Patent Application
20220211898
In various embodiments, the present invention relates to hemostatic devices and methods utilizing silica fibers.
Excessive bleeding or hemorrhaging is a significant cause of mortality after traumatic injury and battlefield injuries. Excess bleeding is also a complication during surgical procedures. Hemostatic products and processes are intended to assist in the rapid initiation of a hemostatic plug formed through platelet activation, aggregation, adhesion and gross clot formation at a tissue target site.
While a wide variety of hemostatic products have been made from different base materials, such as collagen, gelatin, cellulose, chitosan, and fibrin, these materials fail for many applications, such as internal hemorrhage where direct pressure to the wound is difficult or impossible.
The present invention in various aspects and embodiments provides hemostats for rapid control of hemorrhages, as well as methods and kits for their use.
The present invention provides compositions, kits, and methods for treating hemorrhage (bleeding) in a subject. In various aspects, the invention provides compositions comprising electrospun silica fibers, that when applied to a site of hemorrhage, are able to quickly stop the hemorrhage. Thus, the invention provides hemostatic devices and methods beneficial for treating subjects experiencing severe injuries, including for emergency treatment at the site of the injury. The invention further is useful in the surgical setting for management of bleeds during surgery. In various embodiments, the invention finds use for treating external wounds and injuries of varying severity. Embodiments of the invention also provide delivery devices for the hemostatic device and material.
The electrospun silica material is able to hold many times its weight in water, (e.g., typically more than 50 times its weight in water), which allows the material to absorb a large amount of blood, while being impenetrable by blood cells and quickly forming a physical barrier. In various embodiments, the silica fiber composition enhances coagulation pathways. The silica fiber material may be applied as a flocculent material, or alternatively, applied as a powder or dust, gel, paste, or as an additive to a flowable base material.
In some embodiments, the silica fiber composition is a lightweight structure consisting essentially of silica fiber (e.g., silicon dioxide nanofiber). In various embodiments, the fiber composition consists essentially of SiO2, i.e., contains only SiO2 and unintentional impurities, and, in some embodiments, species and/or complexes resulting from the incomplete conversion of the sol to SiO2 (e.g., water and/or chemical groups such as ethoxy groups, silanol groups, hydroxyl groups, etc.). The composition may be formed from a gelatinous material that is electrospun to form a fiber mat (e.g., a non-woven mat). For example, the composition may be prepared by electrospinning a sol-gel. An exemplary sol-gel is prepared with a silicon alkoxide reagent, such as tetraethyl ortho silicate (TEOS), alcohol solvent, and an acid catalyst. In various embodiments, the sol is transitioned for at least two days (and, in various embodiments, less than seven days) under conditions where humidity and temperature are controlled. The sol-gel is electrospun to create a silica fiber mat with superior texture and properties, which may find use as or in a hemostatic device. The fibers may have a variable diameter, such as in the range of from about 50 nm to 5 μm.
The material may be used as fiber mat portions that are folded and/or clumped to prepare a suitable mass of material for packing a hemorrhaging site, including a hemorrhage in a body cavity. In some embodiments, the silica fiber material is processed into a flocculent material that is loosely clumped, and may be created by shredding and/or clumping portions of the electrospun fiber mats. In some embodiments, the silica fiber material is provided with a material to facilitate handling and application to the wound site, such as any suitable backing material or flexible container. Alternatively, the silica fiber material may be applied as a powder or dust, gel, paste, or as an additive to a flowable base material, and such compositions may optionally comprise one or more bulking agents. Exemplary bulking agents include, but are not limited to, various synthetic and natural polymers.
In some embodiments, the fiber composition is applied directly to the site of hemorrhage by packing the site with the material, in any form, and applying pressure where and as possible. The fiber composition will absorb the blood and large amounts of fluid, although the blood cells cannot penetrate the material, and will quickly form a physical barrier against further loss of blood. In various embodiments, blood or extracellular matrix proteins will bind to the material, to aid the formation of a barrier, and which may provide additional benefits such as the reduction of pain and facilitation of healing. In some embodiments, even for severe hemorrhage (e.g., grade 3 or 4 hemorrhage), the silica fiber material can stop blood flow within about 60 seconds, or in some embodiments, within about 30 seconds, or in some embodiments within about 15 seconds. By quickly stopping a severe hemorrhage at the site of injury, the patient may more quickly and safely be transported to a surgical facility. The silica fiber material may be easily removed by a physician during surgery.
In some embodiments, the hemorrhage is bleeding during or after surgery. In some embodiments, the hemorrhage is a traumatic injury bleed, such as a non-compressible hemorrhage. In various embodiments, the hemorrhage is a result of a crushing injury, a gunshot injury or explosion injury.
Other useful applications include epistaxis and external wounds. For example, the silica fiber material may be shaped as pads or bandages, or used with various types of conventional bandage materials (e.g., cotton gauze) and/or wound dressings to promote bleeding control.
Other aspects and embodiments of the invention will be apparent from the following non-limiting examples.
In an aspect, embodiments of the invention feature a method for treating a subject for hemorrhage. The method includes, consists essentially of, or consists of applying a silica fiber composition (e.g., an electrospun silica fiber composition) to said hemorrhage in an amount and under conditions sufficient to stop or slow the hemorrhage.
Embodiments of the invention may include one or more of the following in any of a variety of combinations. The composition may be prepared by electrospinning a sol. The sol may be prepared with tetraethyl orthosilicate (TEOS). The sol may contain 70% to 90% TEOS by weight, 8% to 25% ethanol by weight, an acid catalyst, and the balance water. The sol may contain 70% to 90% TEOS by weight, 8% to 25% ethanol by weight, 1% to 10% water by weight, and the acid catalyst. The sol may contain 75% to 85% by weight TEOS, 12% to 20% by weight ethanol, and about 2% to 5% by weight water. The sol may contain about 80% by weight TEOS, about 17% by weight ethanol, and about 3% by weight water. The acid catalyst may include, consist essentially of, or consist of HCl. The sol may contain less than about 0.1% of the acid catalyst by weight. The sol may contain from 0.02% to 0.08% of the acid catalyst by weight.
The sol may be allowed to transition for at least 2 days under conditions where humidity is within the range of about 40% to about 80%, and the temperature is within the range of 50° F. to 90° F. The sol may be allowed to transition for at least 3 days, at least 4 days, at least 5 days, at least 6 days, or at least 7 days. The sol may be allowed to transition for 2 days to 7 days. The sol may be electrospun when the weight is at from 20% to 40% of the starting weight before ripening (transitioning). The sol may be electrospun when the production of ethylene vapor is 10% to 20% relative to the peak production of ethylene vapors during ripening (transitioning). The sol may be electrospun when the production of ethylene vapor therefrom is 10% to 40% relative to the sol before ripening (transitioning). The sol may not exposed to heat over 150° F. or heat over 100° F. Fibers of the silica fiber composition may have a variable diameter of from about 50 nm to about 5 μm. The fibers may have a variable diameter of from about 200 nm to about 1000 nm. The composition may include, consist essentially of, or consist of SiO2. The composition may be electrospun with a thickness of from about ⅛ inch to about ¼ inch. The composition may be electrospun with a thickness of greater than about ⅛ inch, or greater than about ¼ inch. The fiber composition may include, consists essentially of, consist of, or be processed into a powder or dust or a plurality of fibrous fragments.
The subject may be a mammal. The subject may be a veterinary patient, e.g., a dog, cat, or horse. The subject may be a human patient. The hemorrhage may be at least a Grade 2 hemorrhage, for example a Grade 3 or Grade 4 hemorrhage. The hemorrhage may be an arterial hemorrhage. The hemorrhage may be a venous hemorrhage. The hemorrhage may be bleeding during or after surgery. The hemorrhage may be an organ bleed (e.g., such as liver, lungs, heart, kidney, pancreas, stomach, intestine). The hemorrhage may be a primary hemorrhage. The hemorrhage may be a reactionary hemorrhage. The hemorrhage may be a secondary hemorrhage. The hemorrhage may be a traumatic injury bleed. The hemorrhage may be a non-compressible hemorrhage. The hemorrhage may be a cavity bleed. The injury may be a crushing injury, a gunshot injury, or an explosion injury. The hemorrhage may be epistaxis. The hemorrhage may be external on the subject. The subject may be on therapy inhibiting the coagulation pathway. The subject may have a coagulation disorder. The subject may have hemophilia, thrombocytopenia, low platelet count, or von Willebrand disease.
The silica fiber composition may be applied to the hemorrhage via a delivery device. The delivery device may include, consist essentially of, or consist of a hollow central bore, a movable plunger, and an annular outer compartment coaxial with the central bore. The central bore may have an upper end and an open lower end. The plunger may be disposed at the upper end of the central bore. The plunger may be actuatable by a user of the delivery device to urge the silica fiber composition from the open lower end of the central bore. A portion of the plunger may separate the central bore into a lower compartment and an upper compartment. The outer compartment may be fluidly connected to the upper compartment of the central bore. The outer compartment may define one or more openings for fluid connection with an area proximate the hemorrhage. When the plunger is actuated to urge the silica fiber composition from the open lower end of the central bore to the hemorrhage, fluid proximate the hemorrhage may be simultaneously aspirated into the outer compartment and thence into the upper compartment of the central bore. The central bore may define one or more openings therethrough fluidly connecting the lower compartment with the annular outer compartment.
In another aspect, embodiments of the invention feature a delivery device for application of a silica fiber composition proximate a hemorrhage. The delivery device includes, consists essentially of, or consists of a hollow central bore, a movable plunger, and an annular outer compartment coaxial with the central bore. The central bore has an upper end and an open lower end. The plunger is disposed at the upper end of the central bore. The plunger is actuatable by a user of the delivery device to urge the silica fiber composition from the open lower end of the central bore. A portion of the plunger separates the central bore into a lower compartment and an upper compartment. The outer compartment is fluidly connected to the upper compartment of the central bore. The outer compartment defines one or more openings for fluid connection with an area proximate the hemorrhage. When the plunger is actuated to urge the silica fiber composition from the open lower end of the central bore to the hemorrhage, fluid proximate the hemorrhage is simultaneously aspirated into the outer compartment and thence into the upper compartment of the central bore.
Embodiments of the invention may include one or more of the following in any of a variety of combinations. The central bore may define one or more openings therethrough fluidly connecting the lower compartment with the annular outer compartment. The silica fiber composition may be disposed within the lower compartment of the central bore. The silica fiber composition may include, consist essentially of, or consist of a plurality of silica fibers. The silica fiber composition may include, consist essentially of, or consist of a powder or dust.
In yet another aspect, embodiments of the invention feature a kit for treating a subject for hemorrhage. The kit includes, consists essentially of, or consists of a silica fiber composition and a delivery device.
Embodiments of the invention may include one or more of the following in any of a variety of combinations. The delivery device may include, consist essentially of, or consist of a hollow central bore, a movable plunger, and an annular outer compartment coaxial with the central bore. The central bore may have an upper end and an open lower end. The plunger may be disposed at the upper end of the central bore. The plunger may be actuatable by a user of the delivery device to urge the silica fiber composition from the open lower end of the central bore. A portion of the plunger may separate the central bore into a lower compartment and an upper compartment. The outer compartment may be fluidly connected to the upper compartment of the central bore. The outer compartment may define one or more openings for fluid connection with an area proximate the hemorrhage. When the plunger is actuated to urge the silica fiber composition from the open lower end of the central bore to the hemorrhage, fluid proximate the hemorrhage may be simultaneously aspirated into the outer compartment and thence into the upper compartment of the central bore. The central bore may define one or more openings therethrough fluidly connecting the lower compartment with the annular outer compartment. The silica fiber composition may include, consist essentially of, or consist of an electrospun silica fiber composition. The silica fiber composition may include, consist essentially of, or consist of a plurality of silica fibers. The silica fiber composition may include, consist essentially of, or consist of a powder or dust.
These and other objects, along with advantages and features of the present invention herein disclosed, will become more apparent through reference to the following description, the accompanying drawings, and the claims. Furthermore, it is to be understood that the features of the various embodiments described herein are not mutually exclusive and may exist in various combinations and permutations. As used herein, the terms “approximately,” “about,” and “substantially” mean±10%, and in some embodiments, ±5%. The term “consists essentially of” means excluding other materials that contribute to function, unless otherwise defined herein. Nonetheless, such other materials may be present, collectively or individually, in trace amounts.
In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In the following description, various embodiments of the present invention are described with reference to the following drawings, in which:
The present invention provides compositions and methods for treating hemorrhage (bleeding) in a subject. In various aspects, the invention provides compositions comprising electrospun silica fibers, that when applied to a site of hemorrhage, are able to quickly stop the hemorrhage. Thus, the invention provides hemostatic devices and methods beneficial for treating subjects experiencing severe injuries, including for emergency treatment at the site of the injury. The invention further is useful in the surgical setting for management of bleeds during surgery. In various embodiments, the invention finds use for treating external wounds and injuries of varying severity.
The electrospun silica material is able to hold many times its weight in water, (e.g., typically more than 50 times its weight in water), which allows the material to absorb a large amount of blood, while being impenetrable by blood cells and quickly forming a physical barrier. In some embodiments, the silica material will bind extracellular matrix proteins and/or serum proteins, aiding in the formation of a barrier. In various embodiments, the silica fiber composition enhances coagulation. In the case of cavity wounds, the hemorrhaging site and/or cavity may be filled or packed with the silica fiber material. In some embodiments, the silica fiber material is applied more discriminately to the site of hemorrhage. The silica fiber material may be applied as a flocculent material, or alternatively, applied as powder, dust, gel, paste, or as an additive to a flowable base material.
In some embodiments, the silica fiber composition is a lightweight structure consisting essentially of silica fiber (e.g., silicon dioxide nanofiber). The composition may be formed from a gelatinous material that is electrospun to form a fiber mat (e.g., a non-woven mat). For example, the composition may be prepared by electrospinning a sol-gel.
An exemplary sol-gel is prepared with a silicon alkoxide reagent, such as tetraethyl ortho silicate (TEOS), alcohol solvent, and an acid catalyst. In various embodiments, the sol is transitioned for at least two days (and, in various embodiments, less than seven days) under conditions where humidity and temperature are controlled. The sol-gel is electrospun to create a silica fiber mat with superior texture and properties, which may find use as or in a hemostatic device.
Known processes do not yield a silica fiber composition with sufficient flexibility for many applications, including for wound care or health care applications. Instead, these structures are comparatively brittle, rigid, and compact; mats will easily fracture or break; fiber layers are difficult to separate; and generally lack the physical characteristics for use in health care applications. In various embodiments, to achieve a superior material for tissue repair, it is important to electrospin the sol-gel once it is appropriately ripened (or “transitioned”), to achieve a composition with the desired physical characteristics. By transitioning the sol under controlled environmental conditions, and/or monitoring the preparation of the sol-gel during the ripening process, the relatively short window to successfully electrospin the sol-gel may be identified. In accordance with embodiments of the invention, the composition is non-rigid and has a soft texture similar to that of cotton.
The fibers may have a variable diameter, such as in the range of from about 50 nm to 5 μm. In some embodiments, the fibers are predominately in the range of about 100 nm to about 2 μm, or predominately in the range of about 200 to about 800 nm.
In some embodiments, the sol-gel for preparing the silica fiber composition is prepared by a method that includes preparing a first mixture containing an alcohol solvent, a silicon alkoxide reagent such as tetraethyl ortho silicate (TEOS); preparing a second mixture containing an alcohol solvent, water, and an acid catalyst; fully titrating the second mixture into the first mixture; and processing (ripening) the combined mixture under controlled environmental conditions to form a gel for electrospinning.
In some embodiments, the silicon alkoxide reagent is TEOS. Alternative silicon alkoxide reagents include those with the formula Si(OR)4, where R is from 1 to 6, and preferably 1, 2, or 3. In some embodiments, the alcohol solvent is an anhydrous denatured ethanol, or in some embodiments, methanol, propanol, butanol or any other suitable alcohol solvent. The first mixture may be agitated, for example, using a magnetic stirrer or similar agitation means. The second mixture contains an alcohol solvent, water, and an acid catalyst. The alcohol solvent in the second mixture may also be an anhydrous denatured alcohol, or may be methanol, propanol, butanol or any other suitably provided alcohol solvent. Water may be distilled water or deionized water. Enough acid catalyst is added to the mixture to aid in the reaction. This acid catalyst may be hydrochloric acid, or may be sulfuric acid or other suitable acid catalyst. The second mixture may be agitated, for example, with a magnetic stirrer or other agitation means. In some embodiments, the first mixture (or sol) and the second mixture (or sol) are created without the use of direct heat.
In some embodiments, the sol will contain about 70% to about 90% by weight silicon alkoxide (e.g., TEOS), about 5% to about 25% by weight alcohol solvent (e.g., anhydrous ethanol), an acid catalyst (e.g., less than about 0.1% by weight when using HCl) and the balance water.
In some embodiments, the sol contains 70% to 90% tetraethyl orthosilicate (TEOS) by weight, 8% to 25% ethanol by weight, 1% to 10% water by weight, and an acid catalyst. In some embodiments, the sol contains 75% to 85% by weight TEOS, 12% to 20% by weight ethanol, and about 2% to 5% by weight water. An exemplary sol contains about 80% by weight TEOS, about 17% by weight ethanol, and about 3% by weight water. In some embodiments, the acid catalyst is HCl. For example, the sol may contain less than about 0.1% HCl by weight. For example, the sol may contain from 0.02% to 0.08% HCl by weight. In various embodiments, the sol does not contain an organic polymer, or other substantial reagents, such that the fiber composition will be substantially pure SiO2. In various embodiments, the sol does not include inorganic salts (e.g., sodium chloride, lithium chloride, potassium chloride, magnesium chloride, calcium chloride, and/or barium chloride), nor are, in various embodiments, inorganic salts mixed with other components of the sol or into the sol itself. In various embodiments, the fiber composition (and the sol) does not include metals or metal oxides (e.g., TiO2 or ZrO2). In various embodiments, the fiber composition consists essentially of SiO2, i.e., contains only SiO2 and unintentional impurities, and, in some embodiments, species and/or complexes resulting from the incomplete conversion of the sol to SiO2 (e.g., water and/or chemical groups such as ethoxy groups, silanol groups, hydroxyl groups, etc.).
According to various embodiments, the first mixture and the second mixture are combined by dripping or titrating the second mixture into the first mixture, preferably with agitation. The combined mixture is then further processed by allowing the sol to ripen in a controlled environment until a substantial portion of the alcohol solvent has evaporated to create a sol-gel suitable for electrospinning.
In various embodiments, the sol is not exposed to heat over 150° F. or heat over 100° F., so as to avoid accelerating the transition. The controlled environment may include an enclosure with at least one vent and optionally an exhaust fan to draw gases away from the mixture. The enclosure may involve controlled conditions in terms of humidity, temperature, and optionally barometric pressure. For example, the humidity may be controlled (e.g., via use of conventional humidifiers and/or dehumidifiers) within the range of about 30% to about 90%, such as from about 40% to about 80%, or in some embodiments, from about 50% to about 80%, or from about 50% to about 70% (e.g., about 55%, or about 60%, or about 65%). Some humidity may be helpful to slow evaporation of solvent, and thereby lengthen the window for successful electrospinning. In some embodiments, the temperature is in the range of from about 50° F. to about 90° F., such as from about 60° F. to about 80° F., or from about 65° F. to about 75° F. In some embodiments, barometric pressure is optionally controlled (e.g., using a low pressure vacuum source such as a pump or a fan). By controlling the environmental conditions during ripening, the gel can be electrospun during the time when spinning is optimal, which may occur in a small window of only several minutes if the ripening process is too accelerated, such as with direct heat. When ripening the sol at a constant humidity of about 55% and temperature of about 72° F., the sol will ripen (gelatinize) in a few days, and the window for successful electrospinning may be expanded to at least several hours, and in some embodiments several days. In various embodiments, the ripening process takes at least 2 days, or at least 3 days in some embodiments. However, in various embodiments the ripening does not take more than 10 days, or more than 7 days. In some embodiments, the ripening process takes from 2 to 7 days or from 2 to 5 days or from 2 to 4 days (e.g., about 2, about 3, or about 4 days). In various embodiments, the sol-gel is spinnable well before it transitions into a more solidified, non-flowable mass.
The enclosure space for ripening the sol-gel may include a vent on at least one surface for exhausting gases from within the enclosure, and optionally the vent may include a fan for exhausting gases produced during the ripening process. The enclosure space may optionally include a heating source for providing a nominal amount of heat within the enclosure space, to maintain a preferred temperature. In some embodiments, a source of humidity (e.g., an open container of water or other aqueous, water-based liquid) is provided within the enclosure environment to adjust the humidity to a desired range or value. The enclosure may further include one or more environmental monitors, such as a temperature reading device (e.g., a thermometer, thermocouple, or other temperature sensor) and/or a humidity reading device (e.g., a hygrometer or other humidity sensor).
In some embodiments, the sol-gel is electrospun after a ripening process of at least 2 days, or at least 36 hours, or at least 3 days, or at least 4 days, or at least 5 days at the controlled environmental conditions (but in various embodiments, not more than 10 days or not more than 7 days under the controlled environmental conditions). By slowing the ripening process, the ideal time to spin the fibers may be identified. The weight of the sol-gel may be used as an indicator of when the sol-gel is at or near the ideal time to electrospin. Without intending to be bound by theory, it is believed that the viscosity of the sol-gel is a poor determinant for identifying the optimal time for electrospinning. For example, in various embodiments, the sol-gel is from about 10% to about 60% of the original weight of the sol (based on loss of alcohol solvent during transitioning). In some embodiments, the sol-gel is from 15 to 50% of the original weight of the sol, or in the range of about 20 to about 40% of the original weight of the sol.
In some embodiments, the sol-gel is ripened for at least 2 days, or at least 36 hours, or at least 3 days, or at least 4 days, or at least 5 days, and is electrospun when the ethylene vapors produced by the composition are between about 10% and about 40% of the vapors produced by the starting sol, such as in the range of about 10% and about 25%, such as in the range of about 10 to about 20%. Ethylene is a colorless flammable gas with a faint sweet and musky odor (which is clearly evident as solvent evaporation slows). Ethylene is produced by the reaction of ethanol and acid. Ethylene may optionally be monitored in the vapors using a conventional ethylene monitor. In other embodiments, gases produced by the sol during the sol ripening process are monitored to determine the suitable or optimal time for electrospinning. Gas profiles may be monitored using gas chromatography.
The processing of the sol-gel mixture may require stirring or other agitation of the mixtures at various intervals or continuously due to the development of silicone dioxide crystalline material on the top surface of the mixtures. This development of crystalline material on the top surface slows the processing time and it is believed that the crystalline material seals off exposure of the mixture to the gaseous vacuum provided within the enclosure space. In some embodiments, any solid crystalline material is removed from the mixture.
Upon completion of the sol-gel process, the sol-gel is then electrospun using any known technique. The sol or sol-gel may be preserved (e.g., frozen or refrigerated) if needed (and such time generally will not apply to the time for ripening). An exemplary process for electrospinning the sol-gel is described in Choi, Sung-Seen, et al., Silica nanofibers from electrospinning/sol-gel process, Journal of Materials Science Letters 22, 2003, 891-893, which is hereby incorporated by reference in its entirety. Exemplary processes for electrospinning are further disclosed in U.S. Pat. No. 8,088,965, which is hereby incorporated by reference in its entirety.
In an exemplary electrospinning technique, the sol-gel is placed into one or more syringe pumps that are fluidly coupled to one or more spinnerets. The spinnerets are connected to a high-voltage (e.g., 5 kV to 50 kV) source and are external to and face toward a grounded collector drum. The drum rotates during spinning, typically along an axis of rotation approximately perpendicular to the spinning direction extending from the spinnerets to the drum. As the sol-gel is supplied to the spinnerets from the syringe pumps (or other holding tank), the high voltage between the spinnerets and the drum forms charged liquid jets that are deposited on the drum as small entangled fibers. As the drum rotates and electrospinning continues, a fibrous mat of silica fibers is formed around the circumference of the drum. In various embodiments, the spinnerets and syringe pump(s) may be disposed on a movable platform that is movable parallel to the length of the drum. In this manner, the length along the drum of the resulting fiber mat may be increased without increasing the number of spinnerets. The diameter of the drum may also be increased to increase the areal size of the electrospun mat. The thickness of the mat may be largely dependent upon the amount of sol-gel used for spinning and thus the amount of electrospinning time. For example, the mat may have a thickness of greater than about ⅛ inch, or greater than about ¼ inch, or greater than about ⅓ inch, or greater than about ½ inch.
Silica fiber mats and compositions produced in accordance with embodiments of the present invention exhibit one or more beneficial properties when compared to fiber compositions spun at non-optimal times (e.g., with inadequate ripening of the sol-gel). For example, fiber mats and compositions in accordance with embodiments of the invention do not burn, char, or visibly degrade upon direct application of heat or open flame. In contrast, various fiber compositions spun at non-optimal times will exhibit charring and/or visible color change when exposed to sufficient heat or open flame. Moreover, fiber mats and compositions in accordance with embodiments of the invention effectively wick moisture (e.g., water or bodily fluids), absorbing such fluid into the fiber mat. In contrast, various fiber compositions spun at non-optimal times will not visibly absorb or wick moisture even when directly applied thereto; such compositions tend to be hydrophobic. Finally, fiber mats and compositions in accordance with embodiments of the invention are fluffy and may be easily shaped to uneven, non-uniform, and/or non-planar (e.g., curved) surfaces or shapes without fracturing or loss of structural integrity; thus, such compositions may be readily applied to or conformed to a variety of different surfaces. In contrast, various fiber compositions spun at non-optimal times tend to be flat, plate-like, brittle, and will at least partially fracture if excessively mechanically shaped or bent.
Fiber layers may be easily separated from the mat for, e.g., application to hemorrhaging tissue. In some embodiments, the composition is electrospun with a thickness of from about ⅛ inch to about ½ inch. For example, the composition may be electrospun with a thickness of greater than about ⅛ inch, or greater than about ¼ inch thick, or about ¼ thick in some embodiments.
The material is able to hold many times its weight in water, typically more than about 50 times or about 70 times its weight in water. This feature allows the material to absorb a large amount of blood, while being impenetrable by blood cells, thereby quickly forming a physical barrier. In various embodiments, the material enhances the coagulation cascade when exposed to blood. The material may be used as fiber mats that are folded and/or clumped to prepare a suitable mass of material for packing a hemorrhaging site, including a hemorrhage in a body cavity. In some embodiments, the silica fiber material is processed into a flocculent material. A flocculent material may be loosely clumped, and may be created by shredding and/or clumping portions of the electrospun fiber mats. The flocculent material may be used to pack the hemorrhaging site. Alternatively, the silica fiber material may be applied as a powder or dust, gel, paste, or as an additive to a flowable base material. Bulking agents may be added to the material, and may include various synthetic and natural polymers, and may include materials such as poloxamers, polyethylene glycol, polyvinyl alcohol, collagen, gelatin, cellulose, chitosan, and fibrin, among others.
In some embodiments, the silica fiber composition is processed into a fine powder or dust, and the powder or dust is applied to the hemorrhage. For example, a sheet of silica fibers may be rubbed through one or more screens, and a range of powder sizes obtainable by varying mesh size. In some embodiments, the powder or dust is mixed with a topical composition, such as a lotion, ointment, paste, cream, foam, or gel. In these embodiments, the topical composition may comprise one or more pharmaceutical or antimicrobial agents, such as an antibiotic, an antiseptic, an anti-inflammatory agent, or immunosuppressant.
In various embodiments, the silica fiber composition may then be divided into small fibrous fragments that may be applied to the hemorrhage. The resulting fibrous fragments are each intertwined collections of silica fibers, rather than unitary solid particles. In some embodiments, the electrospun mat may be fractured, cut, ground, milled, or otherwise divided into small fragments that maintain a fibrous structure. In some embodiments, the mat (or one or more portions thereof) is rubbed through one or more screens or sieves, and the mesh size of the screen determines, at least in part, the size of the resulting fibrous fragments produced from the electrospun mat. For example, the mat or mat portions may be rubbed through a succession of two or more screens having decreasing mesh sizes (e.g., screens having mesh numbers of 100, 200, 300, or even 400), in order to produce a collection of fibrous fragments having the desired sizes.
As used herein, the term “fibrous fragments” (or “fibrous-mat fragments,” or simply “fragments”) refers to small dust-like particles, parts, or flakes of a fibrous mat having an average dimension larger (e.g., 5×, 10×, or even 100×) than the width of at least some of the fibers of the mat. In various embodiments, the average size of a fibrous fragment is in the range of approximately 20 μm to approximately 200 μm along the longest axis. Fibrous fragments may thus resemble microscopic-scale versions of the electrospun mat itself, e.g., intertwined collections of silica fibers, and thus typically are porous. Thus, fibrous fragments may be contrasted with other types of micro-scale particles, such as the substantially spherical particles used in colloidal silica, which are each unitary, individual units or grains, rather than small collections of fibers.
In some embodiments, the silica fibers are provided with a material to facilitate handling and application to the wound site. For example, the silica fiber material may be combined with a backing material (which may be gauze or other fabric in some embodiments), or inside a flexible container (e.g., a bag) made of any material that allows the silica fiber material to be emptied or placed at the site of hemorrhage.
In some embodiments, the silica fiber material itself is applied to the wound site without use of a backing material or container.
In some embodiments, the fiber composition is applied directly to the site of hemorrhage by packing the site with the material, in any form, and applying pressure where and as possible. The fiber composition will absorb the blood and large amounts of fluid, although the blood cells cannot penetrate the material, and will quickly form a physical barrier for further loss of blood. In some embodiments, even for severe hemorrhage (e.g., grade 3 or 4 hemorrhage), the silica fiber material may stop blood flow within about 60 seconds, or in some embodiments, within about 30 seconds, or in some embodiments within about 15 seconds. By quickly stopping a severe hemorrhage at the site of injury, the patient may more quickly and safely be transported to a surgical facility. The silica fiber material, or at least a portion thereof, may be easily removed by a physician during surgery.
In some embodiments, the rate of blood flow at the site of the hemorrhage is sufficient to render direct application of the fiber composition difficult. For example, blood flow from a ruptured blood vessel may resist or prevent contact between the silica fiber material and the damaged vessel. Thus, in various embodiments the fiber composition is applied directly to the site using a delivery device that simultaneously delivers the fiber composition to the wound site while aspirating excess blood at or near the wound site. In this manner, direct contact between the fiber composition and the wound site is facilitated.
In order to facilitate sufficient contact between the fiber composition and a bleeding wound without the fiber composition being drawn away from the wound by the flow of blood, in various embodiments the delivery device 300 aspirates away excess blood simultaneously with the delivery of the fiber composition. As shown in
As shown in
In various embodiments, the openings fluidly connecting the outer annular compartment 320 with the wound site and/or with the upper compartment are sufficiently small such that little or none of the fiber composition is inadvertently aspirated away from the wound site. Alternatively or in addition, the openings may include filters or screens thereon that prevent the flow of the fiber composition (at least larger pieces thereof) or other solids from being aspirated into the outer annular compartment and/or the upper compartment of the delivery device. As also shown in
In various embodiments, all or a portion of the delivery device 300 includes, consists essentially of, or consists of one or more biocompatible materials, e.g., one or more plastics, other polymeric materials, or stainless steel.
The silica fiber material may be used for human and animal treatment. In some embodiments, the subject is a mammal. Subjects include veterinary patients such as a dog, cat, pig, or horse, among others. In some embodiments, the patient is a human patient.
The World Health Organization includes grades of hemorrhage from 0 to 5. In some embodiments, the hemorrhage is at least a Grade 2 hemorrhage (e.g., a Grade 3 or Grade 4 hemorrhage). A Grade 2 hemorrhage is mild but clinically significant. In some embodiments, the hemorrhage is a Grade 4 hemorrhage. A Grade 4 hemorrhage is defined as severe bleeding that would typically require transfusion. A Grade 5 hemorrhage is associated with fatality. In some embodiments, the hemorrhage is an arterial hemorrhage. Arterial hemorrhage often exhibits spurting as a jet which rises and falls in time with the pulse. In protracted bleeding, and when quantities of intravenous fluids other than blood are given, it can become watery in appearance. In some embodiments, the hemorrhage is a venous hemorrhage. Venous hemorrhage is a darker red, a steady and copious flow. Blood loss is particularly rapid when large veins are opened.
In some embodiments, the hemorrhage is bleeding during or after surgery. For example, the hemorrhage may be an organ bleed, including but not limited to an organ selected from liver, lungs, heart, kidney, pancreas, stomach, and intestine. In these embodiments, the silica fiber material may be applied directly to the bleed, using portions of silica fiber mats, or various other forms, such as powder or dusts, pastes or gels, or a flowable base comprising silica fiber dust.
In some embodiments, the hemorrhage is a primary hemorrhage, which occurs at the time of injury or operation. In some embodiments, the hemorrhage is a reactionary hemorrhage. Reactionary hemorrhage may follow primary hemorrhage within 24 hours (usually 4 to 6 hours) and is mainly due to rolling (‘slipping’) of a ligature, dislodgement of a clot or cessation of reflex vasospasm. In some embodiments, the hemorrhage is a secondary hemorrhage. Secondary hemorrhage occurs after 7 to 14 days, and is due to infection and sloughing.
In some embodiments, the hemorrhage is a traumatic injury bleed. For example, the hemorrhage is a non-compressible hemorrhage. In some embodiments, the hemorrhage is a cavity bleed. In some embodiments, the injury is a crushing injury. In some embodiments, the injury is a gunshot injury or explosion injury.
In some embodiments, the hemorrhage is epistaxis, and the silica fiber material packed inside the nasal cavity.
In some embodiments, the hemorrhage is external. For example, the silica fiber material may be shaped as pads or bandages, or used with various types of conventional bandage materials (e.g., cotton gauze) and wound dressings to encourage bleeding control.
In some embodiments, the patient is on therapy inhibiting the coagulation pathway. These therapies can include heparin (unfractionated or LMWH). Alternatively, the patient may be on therapy with a Factor Xa inhibitor or direct thrombin inhibitor, or other direct inhibitor of the coagulation pathway. In some embodiments, the patient has a genetic coagulation disorder, such as hemophilia, thrombocytopenia, low platelet count, or von Willebrand disease.
Other aspects and embodiments of the invention will be apparent from the following non-limiting examples.
SiO2 fibers were prepared using an electrical spinning process, where a sol-gel is spun onto a roller system creating a sheet. The sol-gel is made in two parts. First, TEOS is mixed with ethanol, and then a second mixture containing HCl, water, and ethanol is titrated into the mixture. The sol-gel is then allowed to ripen for a few days under controlled conditions before spinning.
In one example, the first sol was made by weighing out 384 grams of (TEOS) tetraethyl orthosilicate 98% and 41.8 grams of anhydrous denatured ethanol, and pouring together. The first sol was allowed to let stand in a beaker and a magnetic stirrer was used to create a homogenous solution. The second sol was made by weighing 41.8 grams of anhydrous denatured ethanol, 16.4 grams of distilled water, and 0.34 grams of hydrochloric acid, which was then poured together and mixed for 8 seconds with a magnetic stirrer until a homogenous second sol was formed.
The second sol was then poured into the titration device, which was placed above a beaker containing the first sol. The titration device then dripped about 5 drops per second until a third sol was formed mixing the first sol and the second sol. During the dripping process, the first sol continues to be mixed with a magnetic stirrer while the second sol is dripped into the first sol.
The combined third sol was then placed into an enclosure box. A low pressure vacuum is provided by a fan on medium speed to remove fumes. In the experiment, the air temperature within the box was 72° F. with 60% humidity. In the experiment, the third sol was allowed to sit and process for about three (3) days. By ripening the sol-gel slowly over several days, the sol-gel will transition slowly such that the ideal time to electrospin can be identified.
The mixtures were agitated daily to reduce the build-up of crystalline structures. The third sol begins to transition to sol-gel with evaporation of the alcohol solvent. Sol-gel may be monitored to determine an approximate amount of C2H4 (ethylene) in the vapors, which can be in the range of about 10-20% relative to the original sol before ripening. Upon proper gelatinization, the sol-gel is loaded into the electrospinning machine or is frozen to preserve for electrospinning. Proper gelatinization occurs when the total mass of the sol-gel was between about 100 grams and about 180 grams.
The above example can be scaled appropriately to produce desirable structures. To further identify the ideal time to electropsin, portions of the gel can be dripped into the electric field to evaluate the properties of the resulting fibers.
A swine model was utilized to study the effect of silica fiber compositions in accordance with embodiments of the invention on the hemostasis of lethal extremity arterial hemorrhage. Specifically, muscle tissue was removed to expose the femoral artery, and a biopunch used to sever the artery. After bleeding for several seconds, silica fiber material was applied with limited pressure to the severed vessel, which quickly stopped the active bleed. The subject was kept alive for a period of 3 hours during which the leg was moved back and forth 10 times and then checked for bleeding. The subject was then moved to a sled and dragged 50 yards to simulate extraction of a soldier in combat. The wound was then checked for bleeding. After this, the subject was euthanized, and the injured vessel was excised for analysis. Control subjects were treated with conventional QuikClot Combat Gauze (i.e., a soft nonwoven gauze impregnated with kaolin for acceleration of clotting) for comparison.
In the experiment, the average blood loss and bleeding time for the subjects treated with the silica fiber composition was decreased by approximately a factor of two compared to the control subjects. The final mean arterial pressure and heart rate were also slightly higher for the subjects treated with the silica fiber composition. The body temperature of the subjects treated with the silica fiber composition also trended lower (i.e., improved) during the duration of the study.
After the experiment, histology was performed utilizing hematoxylin and eosin staining, as shown in
Overall, the silica fiber composition stopped the arterial bleeding much more quickly than the gauze of the control samples. Pressure could be removed, and lack of bleeding observed, even before the end of the three-minute treatment period. When the porcine leg was moved, there was no further bleeding. Hemostasis was maintained, even during manual attempts to dislodge the clot. In contrast, use of the control gauze required more significant pressure to be applied, and there was increased bleeding around the gauze for most of the three-minute treatment period. Unlike the silica fiber composition, the gauze is also designed for removal after hemostasis, and it is therefore not designed to remain within the wound to direct regeneration. The silica fiber composition reduces the time to hemostasis and the amount of total bleeding. It also reduces the number of re-bleeding events, and facilitates tissue coverage and regeneration, ultimately improving the chances of survival of a major bleed.
Uncontrolled hemorrhage remains the leading cause of death for combat casualties and the second leading cause of death in civilian trauma patients. Currently available advanced hemostatic dressings carry significant hemorrhage mortality rate and require urgent surgical attention to permanently repair the damaged vessel or organ. Thus, there is a critical need to test and validate new hemostatic dressings that control lethal hemorrhage while supporting the injured area en route to surgical care. To address these needs, the present disclosure provides a universal trauma dressing that displays hemostatic and wound repair properties. This material can be applied with little training, is light weight, and requires no special storage. In the following study, the multi-modality hemostatic capability of the material is evaluated in porcine, grade IV liver injury (non-compressible wound).
The subjects were anesthetized and stabilized in a supine position and received a grade IV hemorrhagic liver injury. The injuries were treated with either the fiber composition of this disclosure or a QuikClot control. The time to hemostasis, total blood loss, mass of treatment items used, and survival percentage were measured. Following euthanasia, histological samples were collected for assessment of the treated injury site. Specifically, a large grade IV liver injury was induced by cutting “X” shaped wedges into the superior surface of the right and left liver lobes, approximately 3 cm deep and 4×8 cm in dimension. The site was allowed to bleed for up to 30 seconds followed by a timed treatment window, with the surgeon calling out the time when hemostasis was achieved. The injury site was monitored for 60 minutes for re-bleeding, and if the animal was deemed stable, the incision was closed, bandaged, and the animal was monitored off anesthesia for up to 48 hours.
All three non-compressible liver injuries treated with the fiber composition of the present disclosure were rapidly hemostatic and all three study animals survived for two days. Histological analysis demonstrated a fibrin bridge that formed across the open wound. Vessels near the injury site remained patent, providing evidence that good vascular pressure was restored following injury hemostasis. In some samples, newly formed septa were visible on the edge of the transected liver lobules.
As shown in
These results demonstrate the hemostatic properties of the fiber material to stop non-compressible liver hemorrhage. The material is easy to apply, and achieves rapid, stable, multi-day hemostasis. The hemostatic efficacy is evident in histological images that demonstrate a thick fibrin bridge along the hemorrhagic edge of the injuries, with evidence of regenerative healing in the liver.
Taken together, the universal treatment capacity, light weight, and ease of use make this an ideal hemostatic agent for military personnel. Military in far-forward multi-domain battlefields could use this material as a multi-day hemostatic bridge to definitive care.
Using the porcine model described in Example 3, the fiber material was evaluated for hemostasis in abdominal aorta injury. Abdominal aorta punctures were performed using a 4 mm punch biopsy (
Injuries treated with the fiber material of this disclosure had improved survival compared with control (100% vs. 0%), with two animals surviving one day after injury. Furthermore, the wounds treated with the fiber material of this disclosure used 20 times less material weight compared with control treated injuries (20 g vs. 415 g). Histological analysis of the treated injuries demonstrated that the silica fiber-treated wound formed hemostatic plugs of mixed composition with red blood cells, platelets, and fibrin, with a fibrin bridge formed across the inner surface of the injury (
The terms and expressions employed herein are used as terms and expressions of description and not of limitation, and there is no intention, in the use of such terms and expressions, of excluding any equivalents of the features shown and described or portions thereof. In addition, having described certain embodiments of the invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. Accordingly, the described embodiments are to be considered in all respects as only illustrative and not restrictive.
This application is a continuation-in-part of U.S. application Ser. No. 17/011,060, filed Sep. 3, 2020, which claims the benefit of and priority to U.S. Provisional Application No. 62/898,148, filed Sep. 10, 2019, and U.S. Provisional Application No. 63/002,475, filed Mar. 31, 2020, the entire disclosures of each of which are hereby incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62898148 | Sep 2019 | US | |
| 63002475 | Mar 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17011060 | Sep 2020 | US |
| Child | 17685617 | US |
