US20040013715A1

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Publication number: US20040013715A1
Application number: US10/363,994
Authority: US
Inventors: Gary Wnek; Marcus Carr; Gary Bowlin; Kelman Cohen; Kevin Ward; Wayne Barbee; Rao Ivatury
Original assignee: Individual
Current assignee: Virginia Commonwealth University
Priority date: 2001-09-12
Filing date: 2001-09-12
Publication date: 2004-01-22
Also published as: US8497408B2; US20080009898A1; US20130310779A1

Abstract

High-pressure bleeding wounds (and other bleeding wounds) may be treated by applying direct pressure directly in the bleeding wound, such as by applying a back pressure in a confined space around and in the wound. Certain substances and articles may be inserted into the wound, and the wound may be enclosed with that substance or article (such as a hemostatic substance, which may be polymeric), by swelling on contact with molecules (such as water molecules in the blood) encountered in the wound, generates the desired pressure to stop or at least reduce the bleeding without the detrimental effects of a tourniquet Clot-inducing substances may be introduced into the wound contemporaneously with direct pressure application directly in the wound. Compressible and non-compressible wounds are treated. Treatment stops bleeding without producing pressure injury or ischemic damage. Medical devices using this technology are provided, including removable, biodegradable, medic-administrable devices.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention[0001]

The invention is generally related to emergency medicine. In particular, the invention relates to bleeding and bleeding injuries.[0002]

2. Background Description[0003]

The morbidity and mortality from penetrating injuries (such as ballistic injuries in combat, knife wounds, penetrating wounds secondary to motor vehicle accidents, etc.) has decreased over the past fifty years. However, some undesirable results remain. Present treatments for high pressure, i.e. arterial, bleeding can cause ischemia that might contribute to limb loss. Tourniquet use can contribute to the need for amputation. This is especially true if there is a significant delay in definitive treatment.[0004]

As to military trauma, two characteristics of death due to such trauma are seen. First, early death occurs. Soldiers who die due to injury, die early: about 40% die immediately; 25% die within 5 minutes; 15% die within 15 minutes; i.e., a total of 80% dead in the first 15 minutes after trauma. A second feature of military trauma is death due to bleeding, with 2/3 of military deaths due to trauma being due to hemorrhage.[0005]

Ballistic injury is a primary mode of trauma in combat. Such injuries can be associated with rapid blood loss due to vascular disruption. In the Vietnam conflict, ten percent of wounds to the extremity were associated with major artery injury. M. E. Jabaley, H. D. Peterson, “Early treatment of war wounds of the hand and forearm in Vietnam,” Ann Surg 1973; 177:167-73. While bleeding from compressible vessels may respond to direct pressure, blood loss from deep muscular branches (such as those from the profunda femoris artery, etc., e.g., see Table 1) may be severe. S. M. Henry, R Tornetta III, T. M. Scalea, “Damage control for devastating pelvic and extremity injuries,” Surg Clin North Am, 77:879-95 (1997). Despite increasingly aggressive surgical treatment, limb salvage has not improved. P. V. Sharma, S. C. Babu, P. M. Shah, R. H. Clauss, “Changing patterns in civilian arterial injuries,” J. Caridovasc Surg (Torino), 26:7-11 (1985). Death from hemorrhagic shock remains a problem even in very healthy individuals. J. Valentine, S. Blocker, J. H. Chang, “Gunshot injuries in children,” J Trauma, 24:952-6 (1984). As can be appreciated from the following Table 1, combat vascular injuries continue to result in a 12 to 30 percent amputation rate depending on the involved vessel.[0006]

TABLE 1


(Incidence of major lower extremity vascular injuries
in the three great wars)
(Source: Vascular Trauma, Rich N. M. and Spencer, F. C.
(eds.), W. B. Sunders, Philadelphia, 1978).

	Total	Common	External	Common	Deep	Superficial
War	Arteries	Iliac	Iliac	femoral	Femoral	Femoral	Popliteal

WWI	1202	1	4			366	144
WWII	2471	13	30	106**	23	517	502
Korean	304					95!	79#
Vietnam	1000	9	17*	46***		305@	217#

Nor is the high incidence of deaths and amputations from penetrating wounds only for combat injuries. Treatment of trauma also is important in the civilian arena. At one Level I civilian trauma center in Virginia, from 1995 to 1999, of 66 patients with penetrating extremity vascular injuries, there were five deaths from hemorrhagic shock. Trauma is the most frequent cause of death in the United States in persons under the age of 34. Because trauma occurs most in young people, trauma is the leading cause of life years lost. Up to 80% of all early trauma deaths are from uncontrolled hemorrhage. Each year in the United States, 1 in 100 people will visit an emergency room; 1 in 1000 people will be admitted and transfused; 1 in 3000 will die of trauma. About 50% of civilian deaths due to trauma are secondary to hemorrhage.[0007]

Currently available modalities for treating high pressure bleeding include tourniquets, fibrin glue, etc. However, these current bleeding treatments have significant disadvantages, such as nerve damage, limb ischemia, increased risk of amputation, etc.[0008]

Tourniquets were described more than two millenia (2000 years) ago as an adjuvant to surgical amputation L. Zimmerman, I. Veith,[0009]Great Ideas in the History of Surgery, San Francisco, Calif.: Norman Publishing (1993), 31. Since then, tourniquets have become a primary a primary initial treatment for injuries associated with high pressure bleeding. Unfortunately, tourniquet use is associated with a variety of complications and difficulties including nerve damage, post-tourniquet syndrome, limb ischemia (distal ischemia), compartment syndromes, pulmonary embolus, increased risk of amputation, and limb wastage. A. K. Palmer, “Complications from tourniquet use,” Hand Clinics, 2:301-5 (1986); A. S. Estrera, R. P. King, M. R. Platt, “Massive pulmonary embolism: a complication of the technique of tourniquet ischemia,” J Trauma, 22:60-2 (1982). To decrease these risks, tourniquets must be intermittently loosened. This typically restarts the bleeding and is difficult for treating personnel to accomplish. Despite the potential complications and drawbacks, recent combat (such as the 1991-92 Croatian conflict) has verified the ability of tourniquets to delay shock in lower extremity arterial injuries. Z Lovric, V Lehner, B Wertheimer, L Kosic-Lovric, “Tourniquet occlusion technique for lower extremity artery reconstruction in war wound,” J Cardiovasc Surg (Torino), 38:153-5 (1997).

While fibrin products (such as fibrin glue, fibrin sealant and dry fibrin dressing) have been developed and shown to be effective in stopping venous bleeding, such fibrin products do have drawbacks. Fibrin products have had a tendency to be washed from the wound during high pressure bleeding, relative high cost. Some fibrin products put the patient at risk of viral exposure. Virally inactivated fibrin sealant has been developed, and is being used as an adjuvant to multiple types of surgery. C J Dunn, K L Goa, “Fibrin sealant: a review of its use in surgery and endoscopy,” Drugs, 58:863-86 (1999); M R Jackson, B M Alving, “Fibrin sealant in preclinical and clinical studies,” Curr Opin Hematol, 6:415-9 (1999). Fibrin glue has been shown to be effective in speeding hemostasis along vascular graft suture lines. A A Milne, W G Murphy, S J Reading, C V Ruckley, “A randomised trial of fibrin sealant in peripheral vascular surgery,” Vox Sang, 70:210-2 (1996). Fibrin glue has been tested as an adjuvant to surgery in the treatment of complex hepatic injury. S M Cohn, J H Cross, M E Ivy, A J Feinstein, M A Samotowka, “Fibrin glue terminates massive bleeding after complex hepatic injury,” J Trauma, 45:666-72 (1998). Formulations of fibrinogen and thrombin containing dressings, and dry fibrin sealant dressings have been proposed and studied in pig models of vascular injury and grade V liver injury. M J Larson, J C Bowersox, R C Lim, Jr., J R Hess, “Efficacy of a fibrin hemostatic bandage in controlling hemorrhage from experimental arterial injuries,” Arch Surg, 130:420-2 (1995); J B Holcomb, A E Pusateri, R A Harris, N C Charles, R R Gomez, J P Cole, L D Beall, V Bayer, M J MacPhee, J R Hess, “Effect of dry fibrin sealant dressings versus gauze packing on blood loss in grade V liver injuries in resuscitated swine,” J Trauma, 46:49-57 (1999); J B Holcomb, A E Pusater, R A Harris, T J Reid, L D Beall, J R Hess, M J MacPhee, “Dry fibrin sealant dressing reduce blood loss, resuscitation volume, and improve survival in hypothermic coagulopathic swine with grade V liver injuries, “J Trauma, 47:233-40 (1999). Dry fibrin sealant dressing was recently shown to be more effective than standard gauze in decreasing bleeding and maintaining blood pressure in ballistic injury. J Holcomb, M MacPhee, S Hetz, R Harris, A Pusateri “Efficacy of a dry fibrin sealant dressing for hemorrhage control after ballistic injury,” Arch Surg, 133:32-5 (1998).[0010]

While the development of “dry” products has increased their potential as alternatives to tourniquets for battlefield treatment, several potential problems remain. First, these products are relatively expensive because they are made from human blood (requiring a large amount of starting materials and multiple purification processes). Second, although virally inactivated, the fibrinogen contained in the products comes from multiple human donors and cannot be considered totally safe in terms of viral transmission. Third, these products must be held in place until bleeding stops or the material may simply wash out of the wound. The wash-out problem is especially seen when the bleeding is brisk as with arterial involvement.[0011]

Thrombin-mediated polymerization of fibrinogen has been the staple of hemostat technology for decades. “Hemostatic” means anything with the ability to enhance, speed or support blood clotting. Indeed, a recent patent dealing with hemostat systems still focuses on this process. J J Prior, D G Wallace, D H Sierra, F A DeLustro, “Compositions containing thrombin and microfibrillar nanometer collagen, and methods for preparation and use thereof,” U.S. Pat. No. 6,096,309 (2000).[0012]

Also, treatment of bleeding external wounds also has not progressed much, with conventional treatments not offering much beyond simply covering the wound. Most conventional dressings do little or nothing to promote hemostatis, prevent infection or relieve pain. Current bandages do little more than cover the wound and absorb fluids. There are emerging products that aid in hemostasis (fibrin glue, fibrin sealant, dry fibrin, kitosan, etc.) but most are quite expensive and some carry a risk of viral infection.[0013]

Another difficulty of conventional treatments for bleeding is that the patient loses much of his or her own blood, and transfusion is needed. Blood transfusion suffers from availability problems, purity concerns, etc., and is expensive. Costs of civilian blood transfusion for trauma were about ${fraction (1/2)} billion in 1997.[0014]

None of the current technologies adequately address the problem of treating high pressure arterial bleeding. A tourniquet alternative that is effective, inexpensive, lacks viral risk, and can be easily administered (such as by an army medic) would be a medical advance. A solution is still sought to the problem of assuring hemostatis and homeostasis for a penetrating injury (such as high-pressure bleeding combat wound) until the patient (such as a soldier) can reach a hospital facility for definitive care. Additionally, better treatment of bleeding external wounds is timely. Overall, better treatment of hemorrhage by the first responder would save lives, money and limbs, in military and civilian situations.[0015]

SUMMARY OF THE INVENTION

Leakage (such as bleeding) may be stopped or reduced relatively quickly by pressure equalization comprising enclosing a region around the leak and applying direct-pressure in or around the leak. Notably, bleeding (especially high-pressure bleeding from penetrating injuries such as combat wounds) may be treated by applying direct pressure within the wound, especially by enclosing an area around the wound and applying direct pressure in that enclosed area. Such direct-pressure application advantageously may be by a simple medical device (such as a device administrable by a medic). An inventive medical device may be placed directly in the wound, where it stops high pressure bleeding. The acute dressing is both removable for a definitive treatment, and biodegradable if not removed (such as because removal is not warranted). The inventive device is simple, easy to apply, much less expensive than other biological products, and does not expose the patient to viral contaminants. The invention directly addresses the problem of high pressure by simulating the time honored treatment of direct pressure, particularly, pressure directly within the wound.[0016]

The invention is particularly practical, in that four topics (topics 1a, 1c, 1f, 1g) of the nine research topics proposed in the hemorrhage control section of the Research on Combat Casualty Care program are addressed. The inventive medical devices and methods may be used in compressible (topic 1f) and non-compressible (topic 1a) bleeding. Medical devices and methods according to the invention are suitable for replacing the tourniquet as the primary field hemostat used by the medic (topic 1c). Because medical devices and treatment methods according to the invention are designed to avoid the ischemia associated with tourniquet use, they have no time limit on emergent use (topic 1g). Advantageously, the invention provides acute dressings and other medical devices that may be removed for definitive treatment while also being biodegradable if not removed.[0017]

Advantageously, the present invention moves away from the conventional treatment paradigm for penetrating high-pressure bleeding injuries of “first save the patient, then spare the limb” to a new paradigm of “save the patient and spare the limb.”[0018]

In order to accomplish these and other objects of the invention, in a first preferred embodiment, the invention provides a method of treating a fluid leak (such as a bleeding wound), comprising inserting into the fluid leak a material swellable on contact with the leaking fluid.[0019]

In a second preferred embodiment, the invention provides a method of treating a bleeding wound, comprising applying direct pressure directly in the bleeding wound. Particularly preferred is to place directly in the wound a substance that swells at a rate of 100 to 300% volume increase per minute. Most preferably, direct pressure application continues until bleeding stops.[0020]

In a third preferred embodiment, the invention provides a medical device comprising a hemostatic substance placeable directly in a bleeding wound, wherein the wound is a compressible wound or a non-compressible wound. Advantageously, the invention provides devices that may be removable and/or biodegradable; devices that when placed in a bleeding wound swells at a rate of about 100 to 300% volume increase per minute; devices that produce pressure of greater than about 60 mm Hg in a confined space; devices administrable by a medic, etc.[0021]

Some aspects and features of the invention are now mentioned, without the invention being limited thereto.[0022]

The inventive methods and devices in an especially preferred embodiment may include applying a back pressure in a confined space around and in the wound. In another especially preferred embodiment, the invention may include inserting a direct-pressure-applying substance or article into the wound and enclosing the wound with the direct-pressure-applying substance or article therein. In a further especially preferred embodiment, the invention may include inserting a hemostatic substance or article into the wound and enclosing the wound (such as by placing a dressing over the wound) with the hemostatic substance or article therein.[0023]

Where the invention uses a hemostatic substance or article, in a particularly preferred embodiment, the hemostatic substance or article includes polymer fibers of diameter about 1 micron or less. In another particularly preferred inventive embodiment in which a hemostatic substance or article is used, the hemostatic substance or article swells upon contact with water molecules (such as water molecules contained in blood leaving the wound). Where a hemostatic substance or article is used, the hemostatic substance or article may be lightly crosslinked. Where a hemostatic substance is used, in a particularly preferred embodiment of the invention, the hemostatic substance swells from an initial volume to a 10-fold volume in one minute in a liquid; and/or the hemostatic substance generates at least 60 mm Hg pressure within three minutes of being placed in a bleeding wound.[0024]

In a particularly preferred embodiment of the invention, a membrane or shell encloses the swellable material, hemostatic substance or article, or the like. Most preferably, the membrane or shell stiffens as the interior hemostatic substance or article or swellable material swells.[0025]

The invention in a particularly preferred embodiment provides for using (such as placing in a wound or disposing in a device) a polymeric substance, such as a polymeric substance that is a microporous, hydrogel-forming polymer with rapid swelling kinetics. Preferably, the polymeric substance may be poly(acrylamide), hydroxypropyl cellulose, or a hydrophilic material.[0026]

The invention in a particularly preferred embodiment provides for placing a clot-inducing substance (such as thrombin, batroxobin, reptilase, a fibrinogen activating enzyme, etc.) in a wound to be treated.[0027]

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic of an apparatus for electrospraying or electrospinning production. FIG. 1B shows the apparatus of FIG. 1A in the process of electrospinning production.[0028]

FIGS.[0029]2A-2B are microphotographs showing PEVA deposited from a solution in chloroform that is 9 wt % solution in chloroform (FIG. 2A) and 15 wt % solution in chloroform (FIG. 2B).

FIG. 3 is a screening apparatus for substances for pressure development during swelling in a confined space.[0030]

FIGS.[0031]4A-4B are perspective views of a medical device according to the invention, with FIG. 4A showing a wound treatment device before use and FIG. 4B showing a wound treatment device expanded after exposure to blood, water or another liquid.

FIGS.[0032]5A-5B are representational views of a molecular scale depiction of behavior of a device according to the invention.

FIGS.[0033]6A-C are representational drawings of the invention at a molecular-level, in use treating a bleeding wound, including FIG. 6A where a fresh inventive device has been placed at a wound to be treated; FIG. 6B where the device has been in contact with the bleeding wound for a time; and FIG. 6C where the device has been in contact with the bleeding wound for a sufficient time to equalize pressure.

FIG. 7A is a scanning electron microphotograph of an ethylene vinyl acetate (EVA) electrospun mat; FIG. 7B is a scanning electron microphotograph of EVA[0034]

FIGS.[0035]8A-8B are a graph of swelling properties of swellable materials according to the invention electrospun ethylene-vinyl acetate (EVA) copolymer bags, with time (minutes) plotted against grams water/grams polymer, for poly(acrylamide)co-acrylic acid copolymer (FIG. 8A) and poly(acrylamide)co-acrylic acid copolymer potassium salt (FIG. 8B), respectively.

FIGS.[0036]9A-9F are representational cross-sections of an initially healthy blood vessel (FIG. 9A) that is disrupted (FIG. 9B), with the invention used in treating the disrupted blood vessel (FIGS.9C-9D).

FIGS.[0037]10A-10B diagram filling according to the invention.

FIG. 11 is a representative view of an exemplary layered-system device according to the invention.[0038]

FIG. 12 is an exemplary system according to the invention for use with external hemorrhage.[0039]

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

With the invention, a liquid leak (such as a bleeding wound, etc.) may be stopped or at least reduced by applying direct pressure inside the leak. The direct pressure to be applied may be generated by a swellable material, by pneumatic filling of a bladder, singly or in combinations thereof etc.[0040]

Where a swellable material is used, the swellable material is selected based on the leaking liquid to which it will be exposed, such as blood in a patient, water in a plumbing system, etc. Most preferably, the swellable material absorbs at least 10 times its weight of the leaking liquid, such as, in the case of bleeding, about 10 times its weight of water.[0041]

In a particularly preferred embodiment, the invention provides an exemplary method of treating a bleeding wound, comprising applying direct pressure directly in the bleeding wound, most preferably applying direct pressure in the range of about 50 to 90 mm Hg directly in a high-pressure bleeding wound (such as a wound bleeding at about 60 to 90 mm Hg pressure). The wounds treatable by the invention include high-pressure bleeding wounds, compressible wounds, non-compressible wounds, external wounds, etc. The invention advantageously may be used for treating wounds bleeding in a range of about 60 to 140 mm Hg, or higher, and also may be applied for treating low-pressure bleeding.[0042]

In the case of high-pressure bleeding wounds, a preferred example of applying direct pressure directly in the bleeding wound is to insert a hemostatic (i.e., hemocompatible direct-pressure-producing) substance or article into the wound and to enclose the wound with the hemostatic substance or article therein. By establishing around the wound a confined space, such as the wound covered with an elastic dressing, swelling of a swellable material enclosed therein may be used to produce a back pressure that advantageously stops or at least slows bleeding. By provision of such a back pressure within the wound, clot formation may be supported and enhanced, and high pressure (arterial) bleeding may be stopped or at least slowed, advantageously without compromising collateral blood flow (as occurs with a constrictive treatment such as a tourniquet).[0043]

The application of direct pressure preferably is pressure generated by swelling of at least one swellable material. The amount of pressure applied is in an amount for stopping or at least minimizing bleeding from the wound, preferably such as about 50 to 90 mm Hg pressure (most preferably, about 80 mm Hg pressure) generated from a swelling substance or article in four minutes or less (most preferably about three minutes or less).[0044]

As preferred examples of swellable materials for use in the invention may be mentioned polymers, such as polymers that are hydrogel-forming, micro-fibrous and/or water-absorbing, poly(acrylic acid), poly(ethylene oxide), poly(acrylamide), hydroxypropyl cellulose, other polymers or substances used in diapers and/or incontinence pads, etc., and their salts (such as ammonium, sodium, etc.) and derivatives thereof Most preferred examples of swellable materials are swellable hemostatic substances including the following: poly(acrylic acid); polyacrylamide polyacrylamide (crosslinked); poly(acrylic-co-acrylamide) crosslinked (such as N, N-methylene bis-acrylamide crosslinked); crosslinked and modified polyacrylamide; polyhydroxyethyl methacrylate) PHEMA; hydrogels based on poly(vinyl alcohol) (PVA); alginate based hydrogels; HEM-co-acrylic acid-co-sodium acylate copolymeric hydrogels; isopropylacrylamide-co-acrylic acid-co-sodium acrylate hydrogels; and gelatin gels. Some polymer structures are shown in Table 2, below.[0045]

TABLE 2


Examples of absorbent polymers

Polymer	Structure


Poly(acrylic acid) (linear)

Polyacrylamide Polyacrylamide (Crosslinked) (linear)

Poly(acrylic-co-acrylamide) crosslinked (N,N-methylene bis- acrylamide crosslinked) (linear copolymer structure)

Crosslinked and modified Polyacrylamide
	X = various groups

Poly(Hydroxyethyl methacrylate) PHEMA (linear)

Hydrogels based on Poly(vinyl alcohol) PVA (linear)

As to the polymer size, preferable to use are polymer fibers of diameter about 10 microns or less, most preferably 1 micron or less. That small-diameter polymer fibers are particularly preferred may be seen by considering that, for a gel fiber, the contraction rate t is equal to a contraction rate constant c times the square of the diameter; this relationship may be used to evaluate particular polymer fibers (such as fibers of particular diameters) for whether they have rapid swelling kinetics. For example, for polyacrylamide, c is approximately 2×10[0046]⁹s/m²and therefore polyacrylamide gels with a diameter of 1 cm take about 2.5 days to swell, while micron diameter polyacrylamide fibers take milliseconds. See E S Matsuo, T Tanka, “Kinetics of discontinuous volume-phase transition of gels,” J Chem Phys, 89:1988 (1988).

For formulating polymers useable in the invention, preferably electric field-mediated polymer processing is used, most preferably with electrospraying and/or electrospinning. J Stetzel, G L Bowlin, K Mansfield, G E Wnek, D G Simpson, “Electrospraying and electrospinning of polymers for biomedical appliations, poly(lactaic-co-glycolic acid) and poly(ethylene-co-vinylacetate), Proc. SAMPE Conf., Boston, November 2000; D H Reneker, I Chun, “Nanometer diameter fibers of polymer produced by electrospinning,” Nanotechnology, 7:216-223 (1996). Electrospinning may be used to afford small diameter (i.e., 10 microns or less) hydrogel-forming polymer fibers having rapid swelling kinetics.[0047]

Starting materials suitable for electrospinning or electrospraying include elastomeric materials such as thermoplastic elastomers, such as segmented polyurethanes, ethylene-vinylene acetate (EVA) copolymer, etc. Biocompatible starting materials (such as EVA copolymer) are particularly preferred, and biocompatible starting materials that serve as a host for the delivery of a wide variety of small and large therapeutic molecules (such as EVA copolymer) are most preferred. J Folkman, R Langer, “Polymers for the Sustained Release of Proteins and Other Macromolecules,” Nature, 263:797 (1976). Although theoretically non-biocompatible materials could be used if enclosed in an expandable impermeable membrane (such as a syringe port), such a course is not preferred and to be avoided when the staring materials are to be used to formulate a system for wound treatment or other use on or in a patient.[0048]

As shown in FIG. 1A, an apparatus for an electrospraying or electrospinning system comprises a[0049]

syringe pump

100 for pumping a starting material solution or melt100A to be sprayed or spun, a high voltage system99 (such as a 15 kV system), a collector (ground)electrode98, and asource electrode97. The starting material solution or melt100A is preferably confined in any material formed into a nozzle with various tip bore diameters (such as a disposable pipette tip), with a verythin source electrode97 immersed in it. Thecollector98 can be a flat plate, wire mesh, rotating metal drum or plate on which the polymer is wound, etc. Thesolution100A to be spun or sprayed can be doped with various substances, such as, in the case of electrospun fibers, doping with various substances that can be released from the electrospun fibers. The electrospinning process preferably is continued until a mat accumulates (such as an EVA mat) of approximate dimensions as desired, such as on the order of mm by mm, or cm by cm by length and width, and micrometers to millimeters for thickness.

Additionally, swellable materials may be obtained commercially, such as alginate based hydrogels; HEMA-co-Acylic acid-co-Sodium acylate copolymeric hydrogels; poly(vinyl alcohol)/poly(acylic acid) hydrogels; isopropyylacrylamide-co-acrylic acid-co-sodium acrylate hydrogels; gelatin gels; etc.[0050]

When a polymer is used as the swellable material, the polymer may be uncrosslinked or crosslinked, preferably crosslinked. Crosslinking can be accomplished during polymerization with the use of polyfunctional monomers such as bisacrylamide, or by treatment of the polymer with ionizing radiation (e.g., □-radiation). Where electrospinning is carried out from solution or the melt using un-crosslinked polymers, preferably the polymer is treated with ionizing radiation.[0051]

The swellable material may be provided for use with a leaking material in a variety of forms, such as a mat of a swelling material, a swelling material contained within a shell or membrane, a swelling material dispensed from a tube or aerosol, etc. The form used may be selected based on the characteristics of the leak to be treated, the likely treatment setting, etc.[0052]

In the case of wound treatment, especially high-pressure wound treatment, the swellable material preferably is contained within a biocompatible, hemocompatible shell or membrane that permits the leaking liquid to pass through the shell or membrane to reach the swellable material. The shell or membrane is selected with regard to the leaking material (such as blood), the swellable material, and any other treating material (such as clotting promoters, antibiotics, analgesics, etc.) disposed within the shell or membrane. For selecting a shell or membrane, preferably, the shell or membrane is porous, elastic, provides stiffness as the hydrogel inside swells, and/or allows easy ingress of the particular leaking material (such as blood), and most preferably meets all of these characteristics. Elastomeric polymers and hydrophilic, expansile polymers are particularly preferred as shells or membranes as they typically increase in stiffness when stretched due to chain orientation. Such stiffening of the shell upon swelling of the interior hemostatic substance or article is desirable for generating back pressure. Preferably the to-be-used membrane is formed as a relatively flat bag, with relatively little unoccupied space around the swellable material. Loose-fitting placement of the swellable material within the membrane is preferred, corresponding to the expansion geometry. Namely, as the membrane limits the material expansion, a too-tight between the swellable material and the membrane is not desired because expansion of the membrane would be impeded. Namely, if membrane expansion is limited, correspondingly the amount of pressure that the membrane is able to put on its surroundings (such as a bleeding wound) is limited. The membrane preferably is non-leaking with regard to the swellable material, and, where a polymer is used as the swellable material, polymer leakage may be minimized by crosslinking the outermost portions of the polymer matrix to the membrane.[0053]

When a membrane is used for enclosing the swellable material, preferably the membrane is perforated. Pore sizes are such as to limit the leakage of polymer; the pores can increase with swelling because the size of the polymer inside increases as it binds the water, permitting more blood/water to enter and bringing about equilibrium. The membrane is not required to be completely uniform in its characteristics, and may be customized. For example, where the membrane is perforated, most preferably the perforations are relatively large and numerous on the part of the membrane that is to contact the bleeding (or other leaking material), so that exiting blood and other liquid may enter the membrane and activate the swellable material so that the swellable material swells and exerts a backpressure. It will be appreciated that if the membrane where it contacts the wound is resistant to the exiting blood and liquid and does not permit their entry, they will find an alternate path, i.e., traveling around the resistant membrane and exiting the wound; thus, a too-resistant membrane on the wound side is to be avoided as the swellable material would not be swelled.[0054]

Customizing the membrane on the non-wound side (i.e., the dressing side or medic side) may include features to retain the swelled material, blood, liquid, etc., such as non-perforation, reinforcement of the membrane, coating, etc. It will be appreciated that on the non-wound side, it is not desired that blood, body fluids, or other materials escape. Where a customized membrane with a wound-side and non-wound differential is used, the person to be applying the membrane-enclosed swellable material will require training and/or specific markings on the membrane are included. In determining whether to customize a membrane or to provide a unitary membrane, there may be considered the training of the person who will administer the membrane-enclosed swellable material, whether the membrane can be marked to direct the person administering the swellable material which side to place into the wound, etc.[0055]

To the hemostatic substance or article and/or to the shell, there may be added further substances, such as a clot-promoting substance (such as thrombin, preferably lyophilized thrombin). Including a clot-promoting substance in the shell advantageously promotes blood clotting around the periphery of the shell. Preferably, a concentration of the clot-promoting substance is one that speeds clotting without clogging the swellable material with clot.[0056]

It will be appreciated that, until ready for use, the swellable material must be kept away from materials which may cause it to swell. For example, in the case of a swellable material intended for use with blood and aqueous materials, the swellable material must be kept dry.[0057]

The invention also provides certain devices (such as medical devices), especially those comprising a swellable material (as mentioned above) within a shell (as mentioned above). Most preferable devices are those such as that of FIGS.[0058]4A-4B, FIGS.5A-5B and FIGS.6A-6C. As shown in FIG. 4A, before exposure, a device1 of which the exterior is amembrane2 is relatively small in size. FIGS. 5A and 6A are respective molecular-scale versions corresponding to FIG. 4A, with somemolecules3 constituting the swellable material shown. (Only a fewswellable material molecules3 are shown for simplicity; it will be appreciated that generally a device comprises a large population of molecules3). Before the device has been exposed to a liquid, themembrane2 is loose and there is avoid4 inside the membrane2 (FIG. 5A).

As shown in FIGS.[0059]6A-6C, a device comprising aswellable material3 within amembrane2 is contacted with a leaking material5 (such as blood) and the leak (such as a wound) is enclosed with an enclosure material6 (such as a dressing).

[0060]

Membrane

2 on thewound side2Y permits leaking molecules (such as blood molecules, water, etc.)5 to pass into the interior of the device, and that as such blood molecules, water andother leaking molecules5 come in contact withswellable material molecules3, the blood and other water-containingmolecules5 bond to themolecules3 and remain inside the membrane, causing the membrane to expand. At a certain point expandedmembrane2A has reached its maximum expansion for the pressure being applied by the leakingmolecules5. Leakingmolecules5 inside themembrane2A cannot readily exit themembrane2A on thewound side2Y becausemore leaking molecules5 are entering at thewound side2Y of themembrane2A. While some leakingmolecules5 may escape through expandedmembrane2A at thedressing side2Z of themembrane2A, the relatively greater number of leakingmolecules5 that have been retained within in the device and within the wound should be appreciated. Additionally, themembrane2 on thedressing side2Z during production may have been reinforced or treated to be relatively less porous or less perforated than on thewound side2Y.

As the device is used in a bleeding wound, the[0061]

swellable material

3, the leakingmolecules5 contained within themembrane2A, themembrane2A (including themembrane2A on thewound side2Y and on thedressing side2Z) together and respectively act as a barrier to leakingmolecules5 that are newly approaching themembrane2A on thewound side2Y, so that where leakingmolecules5 earlier had encountered no or little force blocking their exit, they encounter some back-pressure (FIG. 6B) as the device operates and then as the device is maximally activated, they encounter pressure equalization (FIG. 6C).

During exposure to a liquid, device[0062]1 accepts additional molecules andmembrane2 expands, forming expandeddevice1A (see FIG. 4B) of which the exterior is expandedmembrane2. Such expansion is possible because a swellable material within the device controllably swells when exposed to aqueous solutions (such as found in a bleeding wound), with the desired result of the expansion being to generate a back pressure. When a medical device containing a swellable material is introduced into a bleeding wound, and the wound and device enclosed together, bleeding can be stopped or at least reduced by the back pressure generated by the device.

An exemplary device[0063]1 according to the inventive is a clotting-promoter containing device, such as a thrombin-containing device. An example of using a clotting-promoter containing device may be appreciated with regard to FIGS.9A-9E. In FIG. 9A is shown a healthy blood vessel7 (such as a vessel having a typical pressure of T=90 mmHg). Thehealthy blood vessel7 suffers injury and becomes disruptedblood vessel7A (FIG. 9B) having awound8. In FIG. 9C is shown moving a clotting-promoter containing device9 (such as a thrombin-containing device) towards the bleedingwound8. In FIGS. 9A, 9B and9C, arrows show the direction in which blood travels. As shown in FIG. 9D, the device9 is inserted directly into the bleeding wound8, and covered with adressing6. Once the device9 is provided into the bleeding wound8, blood begins to enter the device9 and to contact thedressing6.

After the device[0064]9 has been in thewound8 held by the dressing6 for a time (such as about three minutes), the device will have expanded and will have released clotting-promoters, with thewound8A containing clotting promoters, as shown in FIG. 9E.Expanded device9A as a result of its expansion exerts pressure on its environment, namely on the patient's blood. In addition to the pressure exertion effects provided by expandeddevice9A, the bleeding wound8A also experiences clotting promotion from the clotting promoters released from thedevice9,9A.

As the expanded[0065]

device

9A continues to expand (see FIG. 9F), such as at about four minutes after device insertion, the more-expandeddevice9B will take up more space in the wound. As time progresses (see FIG. 9F), such as about four minutes pass since insertion of the device9 into the bleeding wound, further-expandeddevice9B exerts an equalized pressure on its surroundings in thewound8A, and a pressure equilibrium is reached. As the clotting promoters take further effect, clottedregions10 are formed. The equilibrium situation of FIG. 9F is maintained. Advantageously, the expanding

device

9,9A,9B reduces and stops blood loss. In this particularly preferred inventive embodiment shown in FIGS.9C-9F, direct pressure application inside the wound is combined with clotting promotion to stop blood loss from a penetrating wound in as little as 3 or 4 minutes, or even less.

FIGS.[0066]9C-9F show a

device

9,9A,9B being used to treat a bleeding wound, with the fresh device9 slightly smaller than thewound8 into which it is being placed. When selecting a device size for inserting into a bleeding wound, it is desired that the expandeddevice9B be of a volume at least equal, preferably greater, than the wound. Thus, when confronted with awound8 for treatment, it is desirable to use a device9 that will expand into an expandeddevice9B of greater volume than the wound to be treated. Devices9 of different staring size may be provided. Also, depending on the swellable material used, expandeddevices9B of different volumes may be provided.

Further, combinations of two or more devices (such as device[0067]9) may be used for treating a bleeding wound, such as treating a relatively large penetrating wound with two or more devices (which may be the same or different). In determining how many devices9 to use, or what expandeddevice9B may be desirable for a particular bleeding wound to be treated, it is preferred to insert into the wound a higher direct-pressure application capability than may be needed (such as to use more devices9 or a device9 having the potential of a larger-volume expandeddevice9B than may be needed to stop bleeding), than to insert into the wound insufficient direct-pressure application capability to stop the bleeding.

In the case where an initial application of direct pressure in the wound (such as insertion into the wound of a first device[0068]9 that expands into expandeddevice9B) only reduces bleeding but is insufficient to stop bleeding, further direct pressure in the wound (such as insertion into the wound of a follow-up device) may be applied.

When bleeding stops after insertion of a device[0069]9 into a bleeding wound, expandeddevice9B may be permitted to remain in the wound or may be removed. Whether to remove the expandeddevice9B or not may be based on factors such as need for access to an internal area for surgery, etc. Preferably thedevice9B is left in the patient unless a reason appears for removing thedevice9B.

In using the invention, formulations are desired that promote clotting at a rate of preferably about less than one minute, with relatively faster clotting being preferred. Clotting is desired to proceed apace with the swelling, with clotting to be complete as expansion is complete. Promoting more rapid clotting raises the possible complication of clotting before the device swells sufficiently to develop adequate back pressure. For a device comprising a membrane-encased swellable material, approximate clotting rate can be provided by the amount of hemostatic agent and/or amount of clotting promoter used, and/or by the size and amount of pores in the membrane.[0070]

For the direct pressure useable in the invention, another technique for generating direct pressure comprises filling (such as pneumatic filling, etc.) of a bladder, most preferably, a bladder comprising a membrane enclosing a swellable material wherein the swellable material swells on contact with the leaking material (such as blood in a bleeding wound). An exemplary filling process according to the invention is shown in FIGS.[0071]10A-10B, As shown in FIG. 10A, a device14 (which may be device9) is provided with asyringe port13 for receiving a syringe11 (such as a syringe containing a volume of clotting promoter (such as thrombin) or other biocompatible material; a syringe containing air; a syringe containing water or another liquid, etc.). An initial-settingpressure monitor12 is provided. Upon depressing the syringe plunger1Z, the contents of thesyringe11 are transferred through thesyringe port13 and thedevice13 is inflated. As shown in FIG. 10B,depressed syringe plunger11Y corresponds to activated pressure monitor12A. Theinflated device14A by virtue of its greater volume provides direct pressure on its surroundings (shown by arrows). Thedevice14A may be inflated entirely due to pneumatic filling, or may be inflated by pneumatic filling combined with one or more other inflating methods (such as swelling of a swellable material).

A filler according to the invention may be separable from, or attached to, the device into which it is inserted. The device into which the filler is inserted may be a bladder with or without a swellable material contained therein, such as a bladder comprising a membrane as mentioned herein. As preferred examples of a bladder may be mentioned an elastic non-permeable bladder, an impermeable bladder, a permeable membrane, singly or in combinations thereof etc.[0072]

A device according to the invention optionally may comprise a layered system, such as a layered system of membrane(s) (such as a permeable membrane), bladder(s) (such as an impermeable bladder), membrane contents, and/or bladder contents. An exemplary layered[0073]

system

15 is shown in FIG. 11, comprising an impermeableexpandable bladder16 inside apermeable membrane17. Theexpandable bladder16 may be expanded by adding water, air, etc., such as addition throughsyringe port13 usingsyringe11. Between themembrane17 and thebladder16 no contents are required but most preferably are includedcontents18 comprising one or more of a swellable material (such as an absorbent polymer), a clotting promoter (such as thrombin), antibiotics, analgesics, anesthetics, singly or in combination, etc. Ascontents18, a swelling material preferably included, most preferably a swelling material including an absorbent polymer.

A layered[0074]

system

15 preferably may be used by, once the layeredsystem15 is placed in a bleeding wound, inflating or expandingbladder16. The expansion ofbladder16 applies force to thecontents18 in the direction of moving thecontents18 towards themembrane17. Where a swellable material is included incontents18, the swellable material preferably is treated (such as by crosslinking) to minimize passage of the swellable material out of themembrane18. Where a clotting promoter (such as thrombin), antibiotics, analgesics, and/or anesthetics are included incontents18, such materials are provided in a form to maximize their passage through themembrane18 and to the exterior of thesystem15, and their expulsion from thesystem15 is aided by the expansion of thebladder16 and/or swelling of any swellable material incontents18.

The inventive methods and devices are particularly usable by a combat medic in treating bleeding wounds such as combat wounds. As to early treatment of combat wounds, it will be appreciated that the combat medic is a skilled individual, and may readily use the invention Inventive methods and devices also may be used by less skilled or relatively unskilled individuals in treating bleeding wounds.[0075]

Advantageously, the invention provides the treatment paradigm of saving the patient without compromising limb salvage. An acute treatment is provided for both civilian and military medical treatment of penetrating wounds, in human and veterinary medicine. The wounds that may be treated include wounds suffered by human patients and by animals; battlefield injuries and civilian injuries; etc. The invention advantageously stops bleeding without producing pressure injury or ischemic damage. By retaining the patient's blood, the amount of transfused blood is reduced, and the risks associated with transfusion are correspondingly reduced.[0076]

While particular mention has been made herein of the invention's applicability for treating penetrating injuries, external wounds are treatable using the present invention, such as by applying (e.g., self-applying, medic-applying, etc.) a wound care dressing comprising a swellable material to the external wound. Where an external wound cannot receive immediate definitive treatment, application of a wound care dressing according to the invention provides a preferred holding treatment. A wound dressing according to the invention promotes hemostasis, prevents infection, and/or relieves pain, delivering one or more features in a relatively quick time frame. The external wound dressings may be self-administrable. A exemplary system according to the invention for treating an external wound is shown in FIG. 12, with the system comprising a swellable material[0077]19 (such as an absorbent polymer) disposed behind a porous membrane20 (such as a telfa pad) to be placed in contact with the toe-treated external wound. To theswellable material19 optionally may be added one or more of a clotting promoter (such as thrombin), an antibiotic, an analgesic, an anesthetic, etc. An impermeable material21 (such as an impermeable plastic) is provided for avoiding contact of theswellable material19 and/or themembrane20 with the air, etc. A fastener system is provided attached to theimpermeable material21, with a fastener system comprising anelastic fastener22 and aVelcro material23 being preferred. A fastener system (such as a Velcro-free adhesive fastener system, etc.) may be provided depending on the size and/or location of the wound-to-be treated.

While much discussion has been provided of the invention's use in connection with wounds, especially penetrating wounds, and limbs, the invention may be extended to other forms of bleeding (such as intra-abdominal and intra-pleural), including bleeding that otherwise would be difficult to treat (especially in the acute setting). The device is placed in the wound, expanded, and held in place (at least initially) by mechanical pressure.[0078]

The invention further provides a drug delivery system (such as a time released drug delivery system), usable in the presence of a wound (such as by insertion into the wound) or absence of a wound (such as by ingestion, surgical implantation, etc.). Such a drug delivery system comprises a swelling material and at least one drug (such as a hemostatic agent, antibiotic, analgesic, etc.). A swellable material (such as a polymer system) may be used as a drug delivery system, such as to simultaneously enhance hemostasis, prevent infection and/or provide pain relief to acute non-penetrating injuries. E.g., such a drug delivery may be provided as a self-administered dressing (such as an acute dressing). Advantageously, such a self-administered dressing may prolong the “golden period” between injury and treatment.[0079]

While much has been said above about bleeding and medical applications of the invention, it will be appreciated that the invention provides leakage control systems extending beyond the medical and bleeding areas, such as to pressure equalization techniques for a quick temporary plug for any type of liquid high pressure leak (such as a plumbing leak, a boating leak, a container or tanker leak, etc.). Any system where even temporary drops in pressure due to leakage is a significant problem may benefit from the inventive pressure equalization methods. Leaks may be treated by inserting a swellable material into the leak, preferably while maintaining the swellable material in the leak. Where the leak does not involve treating a patient, less biocompatibility may be acceptable than for treatment of wounds, wound dressings, etc. The swellable material is selected based on the leaking liquid to which the swellable material will be exposed. Where the leaking liquid is water or water-based, the water absorbent swellable materials mentioned above for wound treatment may be used.[0080]

The invention also provides a screening apparatus for evaluating the efficacy of a particularly formulation of a swellable material (such as a polymer) when in contact with a particular leaking material (such as a watery liquid), with an exemplary screening apparatus that may be used to screen substances for pressure development during swelling in a confined space shown in FIG. 3. Substances (such as polymers of varying diameters) may be tested-for compaction, flexibility and ability to rapidly swell in the presence of liquid. The ability of a substance to produce pressure in a confined space may be evaluated using a screening apparatus, such as the exemplary apparatus shown in FIG. 3. With reference to FIG. 3, a receptable[0081]200 (such as a petri dish) is provided for receiving a to-be-tested substance202, such as a to-be-tested substance is contained in a highly perforated flexible membrane201 (such as thin latex). The to-be-tested substance is placed in thereceptable200 and secured there by a wrap203 (such as by a cling gauze wrap), optionally including other materials such as agauze pad205. Liquid to be poured onto the upper surface of the to-be-tested substance is disposed in abathing solution container204. Apressure probe206 is placed between themembrane201 and the wall of thereceptable200. As liquid is poured on the upper surface of the to-be-tested substance, the pressure within the confinedspace207 is monitored by thepressure probe206 hooked to pressure monitor208. A baseline criterion of a certain amount of generated pressure (preferably, 80 mm Hg) in a certain time frame (preferably, within 3 minutes or sooner) may be established.

EXAMPLE 1A

In an example of production by electrostatic spraying (or, more simply, electrospraying), charged droplets are generated at the tip of a metal needle (or pipette with a wire immersed in the liquid) with a several kV dc field, and are subsequently delivered to a grounded target. The droplets are derived by charging a liquid typically to 5-20 kV, which leads to charge injection into the liquid from the electrode. The sign of the injected charge depends upon the polarity of the electrode; a negative electrode produces a negatively charged liquid. The charged liquid is attracted to an electrode of opposite polarity some distance away, forming a so-called Taylor cone at the needle tip. Droplets are formed when electrostatic repulsions within the liquid exceed its surface tension. If the liquid is relatively volatile, evaporation leads to shrinkage of the droplets and an increase in excess charge density, leading to break-up into smaller droplets. This can happen many times prior to reaching the target, thereby affording very small droplets. Relatively dilute polymer solutions deposit as nodules as the result of electrospraying.[0082]

EXAMPLE1B

In an example of production by electrospinning, referring to FIGS.[0083]1A-1B, polymer solutions or melts100A are deposited asfibrous mats100B (rather than droplets as in electrospraying), with the advantage taken of chain entanglements in melts or at sufficiently high polymer concentrations in solution to produce continuous fibers, such as a PEVA deposited from 15 wt % solution in chloroform (see FIG. 2B which is a microphotograph of such a fiber). See Stetzel et al, supra. Electrospinning is believed to be mechanistically similar to electrospraying, with differences being that chain entanglements yield a fiber from the Taylor cone. Moreover, rather than break-up into small droplets, entanglements lead to splaying of fibers into thinner ones, which is a particularly attractive aspect of electrospinning.

EXAMPLE 2A

Poly(acrylamide-co-acrylic acid copolymer was disposed in electrospun ethylene-vinyl-acetate (EVA) copolymer bags of dimensions about 6 cm by 6 cm by about 5 mm thick. The bags were exposed to water, and the bags were weighed as time progressed, with the results shown in FIG. 8A where g water/g polymer is plotted against time (minutes).[0084]

EXAMPLE 2B

A sample was prepared and tested as in Example 2A, except that instead of using poly(acrylamide-co-acrylic acid copolymer, there was used poly(acrylamide-co-acrylic acid copolymer potassium salt). The results are shown in FIG. 8B.[0085]

While the invention has been described in terms of its preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims.[0086]