave microparticle and aggregated microberry structure.

[0087] FIG. 10B. Applicator dispensing microberries and concave microparticles of Curaseal®.

[0088] FIGS. 11A-11E. FESEM micrographs for (A) Curaseal® powder with scale bar of 1 mm. (B) Curaseal® powder with scale bar of 100 pm. (C) Surgicel® powder with scale bar of 1 mm. (D) Surgicel® powder with scale bar of 100 pm. (E) Arista® powder with scale bar of 1 mm. (F) Arista® powder with scale bar of 100 pm.

[0089] FIGS. 12A-12F. Micrographs of concave nanoparticles showing convex shapes.

[0090] FIGS. 12G-12L. Micrographs of concave nanoparticles showing convex shapes.

[0091] DETAILED DESCRIPTION

[0092] Starches. A key feature of the microparticles or microberries disclosed herein is the use of starch as an ingredient. The term “starch” as used herein and as components of the disclosed microparticles refers to a plant storage polysaccharide made of many D-glucose units linked mainly by alpha- 1,4 glycosidic bonds typically with some alpha- 1,6 linkages at branch points. It occurs as a mixture of two glucose polymers, liner amylose and highly branched amylopectin, typically forming a white, tasteless and water-insoluble powder in its pure form. It includes, but is not limited to, potato, com, rice, tapioca, wheat, cassava, and waxy starches. It may appear in a form of an OSA-modified starch or a carboxymethyl and crosslinked / high-amylose starch. A starch may be modified, for example, pregelatinized, crosslinked, acetylated or OSA type.

[0093] Starch cross-linkers include sodium trimetaphosphate (STMP), sodium tripolyphosphate (STPP), phosphorous oxychloride and related phosphorous oxy-compounds, epichlorohydrins, glutaraldehyde and dialdehydes, “green” polycarboxylic acids such as citric acid.

[0094] The term “medium chain triglyceride' includes C6 (caproic acid), C8 (caprylic acid) MCT oil, CIO (capric acid) MCT oil, C12 (lauric acid) and blends of the above mentioned MCT oils as well as oils such as coconut oil or palm oil high in MCT content. Those skilled in the art may select a suitable MCT for use in producing the microparticles disclosed herein.

[0095] The term “lipophilic surfactant” includes sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate, glyceryl stearate, glycol distearate, and propylene glycol isostearate. Also included are surfactants whose structure and hydrophilic-lipophilic balance (HLB) make it predominantly oil-soluble rather than water soluble. Those skilled in the art may select a suitable lipophilic surfactant for use in producing the microparticles disclosed herein.

[0096] The term “Curaseal” may be used to describe the concave starch microparticles and powders containing them disclosed herein as well as commercial products distributed and sold under this name.

[0097] Microparticle shapes typically comprise concave microparticles resembling red blood cells (RBCs). These concave-nano-decorated starch powder microparticles have been designated Curaseal®. Curaseal® innovated microparticles are monodispersed and porous, with particle sizes around 10 pm and displaying nano-pores on the surface of the concave microparticles between 50 and 200 nm, see FIG. 1 and FIGS. 11A and 11B.

[0098] hi some embodiments the microparticles have been engineered into an inwardly dimpled concave, uni-concave, bi-concave, bi-concave discoid structure, tri-concave, or toroidal structure resembling red blood cells (RBCs). Other descriptions of these microparticles include that these concave microparticles have or assume a curved, bowl-like shape with an irregular surface featuring multiple small indentations and depressions or perforations as shown by FIGS. 1 and 11. The microparticles disclosed herein may form a mixture highly irregular, non-spherical, erythrocyte-like morphologies with a mixture of toroidal, cup-shaped, and disc-like forms. Microparticles may resemble biconcave “doughnut” or ring shapes with central depressions or open lumens. Other microparticles may show collapsed or invaginated “cup” or “bowl” shapes including deeper cratelike pits giving an overall crenated, wrinkled surface topology. In other embodiments, some or all of microparticles will substantially be non-spherical, non-oval, non-ellipsoid, non-lentricular (disc- like), non-polygonal / angular, and non-elongated. In some embodiments, the microparticles will not have sharp edges or will not lack substantial cavitation or surface depressions.

[0099] Microparticles may exhibit distinct curved depressions or indentations on their surfaces that form concave interfaces. The overall shape can resemble a flattened disc with one side or both sides exhibiting a bowl-like depression, while maintaining relatively uniform thickness throughout the microparticle circumference. The edges can be slightly rounded rather than sharp, and the surface be relatively smooth despite some uneven topography or the presence of nanopores or perforations. The microparticle's surface may exhibit varying depths of concavity across its structure and microparticle average diameter may range from 6 to 15 pm, advantageously from 8 to 12 pm. The thickness of a microparticle as measured peripherally or centrally may vary between about <10, 10, 20, 30, 40, 50, or >50% that of the average diameter of the microparticle.

[0100] In some embodiments, microparticles will have an average thickness at the center about 5, 10, 20, 30, 40, 50, 60, 70, 80%, 90% or <100% of the microparticle thickness at its rim. In some embodiments microparticles will have 1, 2, 3 or more concavities, voids or holes in their surfaces.

[0101] Microberry forms, such as those shown in in FIGS. 1, 10A, 10B, 11 and FIGS. 12A-12L, comprise aggregates of concave micro- or nano-particles. A microberry may comprise 2, 5, 10, 20, 25, 30, 40, 50 or more concave microparticles. A microberry may have an average diameter of about 5-10 pm, preferably about 7-8 pm and may form 10, 20, 30, 40, 50, 60, 70, 80, 90 or >90% by mass of a preparation of concave microparticles.

[0102] Applicator. The microparticle and microberry compositions disclosed herein may be applied using handheld or catheter-based devices that propels and preferably meters, a dry powder or liquid suspension comprising the microparticles or microberries to a target site. The device may be pressure driven or syringe-driven with anti-reflux and interchangeable catheters. Endoscopic sprayers comprising a powder / air mixing chamber, a delivery catheter, and a connecting tube to deliver the microparticles or microberries disclosed herein under consistent air pressure with an anti-reflux design to prevent occlusion and configured to reach hard-to-reach anatomical positions may be employed. CO2 / air-propelled sprayers may also be used. In some embodiments liquid suspension or viscous gel applicators may be used to apply liquid suspensions or gels comprising microparticles or microberries. A clinical applicator may be configured for single use or for multiple uses. One example of an application is shown in FIG. 10B.

[0103] Hemostatic agents which may be incorporated into or used in conjunction with Curaseal® include wax and putty’, such as Bone wax, synthetic putty, such as HemasorbPLUS, matrix agents, such as oxidized regenerated cellulose, such as Surgicel®, a gelatin matrix, such as Gelfoam®, microporous polysaccharide spheres, such as Arista AH®, microfibrillar collagen, such as Avitene®, topical thrombin, thrombin an gelatin matrix, thrombin and fibrinogen, autologous fibrinogen, platelets thrombin and collagen, polyethylene glycol, such as Coseal®, or cyanoacrylates, such as Omnex®. The concave starch microparticles and microberries disclosed herein may be used as the only hemostatic agent or may be used in combination with, or in admixture with, other known hemostatic agents. Additional description of hemostatic agents and their uses are described by, and incorporated by reference to. Brown, K. G. M., et al.. Topical haemostatic agents in surgery, BR. J. SURG., 2023, lll(a):znad361. Trademarked products mentioned herein correspond to the generic products commercially available or described in the literature as of the effective filing date of this application.

[0104] As shown herein, the concave microparticles and microberries (such as Curaseal®”) disclosed herein provide enhanced adhesion compared to existing hemostatic agents. The microberry starch concave microparticles resemble red blood cells facilitating enhanced adhesion at a bleed site upon application. Curaseal® starch microparticles were designed to include nanopores that enable rapid fluid absorption and blood penetration upon application. Curaseal® microparticles swell up to 10X their original size providing mechanical pressure to a microbleeding site thus reducing blood loss and providing clotting upon application. For example, they may swell >1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more their original dry sizes.

[0105] Curaseal® microparticles are made of biocompatible starches which are fully degradable within 48 hours of application.

[0106] Example

[0107] As shown and exemplified herein, non-spherical, concave microparticles (“microberries”) as described herein are obtainable by a process thoroughly explained in the following main steps.

[0108] (a) Gelatinization of starch. An aqueous dispersion of a polysaccharide comprising starch (e.g., corn or potato starch) is prepared at a starch concentration of about 3-15 wt.% based on the total weight of the dispersion. The pH of the dispersion is adjusted to an alkaline pH of at least 10, preferably about 10.5-11.5, by addition of a base, such as sodium hydroxide, under continuous stirring. The dispersion is heated to a temperature above the gelatinization temperature of the starch, typically about 75-95 °C, and maintained for 10-60 minutes to obtain a gelatinized starch solution.

[0109] (b) Partial crosslinking of gelatinized starch. The gelatinized starch solution is cooled to about 40-60 °C and a starch-reactive crosslinker (e.g., sodium trimetaphosphate) is added in an amount of about 1-10 wt.% based on the dry weight of starch. The mixture is stirred for 15-120 minutes under alkaline conditions to obtain a partially crosslinked starch hydrogel. The degree of crosslinking is selected such that the starch network maintains sufficient rigidity during subsequent spray drying to support shell formation and collapse, thereby promoting concave particle morphology. As well as, maintaining initial particle integrity after blood contact.

[0110] (c) Neutralization. The reaction mixture is cooled, and the pH is adjusted from alkaline to a non-alkaline pH, typically pH 6.0-7.5, by addition of an acid (e.g., hydrochloric acid), to yield a neutral or slightly acidic aqueous starch phase.

[0111] (d) Preparation of hydrophilic co-polymer solution. In a separate vessel, sodium alginate is dissolved in water at a concentration of about 0.3-2 wt.%, optionally with gentle heating (e.g., 40-70 °C) until a clear and homogeneous solution is obtained, followed by cooling to room temperature.

[0112] (e) Preparation of oil phase. In a further vessel, an oil phase is prepared by dissolving a surfactant (e.g., polysorbate 80) in a non-volatile triglyceride oil (e.g., medium-chain triglycerides, soybean oil, or similar). The oil is typically used at about 10-50 wt.% relative to the surfactant. The oil phase is mixed until clear and homogeneous.

[0113] (f) Formation of composite emulsion. The sodium alginate solution is combined with the neutralized, partially crosslinked starch solution under stirring to form a uniform aqueous polysaccharide phase. The oil phase is then added to the aqueous phase under high-shear mixing and / or homogenization to form an oil-in-water emulsion in which droplets of the non-volatile oil (typically having a droplet size in the submicron to low-micron range) are dispersed within the starch / alginate continuous phase. The total solids content of the emulsion is typically adjusted to about 5-30 wt.%.

[0114] (g) Removal of organic solvent (if present). Where a volatile solvent is present in the oil phase, the emulsion is stirred at ambient or elevated temperature to evaporate the solvent and obtain a stable, high-solids emulsion containing non-volatile oil droplets and the polysaccharide matrix.

[0115] (h) Spray drying to form concave microberries. The emulsion is atomized in a spray-dryer (e.g., two-fluid or rotary atomizer) at an inlet temperature typically in the range of about 120-140 °C and an outlet temperature of about 70-90 °C. Under these conditions, rapid evaporation of water from the droplet surface and the presence of the internal non-volatile oil phase cause early formation of a polysaccharide shell rich in gelatinized, partially crosslinked starch and alginate. As drying proceeds, differential shrinkage of the shell and the internal matrix, together with the rigidity conferred by the crosslinked starch, leads to buckling and collapse of the shell to produce non-spherical, concave and multi-faceted particles resembling red-blood-cell-like “microberries.” The internal oil droplets act as porogens, giving rise to a porous surface and internal voids, whereas the alginate enhances hydrophilicity and wettability, thereby promoting rapid penetration of the powder into blood and improved hemostatic performance. The concave and non-spherical morphology is obtained when the above steps are carried out such that: (i) the starch is gelatinized under strongly alkaline conditions and partially crosslinked prior to spray drying; (ii) a non-volatile oil phase is emulsified within the polysaccharide continuous phase; (iii) the total solids content and spray-drying temperatures are selected to promote rapid shell formation and subsequent shell collapse rather than uniform shrinkage. In the absence of one or more of these conditions (e.g., absence of oil, absence of crosslinking, or significantly milder spray-drying conditions), the process yields predominantly spherical or near-spherical particles instead of the concave microberries described herein.

[0116] Composition Ranges. In certain embodiments, the spray-drying feed comprises:

[0117] • about 1-15 wt% starch, preferably about 2-6 wt%, e.g., about 3 wt%;

[0118] • about 0.05-1 wt% of a starch crosslinker selected from epichlorohydrin, glutaraldehyde and sodium trimetaphosphate, preferably about 0.1-0.4 wt%, e.g., about 0.2 wt%;

[0119] • about 0.1-5 wt% sodium alginate, preferably about 0.3-1 wt%, e.g., about 0.5 wt%;

[0120] • about 0.05-5 wt% of a non-volatile triglyceride oil, preferably about 0.1-1 wt%, e.g., about 0.25 wt%;

[0121] • about 0.05-2 wt% of a surfactant, such as Span 80, preferably about 0.1-0.5 wt%, e.g., about 0.25 wt%; and

[0122] • water and pH adjusters to 100 wt%.

[0123] In a particular embodiment, the feed comprises about 3 wt% corn starch, about 0.2 wt% starch crosslinker, about 0.5 wt% sodium alginate, about 0.25 wt% medium-chain triglyceride oil and about 0.25 wt% Span 80, based on the total weight of the feed.

[0124] In the Examples disclosed herein the amounts of the recited ingredients in wt.% or process conditions such as inlet or outlet temperature, pressure, atomization air, pressure, and feed rate may individually vary by ±0, 0.5, 1, 2, 5, 10, 20, 25% or more

[0125] Example 1

[0126] Preparation of Polysaccharide-based or starch-based microparticles A feed was prepared having the composition shown in Table 1 (all percentages by weight of the total feed):

[0127] • Corn starch: 3.0 wt%

[0128] • Crosslinker (epichlorohydrin, glutaraldehyde or STMP): 0.20 wt%

[0129] • Sodium alginate: 0.50 wt%

[0130] • Span 80: 0 wt%

[0131] . MCT oil: 0 wt% • Sodium hydroxide / acid: q.s. for pH adjustment

[0132] Corn starch (3.0 g) was dispersed in approximately 80-85 g water, the pH was adjusted to about 11.0 with 2 M NaOH under stirring (about 500-800 rpm), and the dispersion was heated to about 80-85 °C for about 20-30 minutes until a clear gelatinized solution formed. The solution was cooled to about 45-50 °C, and 0.20 g crosslinker dissolved in 5-10 g water was added over about 5 minutes. The mixture was stirred at pH 10-11 for about 30-60 minutes to partially crosslink the starch, then cooled to about 30-35 °C and neutralized to pH 7.0 ± 0.2 with acid.

[0133] Separately, 0.50 g sodium alginate was dissolved in about 10-15 g water at about 50-60 °C until clear, cooled to room temperature, and added to the neutralized starch hydrogel under stirring. Water was added q.s. to bring the feed to 100 g total mass (3.0 wt% starch, 0.5 wt% alginate, 0.2 wt% crosslinker).

[0134] The feed was spray-dried using a two-fluid nozzle spray-dryer at an inlet temperature of about 140°C, an outlet temperature of about 72 °C, an atomization air pressure of about 2.0 bar and a feed rate of about 4-6 mL / min.

[0135] Example 2

[0136] Starch-based concave microparticles

[0137] A second feed was prepared as follows (wt% of total feed):

[0138] • Corn starch: 3.0 wt%

[0139] • Crosslinker (epichlorohydrin, glutaraldehyde or STMP): 0.20 wt%

[0140] • Sodium alginate: 0 wt%

[0141] • Span 80: 0.25 wt%

[0142] . MCT oil: 0.25 wt%

[0143] • Sodium hydroxide / acid: q.s.

[0144] Starch gelatinization, crosslinking and neutralization were carried out as in Example 1 to obtain a neutralized, partially crosslinked starch solution (3.0 wt% starch, 0.2 wt% crosslinker).

[0145] In a separate vessel, 0.25 g MCT oil and 0.25 g Span 80 were mixed until homogeneous. The oil phase was slowly added to the neutralized starch solution under high-shear mixing (about 10,000-12,000 rpm for about 3–4 minutes) to obtain an oil-in-water emulsion. Water was added q.s. to bring the feed to 100 g (3.0 wt% starch, 0.25 wt% MCT, 0.25 wt% Span 80, 0.2 wt% crosslinker). The emulsion was spray-dried using the same spray-dryer conditions as Example 1 (inlet about 140 °C, outlet about 72 °C, atomization air about 2.0 bar, feed about 4-6 mL / min).

[0146] Example 3

[0147] Starch-Alginate-based microparticles

[0148] A third feed was prepared having the following composition (wt% of total feed):

[0149] • Com starch: 3.0 wt%

[0150] • Crosslinker (epichlorohydrin, glutaraldehyde or STMP): 0.20 wt%

[0151] • Sodium alginate: 0.50 wt%

[0152] • Span 80: 0.25 wt%

[0153] . MCT oil: 0.25 wt%

[0154] • Sodium hydroxide / acid: q.s.

[0155] Corn starch was gelatinized, partially crosslinked and neutralized as described in Example 1 to obtain a neutralized, partially crosslinked starch solution (3.0 wt% starch, 0.2 wt% crosslinker).

[0156] Separately, 0.50 g sodium alginate was dissolved in about 10-15 g water at about 50-60 °C until clear, cooled to room temperature and added to the neutralized, partially crosslinked starch solution under stirring to form a uniform starch / alginate aqueous continuous phase.

[0157] In a separate vessel, 0.25 g MCT oil and 0.25 g Span 80 were mixed until homogeneous to form the oil phase. The oil phase was slowly added to the starch / alginate phase under high-shear mixing (about 10,000-12,000 rpm for about 3-4 minutes) to form a stable oil-in-water composite emulsion. Water was added q.s. to bring the feed to 100 g total mass (3.0 wt% starch, 0.5 wt% alginate, 0.25 wt% MCT, 0.25 wt% Span 80, 0.2 wt% crosslinker).

[0158] The emulsion was spray-dried in a two-fluid nozzle spray-dryer at an inlet temperature of about 120-140 °C, an outlet temperature of about 68-72 °C, an atomization air pressure of about 2.0-2.5 bar and a feed rate of about 3-6 mL / min, yielding a free-flowing, low-density powder.

[0159] Characterization of the developed Concave-nano-decorated Starch Microparticles.

[0160] The developed microparticles were characterized for their physical and biological properties both in vitro and in vivo as described below.

[0161] Morphological assessment of concave microparticles via Field emission scanning electron microscopy (FE-SEM) micrographs (FIGS. 1 and 11). In order to characterize the surface topography of concave-nano-decorated starch microparticles (Curaseal® ), Leo Supra 55 (FE-SEM) was utilized. Prior to the imaging process, the samples were gold sputtered in an ionizing chamber with a current of 15 mA for 2-3 minutes to avoid any charging issues.

[0162] Brunauer-Emmett-Teller (BET) surface area analysis. The concave-nano-decorated starch microspheres (Curaseal® ) were examined for their porous structures, N2adsorption / desorption tests were conducted through Micromeritics ASAP 2020. The outcomes were later utilized to compute the BET surface area and pore size.

[0163] Physicochemical characteristics. Different physicochemical descriptors for powder, such as bulk density (e.g., 0.676 gr / ml), tapped density, Carr's index, and angle of repose (<p)(15.90°), were calculated according to Equations 1-4 and methods known in the art.

[0164] Different physicochemical descriptors for powder, such as bulk density (b), tapped density (tap), Carr's index, and angle of repose (<p), were calculated according to Equations 1-4:

[0165] •' -s’.

[0166] Carr’s iadex=— — x 100

[0167]

[0168] = -37-

[0169] Where m is the mass of the powder in g, Vband Vt are the powder bulk volume and tapped volume in cm3. Finally, d and h are the diameter of the powder heap and the cone height, respectively.

[0170] The capability of the microparticles to swell and form a gel was assessed by adding a fixed amount of 500 mg of powder to 40 mL of water. Subsequently, all tubes were vortexed for 60 sec, followed by incubation at 37°C for 30 min. at different time intervals, from 1 to 30 minutes. Afterward, the solution was centrifuged at 3000 RPM, the supernatant was removed, and the powder was reweighted to assess the water absorption capability. The swelling index was calculated according to:

[0171] Swelling index (%)=Wt-W0Wt x 100 (5)

[0172] Morphological assessment via Field Emission Scanning Electron Microscopy (FE-SEM) Micrographs Field Emission Scanning Electron Microscopy (FE-SEM) was used to examine the surface morphology of the innovated starch concave-nanoperforated microparticles (Curaseal® ) as well as the commercial products Arista® and Surgicel® powder. The results reveal that the innovated Microparticles display a unique meticulously engineered concave morphology as compared to the fully spherical starch Arista® Microparticles and the rod structure of the regenerated oxidized cellulose of the Surgicel® powder, FIGS. 11C, HD. Such concave morphology allows better adhesion to the bleeding site and thus lower blood loss. Additionally, Curaseal® innovated microparticles shown in FIGS. 1A-1D and FIGS. 11 A and 11B are monodispersed and porous, with particle sizes around 10 μm and displaying nano-pores on the surface of the concave Microparticles between 50 and 200 nm. This unique nano-pores on the surface of the particles allow it to display excellent capabilities and swell 12X their weight allowing the microporous starch powder to display penetrate the blood instantly and exhibit mechanical pressure at the bleeding site. Comparing the morphology of Curaseal® powder with other commercial powders provides insights into its biological efficacy. Although both Curaseal® and Arista® are starch-based microparticles, their structures are notably different. As shown in FIGS. HE and HF, Arista® has a spherical shape with limited porosity, while Curaseal® exhibits meticulously engineered concave structure with nanopores displayed on its surface allowing high porosity and structural irregularity (FIGS. HA and 11B)., that enhance adhesion and blood penetration. Another competitor, Surgical powder made of oxidized regenerated cellulose features a non-porous, rod-like structure. These findings highlight how Curaseal® ’s balance of porosity and structural characteristics enhance its interaction with blood components, contributing to its superior efficacy.

[0173] Contact angle (CA) measurement (FIG. 2A).. The surface hydrophilicity of the concave-nano-decorated starch microparticles starch powder (Curaseal® )was determined using contact angle measurements. The powder was spread on a glass substrate using spin coating, and then the solvent evaporated. Subsequently, the powder film was examined using atomic force microscopy to ensure its smoothness. Following that, a micro syringe was employed to introduce 10 pL of water droplets onto the surface of the powder layer. The contact angle was measured using a KRUSS coupled-device camera and commercial image acquisition software.

[0174] Contact angle (CA) measurement results. Curaseal® powder demonstrated superior hydrophilicity and water absorption as compared to Arista® and Surgicel®. It had the lowest initial contact angle (53.00°) as compared to (92.20°) and (74.70°) for Arista® and Surgical as shown in FIG. 2 A. The contact angel of Curaseal® decreased to 11.90° after 2 minutes, indicating excellent wettability.

[0175] In a swelling test, Curaseal® also absorbed up to nine times its weight in water within one minute, reaching a steady state at eleven times its initial weight after 30 minutes as shown in FIG.

[0176] 2B depicting swelling capacity over time.

[0177] hi the degradation test, Curaseal®, produced using starch, steadily lost weight over a 120 hour (5 day) period as shown by FIG. 2C. The use of other matrix materials such as cellulose or gelatin can prolong degradation times which increase foreign body burden, increase the risk of complications, and increase risk of invention. In contrast, the concave microparticles of the invention, which are based on starch, provided rapid hemostasis and early clearance once bleeding is controlled reducing the risk associated with other types of microparticles having longer degradation times. These results highlight Curaseal®’s exceptional water absorption and swelling capacity, which are linked to its hydrophilic properties and potential for enhanced clotting factor concentration.

[0178] Physicochemical Characteristics In biomedical product research and development, key physicochemical descriptors such as true density, bulk density, flowability, and porosity play a crucial role in determining product quality. These properties are primarily influenced by the material's morphological structure and chemical composition. The typical values of the physicochemical descriptors for Curaseal® as compared to Arista® and Surgicel® are shown in Table 1. The data shows that Curaseal® powder has the highest bulk density and the lowest true density.

[0179] Table. 1: Physicochemical characteristics of Curaseal® against Arista® and Surgicel®

[0180] Physicochemical descriptor CurASeal Arista Surgicel

[0181] True density (gm / mL) 1.357 1.115 1.565

[0182] Bulk density (gm / mL) 0.676 0.693 0.888

[0183] Angle of repose (°) 15.90 14.50 12.60

[0184] Porosity (%) 50.18 37.84 43.25

[0185] In vitro Biological Assessments

[0186] Penetration tests (FIGS. 3A-3C).

[0187] The developed Curaseal® concave-nano decorated microparticles were examined for their penetration capability upon contact with blood compared to the commercially available products Arista® and Surgicel®. FIGS. 3A-3C show that Curaseal immediately and completely penetrated the blood samples while Surgicel and Arista products still had not penetrated at the end of the clotting time test.

[0188] Powder Penetration and Clot formation Behavior

[0189] The powder-blood penetration capability, initial interaction to clot formation of Curaseal concave-nano-decorated particles against Arista and Surgicel was evaluated. 3.2% Citrated whole blood (1ml) was added to each well of a 6-well plate with 100 pL of 0.2 M CaC12. An amount of 100 mg of each hemostatic powder was weighed and quickly sprayed onto the blood surface (n = 3). The ability to either fully or partially penetrate was accordingly validated by a two-phase visual observation: initial contact (T=0) and complete clot formation.

[0190] A significant difference in Curaseal® > penetration capability and clot formation behavior compared to Arista® > and Surgicel® > was observed over the two test intervals, upon initial blood contact (FIG.3 A) and after final clot formation (FIG.3B). Curaseal® > showed superior penetration and managed to spread evenly covering almost all the blood surface accounting for its particles’ harmony and size homogeneity, which was not observed significantly in case of Arista® > and Surgicel® □. Additionally, the high porosity and concave structure decorating Curaseal® > particles allowed it to penetrate deeply upon initial contact with blood as almost no particles remain on the surface. This is further validated upon complete clot formation, where all Curaseal® > particles successfully managed to overcome the blood surface tension leaving the final clot well integrated and highly stable (FIG. 3A). Arista® > though achieving clotting in the test system, it was incapable of penetrating fully as a huge amount remained on the surface non-interacted with blood due to the low porosity and smooth surface of its starch microparticles. Furthermore, despite Surgicel® > coagulation mechanism of its ORC changes blood PH converting blood hemoglobin into acid hematin, which leads to blood consistency dilution when tested in-vitro accompanied with unfavorable black color.

[0191] Blood Clotting Time Test (BCT)(FIG.4, Table 2). As shown in Table 2, and FIG. 4 Curaseal® achieved clotting 34.1 % faster than the negative control group that received no hemostatic agent. When compared to the commercial products Arista® and Surgicel® powder, Curaseal® demonstrated a significantly faster time to complete clotting, being 1.13 times and 1.18 times quicker, respectively. Clotting time was assessed in minutes for the Curaseal® hemostatic powder and a negative untreated control as well as the commercially available products Arista® and Surgical powder. FIG. 4 and Table 2 show in vitro assessments of clotting time. Clotting time was assessed in minutes for the Curaseal® hemostatic powder and a negative untreated control as well as the commercially available products Arista® and Surgical powder.

[0192] In vitro Assessment of Blood Clotting Time (FIG. 4). Clotting time was assessed in minutes for the Curaseal hemostatic powder and a negative untreated control as well as the commercially available products Arista and Surgical powder. The developed concave-nano-decorated starch powder (Curaseal® ) were analyzed for their clotting time and compared to the commercially available Arista® and Surgical powder. One ml of 3.2% citrated whole blood was added to the plate wells and incubated at 37 °C for 5 minutes. Afterwards, 100 μl of 0.2 CaCl2were added to the wells and mixed with the incubated blood. Hemostatic powder (20 mg) was added to the wells, while observing the clotting time initiation and completion. The plate was tilted carefully every 20 sec to assess clot formation.

[0193] Table 2: In vitro Assessment of Blood Clotting Time Test

[0194] Product Clotting Time (minutes)

[0195] Control 6.4

[0196] Curaseal® 4.05

[0197] Arista® 5.23

[0198] Sugicel® 5.45

[0199]

[0200] In vitro indirect Hemolysis Assay (FIG. 5, Table 3). A pre-weighed sample (20 mg) of the concave-nano-decorated starch powder (Curaseal®) was immersed in 2 ml saline and incubated for 30 minutes at 37°C. RBCs were prepared by adding 4 ml whole citrated blood to 5 ml saline and were then mixed well and centrifuged at 2000 rpm for 10 minutes. Each saline-powder (1 ml) mixture was added to 20 pl RBCs. A positive control was prepared of the following: 10 pl triton + 20 pl RBCs + 1ml saline. The negative control utilized was prepared of saline (0.9 NaCl %). All sample mixtures were centrifuged at 2000 rpm for 5 minutes. The absorbance of the supernatant was then measured at 540 nm. (22). The hemolysis rate (HR %) was calculated using the following formula: HR% = (Dsample – Ddist) / (Ddist - Dsaline) × 100.

[0201] The in vitro Indirect Hemolysis Assay Curaseal® was evaluated for its hemolytic activity via indirect contact with blood and compared to negative and positive controls, as well as Surgicel® and Arista® powders as shown in Table 3 and FIGS. 5 and 6. The optical density (OD) reading for Curaseal® was 0.001 nm lower than the negative control and significantly lower than the positive control by 1.936 nm. Additionally, Curaseal® exhibited lower OD readings than both Surgicel® and Arista® by 0.02 and 0.017 nm, respectively. Curaseal® caused 0% hemolysis in the test system, while Surgicel® induced 0.9% hemolysis and Arista® caused 0.78% hemolysis.

[0202] Table 3. Indirect Hemolysis Assessment. A comparison of Curaseal®’s minimal hemolytic activity as compared to Arista® and Surgicel® as well as to negative (-ve) and positive (+ve) controls.

[0203] Product OD (540 nm) Hemolysis %

[0204] -ve Control 0.045 0 Curaseal® 0.044 0

[0205] Arista® 0.06 0.78

[0206] Surgicel® 0.064 0.9

[0207] +ve Control 1.98 100

[0208] FIG. 5 shows the results of this assay where (a)-(e) show the resulting hemolysis in (a) the negative control, and hemolysis in samples containing (b) Curaseal®, (c) Surgicel®, (d) Arista®, or in (e) the positive control. Determined at 540 nm.

[0209] FIG. 6 compares the hemolytic activity detected by the indirect hemolysis assay. As apparent from FIG.6, both the negative control and Curaseal® produced no hemolysis, while the Arista® and Surgicel® products did.

[0210] In vitro Direct Hemolysis Assay (FIG. 7 and Table 4).. The developed concave-nano-decorated starch powder (Curaseal® ) was examined for its direct hemolysis effect and compared to the commercially available Arista® and Surgical powder. The plasma was separated from the RBCs via centrifugation of 10 mL of 3.5% fresh blood in an EDTA or heparinized tube at 1000 x g for 10 minutes at room temperature. The separated plasma is discarded and RBCs layer is washed in 10 mL of sterile saline solution and centrifuged at 1000 x g for 5 minutes (repeat 2x). RBCs were then resuspended in sterile saline to achieve a 5% dilution. Curaseal®, Surgicel® and Arista® (100mg each) powder were added to 1ml of the 5% RBCs suspension and saline was added consecutively to reach a volume of 9mL. For the positive control, 1 mL of the 5% diluted RBC suspension was added to a 9 mL of distilled water to hemolyze the RBCs completely. For the negative control, 1 mL of the 5% RBC suspension were added to 9 mL of PBS / saline. The absorbance of the supernatant was then measured at 540 nm 22. The hemolysis rate (HR %) was calculated using the following formula: HR% = (Dsample -Ddist) / (Ddist - Dsaline) 100.

[0211] Curaseal® was evaluated using the direct hemolysis assay for its direct hemolytic activity and compared to Arista®, Surgicel®, and the negative and positive controls, which contained no powder samples. Curaseal® exhibited minimal hemolytic activity, causing only 0.4% hemolysis. Arista® showed slightly higher activity at 0.73%, while Surgicel® induced 1.33% hemolysis. All powder samples resulted in lower hemolysis than the positive control and higher than the negative control (Table 4, FIG.7). The direct hemolysis assay measures cytopathic effects of direct contact between Curaseal® and red blood cells. In contrast, the indirect hemolysis assay measures the indirect effects of substances that may leach out from Curaseal®. Table 4. Direct Hemolysis Assessment. A comparison of Curaseal’s hemolytic activity in direct contact with the blood as compared to Arista and Surgicel® powder as well as -ve and +ve controls.

[0212] Product OD (540 nm) Hemolysis %

[0213] -ve Control 0.049 0

[0214] Curaseal® 0.053 0.4

[0215] Arista® 0.06 1.13

[0216] Surgicel® 0.066 1.73

[0217] +ve Control 1.021 100

[0218] Partial Thromboplastin Time Analysis [PTT] (Table 5, FIG. 8). Partial Thromboplastin Time was analyzed for the developed concave-nano-decorated starch powder (Curaseal® ) as well as the commercially available Arista® and Surgicel® powder. Platelet-poor plasma was obtained by centrifugation of citrated whole blood at 3000g for 15 minutes at 4 °C. Platelet-poor plasma (500 pl) and a PTT reagent (500 pl ) were incubated at 37 °C for 3 minutes. After incubation, 2 mg of powder samples were added to 200 pl plasma and incubated for 5 minutes at 37°C. Finally, the PT reagent was added to the plasma-powder mixture, and PT was measured using a semi-automatic coagulation analyzer (TS6000, MD Pacific Biotechnology Co., Ltd, China). Curaseal® powder, Arista®, and Surgicel® powder® were evaluated by PTT analysis for their intrinsic plasma coagulation activity and compared to the negative control. Curaseal® exhibited a longer PTT time than both the control and the other powder samples as shown in Table 5 and FIG.8.

[0219] Table 5. In vitro Partial Thromboplastin Time (PTT) Test.

[0220] Curaseal’s ability to introduce clotting to PPP was assessed and compared to Arista® and Surgicel® powder commercial products.

[0221] Product Clotting Time (min)

[0222] Control group 1.5

[0223] Curaseal® 2.04

[0224] Arista® 1.7 Surgicel® +5, non-stop

[0225] FIG. 8 shows the results of the in vitro partial thromboplastin time (PTT) Test. Curaseal® ’s ability to introduce clotting to PPP was assessed compared to Arista® and Surgicel® powder. As apparent from the data above, Curaseal® exhibit a lower PTT time than the control and either of Arista® or Surgicel®. A lower PTT indicates that Curaseal® is more rapidly and efficiently activating clotting pathways that the other test compounds which is relevant when blood loss must be quickly reduced.

[0226] Red Blood Cell Adhesion. The fibrin formation of PPP on the sample surface was observed by a scanning electron microscope (SEM). PPP (50 mL) along with CMS or TACMS (50 mg) and 5 ml of CaCL (0.2 M) were added to the 24-well culture plate and incubated at 37° C for 30 min. To remove the non-coagulated plasma, the samples were then dip rinsed twice in phosphate buffered solution (PBS). The samples were mixed with 2.5% glutaraldehyde solution (1 mL) for 15 min and dehydrated by a graded series of ethanol solutions. After drying for 12 h at 37 C, the samples were observed by SEM. The red cells were obtained by centrifuging the whole blood at 1500 rpm for 5 min at 4 C, then dip rinsing twice in PBS. The red cell solution was prepared by dispersing the red cells in PBS (v / v 1:1).

[0227] MTT Cytotoxicity Assay (FIG. 9). The cell viability was measured using the 3-(4,5- dimethylthiazol-2-yl)- 2,5-diphenyl tetrazolium bromide (MTT) reduction assay. Mouse fibroblast L929 cells were seeded at a density of 50,000 cells / well in 500 pl complete DMEM media for 24 hours before adding 10 mg of the developed concave-nano-decorated starch powder (e.g., Curaseal®) as well as the commercially available Arista® and Surgicel powder®. Sponges were left in direct contact with the cells for 24 hours. Then, the media was discarded, and 100 pl MTT and 500 pl media were added to each well. The plate was incubated for 2 hours at 37°C. After incubation, the media was discarded, and 600 ul DMSO was added, and incubated at room temperature for 10 minutes before measuring the absorbance at 570 nm using a SPECTROstar® Nano plate reader. The results in FIG.9 suggest that Curaseal®) stimulates cell growth under assay conditions. Unlikely to impair tissue integrity, delay healing, or exert a toxic effect when administered. Cell Viability of L929 Cells was assessed Curaseal®, Arista® and Surgicel®, compared to the untreated negative control.

[0228] Structures (FIG. 10). Graphics describing concave microparticles disclosed herein and an aggregate or microberry of these concave microparticles.

[0229] Comparison of structures of preparations of Curaseal®), Arista®), and Surgicel®) products (FIGS. 11A-11F). FIG. 11A-11F) show FESEM micrographs for (A) Curaseal® Powder with scale bar of 1 mm. (B) Curaseal® Powder with scale bar of 100 μm. (C) Surgicel® Powder with scale bar of 1 mm. (D) Surgicel® Powder with scale bar of 100 μm. (E) Arista® Powder with scale bar of 1 mm. (F) Arista® Powder with scale bar of 100 μm. Morphological assessment via Field Emission Scanning Electron Microscopy (FE-SEM) Micrographs. The morphological characterization for the innovated Curaseal® nano-decorated concave microparticles was assessed.

[0230] As shown above, the concave microparticles and microberries disclosed herein provide for (A) enhanced adhesion, (B) rapid penetration, (C) rapid blood clotting, and (D) degradability.

[0231] Terminology. Terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting of the invention. Chemical terms refer to ingredients forming and used to produce the microparticles disclosed herein.

[0232] As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0233] It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof.

[0234] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “ / ”.

[0235] Any numerical range recited herein is intended to include all sub-ranges subsumed therein. The description and examples provided illustrate possible implementations of the technology, do not limit the technology's scope, and do not exclude other versions with additional or different feature combinations. Examples are given to show how to make and use the technology. Unless explicitly stated, these examples do not represent whether specific versions have been made or tested.

[0236] A trademarked product may be described by reference to the ingredients and properties of a commercially available version of the trademarked product as of the effective filing date of the application describing the trademarked product.

[0237] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference, especially referenced is disclosure appearing in the same sentence, paragraph, page or section of the specification in which the incorporation by reference appears.

[0238] The citation of references herein does not constitute an admission that those references are prior art or have any relevance to the patentability of the technology disclosed herein. Any discussion of the content of references cited is intended merely to provide a general summary of assertions made by the authors of the references and does not constitute an admission as to the accuracy of the content of such references.

[0239] References:

[0240] [1], (Smith et al., 2015) [2], (Peng et al., 2021; Smith et al., 2015) [3], (Szymanski et al., 2023)[4], (Mutschler et al., 2013)

[0241] [5] JiCheng, X., Shi, X., (2013). Modified starch material of biocompatible hemostasis (US8912168B2).

[0242] [6] Tianjin Hongri Aileyi Pharmaceutical Adjuvant Co LTD, (2011). Starch hemostatic microsphere and preparation method thereof (CN 102406956B)

[0243] [7] Ethicon. SURGICEL® Powder Instructions for Use. Available at:

[0244] https: / / www.jnjmedicaldevices.com / en-US / product / ethicon-surgicel-powder. Accessed October 19, 2024

[0245] [8] O’Hanlan, K. A., & Bassett, P. (2022). Exploring adverse events and utilization of topical hemostatic agents in surgery. JSLS: Journal of the Society of Laparoscopic & Robotic Surgeons, 26(3).

[0246] [9] Arisheh MA, Venturero M, Froom P. Oxidized regenerated cellulose during laparoscopic cholecystectomy increases the risk of rehospitalization. Am Surg. 2020;86(4):386-388.

[0247]

[0010] Fagotti A, Costantini B, Fanfani F, et al.. Risk of postoperative pelvic abscess in major gynecologic oncology surgery: one-year single-institution experience. Ann Surg Oncol.

[0248] 2010;17(9):2452-2458.

[0249]

[0011] Behbehani S, Tulandi T. Oxidized regenerated cellulose imitating pelvic abscess. Obstet Gynecol. 2013; 121 (Pt 2 Suppl l):447-449. - PubMed

[0250]

[0012] ACOG Committee on Gynecologic practice. Topical Hemostatic Agents at Time of Obstetric and Gynecologic Surgery: ACOG Committee Opinion, Number 812. Obstet Gynecol.

[0251] 2020;136(4):e81-e89. - PubMed

[0252]

[0013] Piozzi GN, Reitano E, Panizzo V, et al.. Practical suggestions for prevention of complications arising from oxidized cellulose retention: a case report and review of the literature. Am J Case Rep.

[0253] 2018;19:812-819. - PMC - PubMed

[0254]

[0014] Wang H, Chen P. Surgicel® (oxidized regenerated cellulose) granuloma mimicking local recurrent gastrointestinal stromal tumor: a case report. Oncol Lett. 2013;5(5):1497-1500. - PMC -PubMed

Claims

CLAIMS1. A powder comprising non-spherical, concave microparticles comprising nanopores.

2. The powder of claim 1, wherein an average diameter of the concave microparticles ranges from 5 to 35 pm.

3. The powder of claim 1, wherein an average diameter of the concave microparticles ranges from 6 to 15 pm.

4. The powder of claim 1, wherein the nanopores have an average diameter ranging from 50 to 500 nm.

5. The powder of claim 1, wherein the powder comprises microberries or aggregates of two or more non-spherical, concave nanoparticles.

6. The powder of claim 1, wherein the microparticles are produced by glutaraldehyde cross-linking of potato or corn starch, sodium alginate, a lipophilic surfactant, and a medium chain triglyceride oil.

7. The powder of claim 1, wherein the powder does not contain collagen and microfibrous collagen, gelatin, oxidized cellulose, oxidized regenerated cellulose, a cyanoacrylic tissue adhesive, or a fibrin-based hemostatic agent.

8. The powder of claim 1, wherein the powder has a true density of 1.357 g / ml, bulk density of 0.676 gr / ml, angle of repose of 15.90 and porosity of 50.18, wherein each of these values may vary by ± 20%.

9. The powder of claim 1, wherein the non-spherical, concave nanoparticles comprise a plant or plant-derived starch.

10. The powder of claim 1, wherein the non-spherical, concave nanoparticles comprise a plant or plant-derived starch which is cross-linked.

11. The powder of claim 1 that further comprises at least one alginate.

12. The powder of claim 1, wherein the non-spherical, concave microparticles have a true density ranging from 0.1 to 25, bulk density ranging from 0.4 to 0.9 gr / ml, an angle of repose ranging from 11 to 21, and a porosity ranging from 10 to 60.

13. The powder of claim 1, wherein the concave microparticles have a true density of 1.357 g / ml, bulk density of 0.676 gr / ml, angle of repose of 15.90 and porosity of 50.18, wherein each of these values may vary by ± 5, 10 or up to 20%.

14. The powder of claim 10, wherein the crosslinked starch is crosslinked glutaraldehyde, epichlorohydrin, or another cross-linker.

15. The powder of claim 10, wherein the crosslinked starch is crosslinked corn starch or other cross-linked plant starch.

16. The powder of claim 1 that comprises 1 to 10 wt.% of crosslinked corn starch and 0.1 to 0.5 wt.% of sodium alginate.

17. The powder of claim 1 that further comprises a lipophilic surfactant and / or another nonvolatile triglyceride oil or medium chain triglyceride oil.

18. The powder of claim 1, wherein an average diameter of the nanopores range in size from 100 to 400 nm.

19. The powder of claim 1, wherein the microparticles have an internal porosity ranging from 40 to 60% of a total particle volume.

20. The powder of claim 1, wherein the starch is corn starch or potato starch and the alginate is sodium alginate, wherein the powder further comprises a lipophilic surfactant, wherein the powder has a true density of > 0.1 to < 30 g / ml; and wherein the pores range in average diameter from 50 to 500 microns.

21. The powder of claim 1, wherein the microparticles comprise 1 to 10 wt% of the crosslinked starch, 0.1 to 0.5 wt. % of the alginate, 0.1 to 0.3 wt. % of a lipophilic surfactant, and 0.1 to 0.3 wt. % of a non-volatile triglyceride oil.

22. The powder of claim 1 that does not contain collagen and microfibrous collagen, gelatin, other animal products, oxidized cellulose, oxidized regenerated cellulose, a cyanoacrylic tissue adhesive, or a fibrin-based hemostatic agent.

23. The powder of claim 1, further comprising gelatin, thrombin, fibrinogen, oxidized cellulose, oxidized regenerated cellulose, a cyanoacrylic tissue adhesive, and / or a fibrin-based hemostatic or other hemostatic material.

24. The powder of claim 1, wherein the powder when dry has a capacity to absorb up to 1 to 15-times its weight in water, blood, plasma, tissue fluid, CSF, saliva, mucous, urine, or other biological fluid.

25. The powder of claim 1, wherein the powder when dry absorbs water, blood, plasma, tissue fluid, CSF, saliva, mucous, urine, or other biological fluid at a rate up to 0.4 ml / s.

26. The powder of claim 1 in a form suitable to induce hemostasis, control bleeding, promote tissue adhesion, or control fluid accumulation when applied to a tissue or wound.

27. A dressing, bandage, gauze, sponge, or sealant comprising the powder of any one of claims 1-26.

28. A composition, supply, or device comprising or formulated using the powder of any one of claims 1-26.

29. The composition of claim 28 that is formulated as a foam that comprises 3 wt. % corn starch, 0.5 wt. % sodium alginate, 0.25 wt. % Span 80 (sorbitan monooleate), and 0.25 wt. % medium chain triglyceride oil, wherein each of these values may vary by ± 1, 2, 5, 10 or 20 wt.%.

30. The composition of claim 28 comprising an aggregation or microberry of two or more microparticles of claim 1, wherein said aggregation has an average diameter 50 to 500 pm.

31. The composition of claim 28, wherein said aggregation or microberry comprises interparticle spaces with diameters ranging from about 50 to 500 nm.

32. The composition of claim 28 in the form of a foam, particle, granule, flowable agent, spray, gel, or sealant.

33. A method for inducing hemostasis, controlling fluid accumulation, or inducing tissue adhesion comprising contacting a tissue or wound with the powder of any one of claims 1-25, or a composition, dressing, bandage, gauze, sponge, or sealant comprising said powder.

34. The method of claim 33, wherein the wound is a skin wound.

35. The method of claim 33, wherein the wound is an abrasion, puncture, laceration avulsion; bite wound; oral, buccal, gingival, other dental wound; or bum.

36. The method of claim 33, wherein the wound is a surgical wound.

37. The method of claim 33, wherein the wound is an internal wound.

38. The method of claim 33, wherein the wound is an intracranial hemorrhage, subdural hemorrhage, epidural hematoma or other head injury; hemothorax, hemoperitoneum, splenic rapture, liver laceration or other chest or abdominal wound; a peptic ulcer, esophageal varices, gastritis, Mallory-Weiss tear, or other gastrointestinal bleeding; an aneurysm rapture, arteriovenous malformation, or other vascular condition; ectopic pregnancy rapture, postpartum hemorrhage, or other obstetric or gynecological condition; advanced stage cancer invading blood vessels or organs, or other cancer- or tumor-related condition; hemophilia, Von Willbrand disease, platelet disorder or other hematological disorder; or anticoagulant complication, antiplatelet drug-related bleeding or other medication-induced bleeding; or a dental wound.

39. The method of claim 33 comprising applying the powder to a tissue or anatomical site to promote tissue adhesion.

40. The method of claim 33 comprising applying the powder to close a wound, applying the powder to promote adhesion of a skin graft or to guide tissue expansion in breast reconstruction or another reconstructive procedure; or applying the powder to or around a tom tendon, ligament or other fascia to facilitate repair or healing.

41. The method of claim 33, wherein the wound comprises non-variceal Upper Gastrointestinal Bleeding (NVUGIB).

42. The method of claim 33 comprising applying the powder to a tissue or anatomical site to control fluid accumulation.

43. A method for manufacturing the powder of any one of claims 1-25 comprising:(i) combining an aqueous crosslinked gelatinized starch or polysaccharide with an alginate and forming an o / w emulsion with an oil phase comprising a lipophilic surfactant and a triglyceride oil, and(ii) spray drying the emulsion at a temperature and under other conditions suitable for forming said concave microparticles, thereby forming said powder.

44. The method of claim 43, wherein the spray drying is conducted with an emulsion at a temperature and under reaction conditions sufficient to form said non-spherical, concave microparticles.

45. The method of claim 43, wherein the spray drying is conducted with an emulsion and at a temperature and under reaction conditions sufficient to form aggregates or microberries of said non-spherical, concave microparticles.

46. A powder comprising non-spherical, concave microparticles comprising:cross-linked starch or polysaccharides; andan alg c-inate.

Images