HK1155676B - Device and method for treating central nervous system pathology - Google Patents

Description

Devices and methods for treating central nervous system pathologies

RELATED APPLICATIONS

This patent application claims priority from U.S. provisional patent application 61/019968 filed on 9/2008 and U.S. provisional patent application No.61/081997 filed on 18/7/2008, which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates generally to devices and methods for treating central nervous system tissue using sub-atmospheric pressure, and more particularly, but not exclusively, to devices and methods for treating brain tissue using sub-atmospheric pressure.

Background

The anatomical, physiological and pathological processes associated with the Central Nervous System (CNS) make CNS tissues unique. Preservation of three-dimensional anatomical and neuronal microdissection relationships (neuronal function is specifically dependent on spatial relationships with other neurons and other supporting cells) and maintenance of a properly oxygenated blood flow and a homogeneous matrix in which neurons survive are critical to the survival and function of central nervous system tissue. Furthermore, the non-regenerative nature of central nervous system cells underscores the need to maximize survival of each possible neuron. For these reasons, the treatment of open and closed space pathologies in the central nervous system is unique.

Among the clinical problems threatening the survival of CNS tissues, the control of central nervous system edema, infection and blood supply is central. The brain responds to trauma and trauma by collecting a large amount of interstitial edema. As the brain is enclosed in a closed space (dura mater and skull), edema causes compression and impairment of the blood flow and nutritional manifestations of the CNS, greatly impairing physiological recovery of the central nervous system and itself often leading to the development of CNS parenchymal damage and death. Currently available treatments for reducing edema include agents that decrease vascular permeability (glucocorticoids: dexamethasone, prednisone, methyl dehydrocortisol), diuretics, mechanical ventricular drainage, cerebral parenchyma resection, and extensive craniectomy. However, disadvantages of these treatments include poor outcomes, drug-induced complications, and inconsistent outcomes.

The need for rapid and effective treatment remains crucial due to the severe consequences and high likelihood of rapid progression of infection and edema in the CNS. Currently, few successful methods are available for treating pathologies affecting intracranial and spinal lumens, CNS parenchyma, and surrounding structures. In other cases where tissue may be treated by changing dressings, the CNS is not suitable for such treatment due to its poor access, uncertain structure, susceptibility to infection and wound development. There is evidence that the long-term consequences of inflammation and immune responses to trauma and other pathologies of the central nervous system are comparable to or greater than that of incipient trauma or injury. The response of the CNS to reduced blood flow secondary to edema results in hypoxia and ischemia/reperfusion-mediated trauma. These traumas lead to the development of neuropathological sequelae that greatly contribute to the development of adverse consequences of craniocerebral injury.

In addition, the brain needs to continuously provide oxygenated blood for function and survival. Irreversible brain damage can occur within three minutes of a complete interruption of blood flow to the brain, although the brain can remain viable and recover from reduced blood flow over a longer period of time. There is evidence that focal areas of the brain can remain ischemic and relatively nonfunctional for several days and still be able to recover. This finding has led to the concept of an ischemic zone called the penumbra or halo zone, which surrounds the irreversible wound area. The second phenomenon is the release of excitotoxins locally released by injured neurons, changes in focal blood flow and edema.

Cerebrovascular disease can be caused by: insufficient blood flow to brain cells is caused by direct trauma to local brain areas due to perfusion depression, vessel rupture, and compression of adjacent tissues. Cerebrovascular disease can result from intrinsic cerebrovascular disease such as atherosclerosis, aneurysm, inflammation, or from distant emboli that enter and become lodged in the cerebral vasculature from elsewhere such as the heart. Stroke is a term defining the neurological trauma that occurs as a result of some of the pathological processes. Cerebrovascular disease, the third leading cause of death in developed countries, is found in 5% of the population over age 65. In addition, it often causes life-long debilitations, failure to work and function in society and homes, and frequent need for nursing home treatment. People with strokes often experience severe injury in their remaining lives.

Progressive stroke or progressive stroke refers to a neurological deficit that develops or changes after an initial event. This is believed to be due to the following reasons: progressive spasm or stenosis of the associated artery, development of cerebral edema around the initial trauma, spread of thrombus due to reduced blood flow or local cytokines released by injured brain cells. Fortunately, there is some communication between blood vessels in the brain called collateral circulation. The supply of blood from these collateral vessels prevents the death of brain cells in the ischemic region.

In the case of intracranial hemorrhage, the hemorrhage is usually initiated from a small mass and increases in volume by pressure stripping, and results in displacement and compression of adjacent brain tissue. Edema in the adjacent compressed tissue around the hemorrhage may lead to a mass effect and worsen the clinical condition by damaging a larger area of brain tissue. Edema in the adjacent brain may cause progressive deterioration, which is usually observed within 12 to 72 hours. Edema occurring within one week after intracerebral hemorrhage generally worsens the prognosis, particularly in the elderly. The tissue surrounding the hematoma is displaced and compressed, but not necessarily fatally damaged. This can be improved by resorption of the hematoma and associated tissue re-establishment of function.

Treatment of these conditions has been disappointing. In some cases, surgical decompression of the hemorrhage may help prevent irreversible compression. Agents such as mannitol and some other osmotic agents can reduce intracranial pressure caused by edema. Under these circumstances, the value of steroids is not yet established, and hyperbaric oxygen has recently been proposed for use.

Thus, although the application of negative (or sub-atmospheric) pressure therapy to wounded skin and subcutaneous tissue has shown improved cure rates over traditional methods (as described in U.S. patent nos. 5645081 and 563243, 7198046 and 7216651 and U.S. published patent application nos. 2003/0225347, 2004/0039391 and 2004/0122434, the contents of which are incorporated herein by reference), there remains a need for devices and methods specifically tailored to the use of the unique tissues of the central nervous system.

Brief description of the invention

The present invention relates generally to devices and methods for treating central nervous system tissue using sub-atmospheric pressure, and more particularly, but not exclusively, to devices and methods for treating brain tissue using sub-atmospheric pressure. According to one exemplary procedure of the present invention, there is provided a method of treating damaged central nervous system tissue using sub-atmospheric pressure, comprising positioning a porous material adjacent (proximate) the damaged central nervous system tissue to provide gaseous communication between one or more pores of the porous material and the damaged central nervous system tissue. In some cases, the porous material may be placed directly over the damaged central nervous system tissue. The porous material may be sealed in situ adjacent the damaged central nervous system tissue to provide an area around the damaged central nervous system tissue (about) for maintaining sub-atmospheric pressure at the damaged central nervous system tissue. A vacuum system can then be operably coupled to the porous material and activated to provide sub-atmospheric pressure at the damaged central nervous system tissue. Subatmospheric pressure may be maintained at the damaged tissue for a time sufficient to reduce edema at the central nervous system.

In another aspect of the invention, an apparatus for treating damaged central nervous system tissue is provided. The device may include a porous bioabsorbable material, such as open-cell collagen, having a pore structure configured to allow gaseous communication between one or more pores of the porous material and the central nervous system tissue to be treated. The bioabsorbable nature of the porous material may avoid the need for a secondary procedure to remove the porous material. The apparatus further comprises a vacuum source for generating a sub-atmospheric pressure; the vacuum source may be placed in gaseous communication with the porous material to distribute sub-atmospheric pressure to the central nervous system tissue. The porous material may have pores small enough to prevent tissue growth therein, at least on selected surfaces of the porous material. Further, the porous material may have pore sizes smaller than the sizes of fibroblasts and central nervous system cells at least on selected surfaces of the porous material, and may have pore sizes larger than the sizes of fibroblasts and central nervous system cells at locations other than the selected surfaces. The pore size of the porous material may be large enough to allow albumin size sized proteins to move therethrough. Additionally, the porous bioabsorbable material may comprise at least one sealed surface to prevent transmission of sub-atmospheric pressure therethrough. The device may also include a cover configured to cover the damaged central nervous system tissue to maintain sub-atmospheric pressure below the cover at the damaged central nervous system tissue.

In use, the present invention can provide a pressure gradient to remove edema from the central nervous system, thereby preserving nerve function and increasing the likelihood of recovery and survival in a state closer to physiological preservation. In turn, a reduction in central nervous system edema can lead to a reduction in intracranial pressure, thereby minimizing the risk of central nervous system damage and herniation. In addition to eliminating edema, the present invention may remove mediators, degradation products, and toxins that enhance the inflammatory and neuropathological response of tissues to trauma in the central nervous system.

The present invention can protect the central nervous system from exogenous infections and contamination and facilitate and maximize healing of intracranial and adjacent structures when the tissue is contaminated with central nervous system abscesses, meningitis, ventriculitis, and brain tissue infections. Central nervous system tissues can also be protected from neighboring infections, such as infections present in sinuses (sinuses) in a subclinical state, in the oral cavity, and other potentially infected cavities (spaces) present in normal human conditions, by increasing blood flow and directly decreasing bacterial load. In addition, the devices and methods of the present invention allow for (prepare) central nervous system tissue to be treated and have a reduced bacterial count to allow for successful secondary treatments (e.g., spacers, bone grafts).

The present invention may also facilitate closure of pathological openings that communicate (communicating) between the central nervous system and the epidural space, for example, between the epidural space and the subdural/epidural and/or subarachnoid space. Likewise, the development of pathological processes can be minimized, and disruption of physiological central nervous system integrity and interference with central nervous system blood flow and nutrition can be minimized.

The devices and methods of the present invention may be used to treat the following conditions: exposure of the central nervous system due to trauma, surgery, infection or any other pathological process; treatment of any chamber and tissue surrounding the central nervous system, comprising: subdural/supradural and intraventricular cavities; treatment of central nervous system parenchymal edema secondary to any cause, including: bleeding, trauma, tumor, infection or any other pathological condition; treatment of increased intracranial and intraspinal pressures for any of the above reasons; and treatment of cerebrospinal fluid pathologies, where the spinal fluid is in pathological communication with any non-anatomical and non-physiological chambers. In addition, the present invention may be used to promote the formation of granulation tissue in areas where central nervous system disruption has occurred, and may be used to control leakage of cerebrospinal fluid. In addition, the modified materials of the present invention may be used to control or close defects existing between the central nervous system, the skin space, the nasal cavity and the sinus cavity.

Drawings

The foregoing summary, as well as the following detailed description of preferred embodiments of the present invention, will be best understood when read in conjunction with the appended drawings.

FIG. 1 schematically illustrates, in partial cross-section, a perspective view of an exemplary apparatus of the present invention showing treatment of a brain injury in situ;

figures 2 and 3 show Magnetic Resonance Imaging (MRI) scans of brain wound control animals not treated with sub-atmospheric pressure;

figure 4 shows a magnetic resonance imaging scan of an 8 hour brain injury animal treated with sub-atmospheric pressure;

figure 5 shows a magnetic resonance imaging scan of a brain trauma control animal not treated with sub-atmospheric pressure;

figures 6 and 7 show mri scans of brain trauma animals treated with sub-atmospheric pressure for 24 hours;

figure 8 shows a magnetic resonance imaging scan of a brain trauma control animal not treated with sub-atmospheric pressure;

FIG. 9 schematically shows in partial cross-section a normal anatomical view of a rat skull, including the brain and surrounding muscles, bones and other tissue;

fig. 10 schematically illustrates, in partial cross-section, a picture 12/26 of the animal of fig. 2 showing areas of blood or fluid expression and accumulation;

fig. 11 schematically shows in partial cross-section a picture 12/24 of the animal of fig. 4 showing the area pressed and covered in place (drain in place) with a porous material;

FIG. 12 schematically illustrates in partial cross-section a picture 12/24 of the animal of FIG. 5 showing a region pressed into place with a porous material;

FIG. 13 schematically illustrates in partial cross-section a picture 12/24 of the animal of FIG. 6 showing the area pressed and covered in place with a porous material;

FIG. 14 schematically illustrates a multilayer porous material of the present invention;

figures 15A and 15B show the lower right portion of the mri scans of figures 5 and 6, respectively, enlarged to show relatively more fluid content in the impacted brain of the non-treated animal;

FIG. 16 shows an axial T2-weighted NMR chart showing the location of NMR spectral voxels (voxels) obtained from the rat brain in vivo;

figure 17 shows the singlet nuclear magnetic resonance spectra obtained from sham operated, wounded, and wounded and treated brains. The metabolites were labeled Ins (inositol), Tau (taurine), Cho (choline-containing compound), Cr + PCr (creatine and phosphocreatine), Glu + Gln (glutamic acid and glutamine), NAA (N-acetyl aspartic acid), GABA (gamma-aminobutyric acid) and Lac (lactic acid)); and

figures 18A and 18B show immunohistochemical analysis of neuronal degeneration and death by nitrotyrosine staining of brain samples harvested 72 hours post-impact with treatment groups exposed to subatmospheric pressure for 72 hours; the dark brown spots are dead and dying cells.

Detailed Description

Referring now to the drawings, wherein like elements are designated by like numerals throughout, the present invention relates to devices and methods for treating damaged central nervous system tissue using sub-atmospheric (or negative) pressure. As used herein, "damaged" tissue is defined to include tissue that is wounded, damaged, or damaged in any other way, e.g., as a result of trauma, disease, infection, surgical complications, or other pathological processes. Referring specifically to FIG. 1, an exemplary configuration of a sub-atmospheric central nervous system treatment device 100 of the present invention is shown. The sub-atmospheric central nervous system treatment device 100 can include a porous material 10 positioned adjacent to the damaged central nervous system tissue (e.g., such as brain tissue 9) for delivering and distributing sub-atmospheric pressure to the damaged brain tissue 9. The sub-atmospheric central nervous system treatment apparatus 100 can also include a vacuum source 30 in gaseous communication with the porous material 10 through the tube 20 to provide sub-atmospheric pressure to the damaged brain tissue 9.

Turning now to FIG. 1 in more detail, an exemplary configuration of a sub-atmospheric central nervous system treatment device 100 of the present invention is shown in situ in a sectioned animal having surrounding tissue. The illustrated tissues include skin 2, muscle tissue 4, skull 5, and damaged brain tissue 9, with a portion of the skull 5 missing from the damaged brain tissue 9 to provide access to the damaged brain tissue 9 (cement treatment access to the damaged brain tissue 9). The porous material 10 may be placed in a space (space) adjacent to the brain tissue 9 to provide sub-atmospheric pressure treatment to the damaged brain tissue 9. Such treatment may include, for example, lowering intracranial pressure, reducing edema, removing harmful fluids or unwanted compounds, and the like.

The porous material 10 may have pores large enough to enable removal of unwanted compounds from the brain tissue 9 and surrounding space/tissue or spaces and may have pores small enough to impede or prevent ingrowth of brain tissue into the porous material 10. In this regard, the pore size may be large enough to allow transport of materials such as cytokines, toxic substances or other mediators (mediators) out of the brain tissue 9 to reduce such materials to clinically desirable levels. For example, the pore size may be large enough to allow albumin to pass through the porous material 10. Furthermore, the pores may be small enough (at least where the porous material 10 is in contact with the brain tissue 9) to stop or prevent tissue growth into the porous material 10 such that the porous material 10 does not adhere to the brain tissue 9 and does not cause damage to the brain tissue 9 when removed. For example, the pore size may be smaller than the size of fibroblasts and brain cells in order to minimize ingrowth and avoid overproduction of granulation tissue that may interfere with brain physiological function.

The porous material 10 may be homogeneous in composition and/or morphology, or may have relatively large pore sizes within the porous material 10 or at any location where the porous material 10 does not contact the brain tissue 9. For example, the porous material 110 may include a non-ingrowth layer 112 having a pore size small enough to prevent tissue growth therein when placed in contact with the brain, and may have an additional layer 114, the additional layer 114 being a different material having a relatively larger pore size (e.g., larger than fibroblasts and brain cells) that is in contact with the non-ingrowth layer 112 but not in contact with the brain, as in fig. 14. For example, the porous material 10 may have a pore size large enough to promote the formation of granulation tissue at other tissues in the space surrounding the damaged brain tissue 9. In addition, the porous material 10 may include one or more sides or faces of the porous material 10 that are sealed to prevent the transmission of sub-atmospheric pressure therethrough and that simultaneously have at least one face through which sub-atmospheric pressure may be transmitted. This configuration of the porous material 10 may provide preferential treatment of tissue on one side of the porous material 10 without treating tissue on the sealed side. Such a porous material 10 may be used, for example, when placed on the brain parenchyma at the interface of the brain parenchyma and the ventricular cavity. The host substance may be treated by a face on one side of the porous material 10; while one or more sealing surfaces of the porous material 10 do not drain the ventricular chambers and thus do not remove fluid from them. Similarly, a porous material 10 having a permeability that varies along its length will allow sub-atmospheric pressure to be applied to the brain parenchyma without promoting sub-atmospheric pressure in the cerebrospinal fluid (CSF) cavities, such as the sulcus, ventricles and subarachnoid cavities, and therefore, without preferentially removing cerebrospinal fluid from those cavities.

The porous material 10 may comprise a material that is bioabsorbable or that does not degrade harmlessly over time, such as collagen, or a material that needs to be removed after providing sub-atmospheric pressure therapy. The porous material 10 may be a material that can easily conform to the surface of the brain or chamber wall without excessive packaging and can achieve such a requirement without excessive finishing and shaping. For example, the porous material 10 may be provided in the form of a band or chain, which may be placed on or in the brain/cranium. The belt or chain may be of sufficient strength so as not to break or leave a residue when it is pulled from the head. For example, the bands or chains of porous material 10 may be gradually and gradually removed as the cavities in which porous material 10 is disposed are filled (fil). Thus, the porous material 10 may be in the form of a band or strip or chain (e.g. 5 x 200 mm) with sufficient elasticity that it can be pulled out of the aperture of the skull 5 after treatment without the need for a secondary operation. The porous material 10 may be a flexible sheet that can be folded and altered to fit into a particular area of the central nervous system, such as directly into the brain parenchyma or the ventricular system following trauma.

Additionally, the porous material 10 may be sufficiently compliant so that it does not compress the injured brain to the extent that it interferes with brain function. However, the porous material 10 may be sufficiently rigid so that it does not collapse so as to pull or deform the brain to a degree that may interfere with brain function. Exemplary materials that may be used in the porous material 10 may include open cell collagen materials, polyglycolic and/or polylactic acid materials, synthetic polymers, flexible sheet-like webs, open cell polymeric foams, foam segments, porous sheets, polyvinyl alcohol foams, polyethylene and/or polyester materials, elastin, hyaluronic acid, alginate, polyglycol citrates, polyhydroxybutyrate, polyhydroxyfumarate, polytrimethylene carbonate, polyglycerol sebacate, aliphatic/aromatic polyanhydrides, or other suitable materials and combinations thereof, any of which may be fabricated by, for example, electrospinning, casting, or printing. Such materials include a chitosan solution (1.33% mass/volume of a 2% acetic acid solution, total volume 20mL) that can be injected into a mold of appropriate size. The solution was then frozen at-70 ℃ for 2 hours, then transferred to a lyophilizer and vacuum applied for 24 hours. The material may be crosslinked by 2.5% to 5% glutaraldehyde vapor for 12 to 24 hours (or by ultraviolet radiation for 8 hours) to provide a cast porous material 10.

In addition, the porous material 10 may be prepared by casting Polycaprolactone (PCL). Polycaprolactone can be mixed with sodium chloride (1 part caprolactone to 10 parts sodium chloride) and placed in a sufficient amount of chloroform to dissolve the components. For example, 8mL of the solution may be poured into a container of appropriate size and shape (contained) and allowed to dry for 12 hours. Then, sodium chloride may be precipitated in water for 24 hours.

It is also possible to use electrospun materials to prepare porous material 10. One exemplary formulation and method of making an electrospun (electrospun) porous material 10 is made using a combination of 76%: 4%: 20% by mass type I collagen: 6-Chondroitin Sulfate (CS): poly 1, 8-octanediol citrate (POC). Two solvents were used for collagen/CS/POC. CS was dissolved in water and collagen and POC were dissolved in 2, 2, 2-Trifluoroethanol (TFE). Then a solution of 20% water/80% TFE solution (v/v) was used. For electrospinning, the solution containing the collagen: CS: POC mixture was placed in a 3mL syringe fitted with an 18Ga needle. The solution was fed to the tip of the needle at a rate of 2.0 ml/hr using a syringe Pump (New Era Pump Systems, Wantaugh, N.Y.). A Voltage of 10-20 kv is supplied by a High Voltage Power Supply (HV Power Supply, Gamma High Voltage Research, or mond beach.fl) and applied between a needle (anode) and a grounded receiver (cathode) that are 15-25 cm apart. The material was then crosslinked with glutaraldehyde (grade II, 25% solution) and heat polymerized (80 ℃ C.) for 48 hours. It is also possible to start electrospinning the type I collagen porous material with a solution of collagen of initial concentration 80 mg/ml in 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol (HFP) and then to use the same electrospinning conditions as the collagen: CS: POC combination.

Another method for creating the porous material 10 is to use thermal inkjet printing techniques. Bioabsorbable materials such as collagen, elastin, hyaluronic acid, alginate and polylactic acid/polyglycolic acid copolymers can be printed. For example, the solution can be printed by dissolving type I collagen (Elastin Products co., Owensville, MO) in 0.05% acetic acid and then diluting to 1 mg/ml with water, and in the same way, 1 mg/ml of an aqueous solution of sodium alginate (Dharma tracing co., san raphael, CA) can also be printed. A mixture of type I collagen (2.86 mg/ml in 0.05% acetic acid) and polylactic acid/polyglycolic acid (PURAC America, Blair, NE) (14.29 mg/ml in tetraethylene glycol (Sigma Aldrich, st. louis MO)) can also be printed. Hardware from a Hewlett Packard 660c printer, which includes a stepper motor and a toner drum carrier, may be mounted to the platform. The height of the hardware above the platform can then be adjusted for layered printing. The porous material 10 may comprise an MRI compatible material so that magnetic resonance imaging may be performed while the porous material 10 is in place.

Following the description of the delivery of sub-atmospheric pressure to the porous material 10 and distribution to the damaged brain tissue 9, the tube 20 may be connected directly or indirectly so as to be in gaseous communication with the porous material 10 at the distal end 22 of the tube 20. For example, the distal end 22 of the tube 20 may be embedded in the porous material 10 or may be placed over the porous material 10. The distal end 22 of the tube 20 may also include one or more perforations to assist in the delivery of sub-atmospheric pressure to the porous material 10 and the damaged brain tissue 9. The tube 20 may extend through an aperture in the skin and subcutaneous tissue 2, which may be secured around the tube 20 with sutures to assist in providing a seal around the tube 20. The proximal end 24 of the tube 20 may be operatively connected to a vacuum source 30, such as a vacuum pump, to provide a sub-atmospheric pressure that is transmitted through the tube 20 to the porous material 10 and the damaged brain tissue 9.

The vacuum source 30 may include a controller 32 to regulate the generation of the sub-atmospheric pressure. For example, the vacuum source 30 may be configured to generate sub-atmospheric pressure continuously or intermittently; for example, vacuum source 30 may be cycled on and off to provide alternating periods of sub-atmospheric pressure production and non-production. The duty cycle between production and non-production may be between 1 to 10 (on/off) and 10 to 1 (on/off). Alternatively, intermittent sub-atmospheric pressure may be applied by a periodic or cyclic waveform (e.g., a sine wave). The vacuum source 30 may be cycled after the initial treatment (e.g., several times per minute) to simulate a more physiological condition. If desired, sub-atmospheric pressure may be intermittently cycled according to conditions determined by monitoring the pressure in the damaged brain tissue 9. In general, the vacuum source 30 may be configured to deliver a sub-atmospheric pressure between atmospheric pressure and 75 millimeters of mercury (Hg) below atmospheric pressure (e.g., about 20 millimeters of Hg) to minimize the likelihood that the sub-atmospheric pressure will cause damage to the brain parenchyma. (too low a negative pressure may cause blood to flow into the host). The application of sub-atmospheric pressure may promote the elimination of edema from the damaged brain tissue 9, thereby preserving neurological function to enhance the likelihood of recovery and survival under more physiological preservation conditions. In addition, the application of sub-atmospheric pressure may normalize intracranial pressure to a clinically desirable level, may normalize tissue volume and density to a clinically desirable level, and/or may normalize at least one of blood pressure and heart rate to a clinically desirable level. For example, the application of sub-atmospheric pressure may normalize intracranial pressure to a substantially normal pre-injury physiological state, may normalize tissue volume and density to a substantially normal pre-injury physiological state, and/or may normalize at least one of blood pressure and heart rate to a substantially normal pre-injury physiological state.

To assist in maintaining sub-atmospheric pressure at the damaged brain tissue 9, a flexible cover/sheet 50 or rigid (or semi-rigid) cover may be disposed adjacent the damaged brain tissue 9 to provide an area around the damaged brain tissue 9 where sub-atmospheric pressure may be maintained. Specifically, referring to fig. 1, 11, 13, an enclosed region around the damaged brain tissue 9 and the porous material 10 may be defined by adhering the cover 50 to tissue adjacent the damaged brain tissue 9 (e.g., skin 2, 202, 502) to position the cover 50 over the damaged brain tissue 9 and the porous material 10. For example, an adhesive such as fibrin glue may be used to adhere the cover 50 to the skin 2, 202, 502 and/or other suitable tissue. The adhesive may include an auto-polymerizing glue and/or it may be desirable to include a filler to provide the adhesive with a volume large enough to allow the adhesive to conform to the shape of the potentially irregular surface with which the adhesive is in contact. The adhesive may be provided as a separate component or as part of the cover 50 to provide a self-adhesive cover 50. For example, the cover 50 may comprise a flexible self-adhesive sheet comprising a suitable adhesive on one or more surfaces thereof.

Sub-atmospheric pressure may be transmitted under the cap 50 by the fit between the cap 50 and the tube 20. Specifically, the cap 50 may include a vacuum port connecting the distal end 22 of the tube 20 to provide gaseous communication between the tube 20 and the space below the cap 40 above the damaged brain tissue 9. Alternatively, the cap 50 may contain a passthrough 52 through which the tube 20 passes to place the distal end 22 of the tube 20 in and gaseous communication with the space below the cap 50 above the damaged brain tissue 9, as shown in fig. 1. In addition, the cover 50 may also protect the damaged brain tissue 9 from exogenous infection and contamination beyond the protection already provided by the porous material 10 and the sutured skin 2. Likewise, the cover 50 may also protect surrounding tissue from transmission of infections that damage brain tissue 9, such as brain abscesses, meningitis and spinal tissue infections. Alternatively, the cover 50 need not be used and the skin 2 and/or dura may be sutured, stapled or clamped closed to provide an area around the damaged brain tissue 9 where sub-atmospheric pressure may be provided.

In another aspect of the invention, the invention also provides a method of treating damaged brain tissue using sub-atmospheric pressure. Specifically, the method may include positioning the porous material 10 adjacent to the damaged brain tissue 9 to provide gaseous communication between the one or more pores of the porous material 10 and the damaged brain tissue 9. The porous material 10 may be sealed in situ adjacent the damaged brain tissue 9 to provide an area around the damaged brain tissue 9 for maintaining sub-atmospheric pressure at the damaged brain tissue 9. A tube 20 may be connected to the porous material 10 at the distal end 22 of the tube 20, and the porous material 10 may be sealed in situ with suture 7 at the skin 2 and subcutaneous tissue to provide an area around the damaged brain tissue 9 for maintaining sub-atmospheric pressure. Other airtight covers or lids 50 may optionally be placed over the suture sites to facilitate airtight sealing. The method may further include the step of adhesively sealing and adhering the cover 50 to tissue (e.g., skin 2) surrounding the damaged brain tissue 9. The cover 50 may be provided in the form of a self-adhesive sheet 50 which may be positioned over the damaged brain tissue 9. In this case, the step of sealing the cover 50 may include adhesively sealing and adhering the self-adhesive sheet 50 to the tissue surrounding the damaged brain tissue 9 to form a seal between the sheet 50 and the tissue surrounding the damaged brain tissue 9. Additionally, the step of operably connecting the vacuum system 30 in gaseous communication with the porous material 10 may include connecting the vacuum system 30 to a vacuum port of the lid 40.

The proximal end 24 of the tube 20 may be connected to a vacuum source 30 so that a sub-atmospheric pressure can be provided to the damaged brain tissue 9 upon activation of the vacuum system 30. For example, sub-atmospheric pressure may be maintained at about 20 to 75 mm Hg below atmospheric pressure. Sub-atmospheric pressure may be maintained at the damaged brain tissue 9 for a sufficient time to: 1) normalizing intracranial pressure to a substantially normal pre-injury physiological state; 2) normalizing tissue volume and density to a substantially normal pre-injury physiological state; 3) normalizing at least one of blood pressure and heart rate to a substantially normal pre-injury physiological state; 4) reducing cytokines, toxic substances or other mediators to clinically desirable levels; and/or 5) improving cognitive, consciousness, motor or sensory function of the patient, which may be indicated by a Glasgow score (Glasgow score). Furthermore, sub-atmospheric pressure may be maintained at the damaged brain tissue 9 for a sufficient time to prepare the brain tissue 9 for a stage of healing and bacteria count reduction such that a second treatment (e.g., a footplate) may be successfully received.

The method may be used for at least three hours, or may be used for multiple days. At the end of the vacuum treatment, the suture 7 can be removed and the skin 2 reopened. The porous material 10 can then be removed and sewn again to close the skin 2.

Examples

Brain trauma and sub-atmospheric pressure Exposure in rats

Experiment 1

Experiments were performed to develop models of cerebral contusion and vacuum treatment of contused brains. Twelve (12)300 grams of spelt-dow rats (Sprague Dawley rat) were obtained and acclimatized to the living environment. For two of the animals, brain mri scans were obtained before performing any other procedures (Bruker Biospin Horizontal Bore 7Tesla small animal scanner, Ettlingen, Germany). These animals were sedated with isoflurane (2% inhalation) and brain scans were obtained. The animals were allowed to recover from anesthesia and returned to the cages. To create the wound, animals were sedated with isoflurane on the day of surgery (2-2.5% inhalation). The top of the head was shaved and the hair removed with depilatory. A midline incision 1 is made down to the bone 5 as in fig. 1. Removing the right skull, thereby exposing the right half of the brain; the dura mater remained intact. Animals were placed on stereotactic holders on an impactor apparatus (pneumatic (cortical) impact apparatus; AmScien Instruments, Richmond VA). The right forebrain of each animal was then impacted. For the first animal, a rod with a diameter of 3 mm was impacted to a depth of 2.0 mm. (Table 1, No. 1 rat). The trauma was considered to be insufficiently obvious. Attempts were made to increase the severity of the trauma for animal 2. The second animal was impacted into its brain to a depth of 2.5 mm with a 6 mm diameter rod. (Table 1, No.2 rat). The trauma is considered to be too severe. For the remaining animals, the right forebrain was impacted to a depth of 2.0 mm with a 6 mm diameter rod. (Table 1, No. 3-12 rats). For two animals that had undergone a magnetic resonance imaging scan prior to surgery, the two animals died within 5 minutes after the impact. (Table 1, No. 3 and No. 8 rats).

Two non-treated control animals were successfully challenged and allowed to recover from anesthesia in heated cages. (Table 1, No. 4 and No.5 rats). After 8 hours, the animals were again anesthetized and mri scans were obtained to visualize the degree of swelling and the presence of water (T2 weighted mri images). Two vacuum-treated animals were then successfully impacted and a small piece of polyvinyl alcohol vacuum overlay (VersaFoam, Kinetic Concepts, inc., San Antonio, TX) equal in size to the removed bone was placed over the brain. (Table 1, No.6 and No. 7 rats). Placing a small hole aspiration tube above the cover and below the skin. The end of the tube is cut at an angle and the tube is placed so that the opening of the end of the tube abuts the cover. A side port was cut into the side of the pump-out tube and the tube was placed so that the port was in contact with the foam cover. The tube is extended out of the incision site and the incision is sutured closed. A piece of film cover (Ioban, 3M, St Paul, MN) was placed over the incision to ensure an airtight seal. The animals were recovered from anesthesia and placed in heated cages. And connecting the small-hole exhaust tube with a vacuum source. A low level vacuum of 25 mm hg (i.e., 25 mm hg below atmospheric pressure) was applied to the wound area of both animals for 8 hours. The animals were then re-anesthetized with isoflurane (2% inhalation) and scanned for magnetic resonance imaging. For one of the animals, the animal compressed the wound site when placed in the mri scanner, causing additional but not quantitative trauma to the brain. (Table 1, No.6 rat). Scanning of the animal showed brain tissue extrusion from one side of the vacuum cover.

Two other control animals were successfully impacted and a piece of polyvinyl alcohol vacuum overlay was placed over the removed bone. (Table 1, No. 9 and No. 12 rats). The area of the vacuum covering is larger than the area of the removed bone and extends slightly beyond the periphery of the hole created to expose the brain (1-2 mm). The skin was then sutured closed and the animals were allowed to recover from anesthesia in a heated cage. Subsequently, the animals were again anesthetized after 24 hours and mri scans were obtained. Two other vacuum-treated animals were successfully impacted, placing a larger vacuum cover that extended slightly beyond the periphery of the hole created to expose the brain (1-2 mm). A small bore suction tube extends out of the incision site and the incision is closed by suturing. The suction tube extends caudally out of the incision site parallel to the atraumatic skin. Suture 7 is placed on the neck skin 2 and the aspiration tube 20 is secured to the skin 2 with the suture 7 to prevent the aspiration tube 20 from shifting as the animal moves. (Table 1, No. 10 and No. 11 rats). A small piece of film cover 50 is again placed to ensure an airtight seal. A low level vacuum of 25 mm hg was applied for 24 hours. Then, the animals were again anesthetized and a magnetic resonance imaging scan was obtained. At this point, it was found that the clot blocked the aspiration tube of one of these animals and it was not possible to discern whether vacuum was actually applied to the wound area. (Table 1, rat # 11). Fig. 2-8 show MRI images of rats as indicated in column 5 of table 1, and fig. 10-13 are schematically illustrated in cross-sections of selected pictures of MRI images, where reference numbers ending with "2" (i.e., 102, 202, 302, 502) represent skin, numbers ending with "3" (e.g., 203) represent air pockets, numbers ending with "4" represent muscles, numbers ending with "5" represent skull, numbers ending with "6" represent brain, numbers ending with "8" represent blood or other fluid, and numbers ending with "9" represent brain impact regions. Fig. 9 schematically shows the same views as fig. 10-13 (i.e., skin 402, muscle 404, skull 405, brain 406) using the same numbering convention in section, but it shows a view in the animal prior to performing any of the procedures used in these experiments.

Animal study results showed that control animals showed significant swelling with excess water at wound tissue 109, 309 at 8 hours and 24 hours post-impact. (Table 1, No. 4, No.5, No. 9 and No. 12 rats, FIG. 2, No. 10, No. 3, No.5, No. 12, No. 8). At 8 and 24 hours post-impact (8 and 24 hours of vacuum treatment), the vacuum treated animals exhibited less swelling and less excess water at the wound areas 209, 509. (rats No. 1, 7 and 10, fig. 4, 11, 6, 13, and rat No. 9, fig. 15A versus rat No. 10, fig. 15B). From these results, it was concluded that impacting the rat brain with a 6 mm diameter rod to a depth of 2.0 mm produced a significant degree of swelling after impact, which was more significant at 24 hours than at 8 hours. The application of 25 mm hg vacuum to the brain significantly reduced brain swelling, with the effect of applying 24 hours vacuum 24 hours after impact being particularly significant.

^*The mri scan is a T2 weighted image, with water represented in white.

TABLE 1

Note that:

rat 1-animal of the developmental model, impacted with a small diameter rod (3 mm) -not included in the results.

Rat 2-animals of the developed model, 6 mm diameter plunger produced large wounds at a depth of 2.5 mm, for the rest of the animals the depth was reduced to 2 mm-not included in the results.

Rats were scanned for mri 3-before impact for comparison with post-impact scans, but animals died within minutes after impact.

Rats 4-control animals were subjected to mri scans 8 hours after the impact and showed brain swelling and protrusion at the impact area.

Rats 5-control animals were subjected to mri scans 8 hours after the impact, showing brain swelling and protrusion at the impact area.

Rats 6-vacuum treated animals, bleeding continued before application of vacuum. A small piece of polyvinyl alcohol covering was placed in the cranial cavity. A magnetic resonance imaging scan was performed 8 hours after the impact/treatment. When the animal is placed in the mri scanner, the mri technician pressing/squeezing the brain causes additional trauma to the brain-not included in the results due to human error.

Rats 7-vacuum treated animals, small pieces of polyvinyl alcohol coverings were placed in cranial cavities. A magnetic resonance imaging scan was performed 8 hours after the impact/treatment.

Rats were scanned for mri before 8-shock for comparison with post-shock scans, but animals died within minutes after shock.

Rat 9-control animal, a larger diameter sponge was placed over the defect in the skull, extending beyond the edge of the defect. The skin was sutured over the sponge. The sponge was placed to determine if the sponge located under the sutured skin would be a mechanical barrier to swelling. A magnetic resonance imaging scan was performed 24 hours after the impact.

Rat 10-vacuum treated animal, a sponge of larger diameter was placed over the defect in the skull and extended beyond the edge of the defect. The skin was sutured over the sponge. Immediately after the impact, vacuum was applied for 24 hours, followed by a magnetic resonance imaging scan.

Rat 11-vacuum treated animal, a sponge of larger diameter was placed over the defect in the skull and extended beyond the edge of the defect. The skin was sutured over the sponge. Immediately after the impact, vacuum was applied for 24 hours, followed by a magnetic resonance imaging scan. The clot occludes the tube and it is not possible to determine when the tube is occluded and whether vacuum is actually applied to the brain. Not included in the results.

Rat 12-control animal, a larger diameter sponge was placed over the defect in the skull and extended beyond the edge of the defect. The skin was sutured over the sponge. The sponge was placed to determine if the sponge located under the sutured skin would be a mechanical barrier to swelling. A magnetic resonance imaging scan was performed 24 hours after the impact.

Experiment 2

Cell death following traumatic brain trauma is biphasic, with initial death due to the trauma itself, and then progressive death being a consequence of excitatory amino acid release, lactic acid accumulation, etc. The release of excitatory amino acids (glutamate, aspartate) causes a disturbance in plasma homeostasis via agonist open channels, thus increasing energy demand and increasing lactate production. It has been shown that an increase in glutamate levels correlates with an increase in lactate levels. This increase in lactate reflects an increase in energy requirement during the period of impaired delivery (ischemia) and is inversely related to patient outcome. The production of lactate results in apoptotic neuronal cell death.

In this preliminary study, an 8 mm diameter craniectomy was performed on anesthetized rats 1 mm lateral to the midline between the forehalogen and the herringbone tip. A dural intact controlled cortical impact wound was created using the apparatus described in example 1. The impactor tip had a diameter of 6 mm and an impact depth of 2 mm. The sham group only had craniectomy; shock on non-treatment controls; and the treatment group was impacted and subatmospheric pressure of 25 mm hg was applied for 48 or 72 hours.

24 hours after brain injury, rats were anesthetized with isoflurane and placed inside a Litz-cage volume coil (38 mm id). All MRI and MRS experiments were performed using a horizontal 7T magnet (Bruker Biospin apparatus in example 1). T2-weighted images were obtained using a Rapid Acquisition Relaxation Enhancement (RARE) pulse sequence with an RARE factor of 8. The repetition Time (TR) is 1500 ms, the echo Time (TE) is 41 ms, the Number of Excitations (NEX) is 1, the field of view (FOV) is 4, and the matrix size is 128 × 128.

A point-resolved spectroscopy series (PRESS) was used with a repetition Time (TR) of 2500 ms, an echo Time (TE) of 20 ms, an excitation Number (NEX) of 256, and a cubic voxel length of 4 mm. Variable power radio frequency water suppression with optimal relaxation delay (vapro) is used when metabolite spectra are acquired.

Tissue volume and bulk density of the wounded (impacted) area were calculated from mri scans taken 24 hours after impact, using the third thoracic chamber of the back as a measurement reference. The results are shown in table 2, which shows the tissue volume and bulk density of the wound area in T2-weighted magnetic resonance imaging. The tissue volume and density of the non-treatment-impacted area of the brain were significantly greater than the area in the sham and treatment groups (p < 0.01). The tissue volume and bulk density of the sham and treatment groups did not differ significantly. Other measures of edema are water content. Table 3 shows the water content (wet weight-dry weight/wet weight%) of brain tissue in the treatment groups with/without 48 hours post-surgery/impact. The water content in the treated area was significantly lower than that in the untreated animal area, p < 0.05.

Tissue volume and bulk density

TABLE 2

Water content% (animal number in brackets #)

	Artificial operation group	Trauma-untreated group	Wound-treating group
					78.90(51 right side)	83.36(9)	80.07(10)
	79.79(51 left side)	83.97(14)	80.02(52)
					78.91(53 right side)	83.72(55)	80.20(54)
	79.06(53 left side)
				Mean. + -. standard deviation of the mean	79.17±0.42	83.68±0.31	80.10±0.09

TABLE 3

Fig. 16 shows a T2-weighted MR image from the axial plane, which image shows the localization of MR spectral voxels, wherein the spectral voxels are marked with white boxes. Fig. 17 shows an example of single voxel MR spectra obtained from sham-operated animals (left), untreated animals (middle) or treated animals (right). The spectra show low lactate levels (arrows) in the sham-operated animals, high levels in the untreated animals and lower levels in the treated animals. Table 4 shows all measured metabolites. The level of lactic acid in the sham group area was significantly lower than in the untreated animals. There was no significant difference in lactic acid levels between the sham and treated animals. The lactic acid levels in the treated animals showed a lower trend than in the untreated animals. The remaining metabolites (and p-values) with significant differences are indicated in table 5, where the treated animals did not show significant differences from the sham operated animals.

TABLE 4

TABLE 5

Nitrotyrosine is a marker of cell degeneration and death. Neuronal degeneration and death analysis was completed by immunohistochemical staining of nitrotyrosine in brain samples harvested 72 hours post surgery/shock. The treated animals were exposed to sub-atmospheric pressure for 72 hours. Fig. 18A shows a tissue section of an untreated brain portion, while fig. 18B shows a treated brain portion. The black dots represent cells that are degenerating and dying. More cells are degenerating and dying in the untreated fraction than in the treated fraction, thereby exhibiting therapeutic benefit.

These and other advantages of the present invention will be apparent to those skilled in the art from the foregoing description. Thus, it will be appreciated by those skilled in the art that changes and modifications may be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments described herein, but is intended to cover all modifications and changes within the scope and spirit of the present invention as set forth in the appended claims.

Claims (24)

1. An apparatus for treating damaged central nervous system tissue, comprising:

a porous bioabsorbable material having a pore structure configured to allow gaseous communication between one or more pores of the porous bioabsorbable material and the central nervous system tissue to be treated, the porous bioabsorbable material having pores small enough to prevent tissue growth therein at least on selected surfaces of the porous bioabsorbable material for placement adjacent the damaged central nervous system tissue; and

a vacuum source for generating a sub-atmospheric pressure, the vacuum source being disposed in gaseous communication with the porous bioabsorbable material so as to distribute the sub-atmospheric pressure to the central nervous system tissue to be treated.

2. The apparatus of claim 1, wherein the porous bioabsorbable material comprises open-cell collagen.

3. The apparatus of claim 1, wherein the porous bioabsorbable material comprises polyglycol citrate.

4. The apparatus of claim 1, wherein the porous bioabsorbable material comprises a polyglycolic acid and/or polylactic acid material.

5. The apparatus of claim 1, wherein the porous bioabsorbable material comprises a strip of porous material.

6. The apparatus of claim 1, wherein the porous bioabsorbable material comprises an open-cell foam.

7. The apparatus of claim 1, wherein the porous bioabsorbable material comprises one or more of a synthetic polymer, a flexible sheet-like mesh, and a porous sheet.

8. The apparatus of claim 1, wherein the porous bioabsorbable material comprises polyglycol citrate and collagen.

9. The device of claim 1, wherein the porous bioabsorbable material comprises elastin, hyaluronic acid, or alginate, and combinations thereof.

10. The apparatus of claim 1, wherein the porous bioabsorbable material comprises an electrospun material.

11. The device of claim 1, wherein the porous bioabsorbable material comprises a cast material.

12. The apparatus of claim 1, wherein the porous bioabsorbable material comprises a printed material.

13. The apparatus according to any one of claims 1-10, wherein the porous bioabsorbable material has a pore size smaller than the size of fibroblasts and central nervous system cells, at least on selected surfaces of the porous bioabsorbable material for placement adjacent the damaged central nervous system tissue.

14. The apparatus of any one of claims 1-10, wherein the porous bioabsorbable material has a pore size inside the bioabsorbable material that is larger than the size of fibroblasts and central nervous system cells.

15. The apparatus of any one of claims 1-10, wherein the porous bioabsorbable material has a pore size larger than the size of fibroblasts and central nervous system cells at locations other than the selected surface.

16. The device of any one of claims 1-10, wherein the pore size of the porous bioabsorbable material is large enough to allow albumin-sized proteins to move therethrough.

17. The device of any one of claims 1-10, wherein the porous bioabsorbable material comprises at least one sealed face to prevent the transmission of sub-atmospheric pressure therethrough.

18. The apparatus of any one of claims 1-10, wherein the porous bioabsorbable material comprises pore sizes on surfaces other than the selected surface of the porous bioabsorbable material that are large enough to promote granulation tissue formation.

19. The apparatus of claim 1, wherein the vacuum source comprises a vacuum pump.

20. The apparatus of any one of claims 1-10, comprising a cover configured to cover the damaged central nervous system tissue to maintain sub-atmospheric pressure below the cover at the damaged central nervous system tissue.

21. The apparatus of claim 20, wherein the cover comprises a self-adhesive sheet.

22. The apparatus of any of claims 1-10, wherein the vacuum source is configured to provide a sub-atmospheric pressure of about 25 mm hg.

23. The apparatus of any of claims 1-10, wherein the vacuum source is configured to provide a sub-atmospheric pressure of up to 75 mm hg.

24. The apparatus of any one of claims 1-10, wherein the selected surface of the porous bioabsorbable material is configured to allow gaseous communication between the one or more pores of the porous bioabsorbable material and the central nervous system tissue to be treated.