Abstract:
The invention provides a device for extracorporeal photo-isomerization of bodily fluid containing bilirubin. The bodily fluid derives from a patient suffering from an elevation of unconjugated bilirubin. The device includes a sterile tubing which accesses the patient&#39;s bodily fluids (especially blood), routes the fluid into an extracorporeal chamber within which irradiation of bodily fluids takes place, and returns bodily fluids to the patient. Bodily fluids are continuously circulated through a single length of sterile tubing using an adjustable pump to regulate the flow, and as the fluid passes into the extracorporeal chamber it is irradiated by blue light within the chamber with an emission wavelength range of approximately 450 to 530 nm. This irradiation induces a photochemical reaction in bilirubin that changes its structure and facilitates improved excretion of bilirubin once it is returned to the patient. The extracorporeal photo-isomerization turns the bilirubin into a more readily excreted form.

Description:
[0001]    This application claims the priority benefit under 35, U.S.C. section 119 of U.S. Provisional Patent Application No. 61/663,333 entitled “Device For Extracorporeal Photo-Isomerization For Hyperbilirubinemia, And Method Thereof” filed on Jun. 22, 2012; which is in its entirety herein incorporated by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to devices and methods for the phototherapeutic treatment of illness and diseases. This invention is also a phototherapy apparatus for treating jaundice, which is also known as hyperbilirubinemia. The invention emits a particular wavelength of blue light that is suitable for the conformational and structural photo-isomerization of bilirubin into water-soluble forms that are easier for the body to eliminate. 
         [0003]    The invention is also directed to an apparatus for extracorporeal irradiation of a liquid containing bilirubin in which bilirubin is converted into its water-soluble photo-isomers. The invention additionally covers a process for the reduction of the bilirubin level in a human being. The instant invention also refers to an apparatus for phototherapy, particularly for the treatment of hyperbilirubinemia and is designed to deliver excellent performance and high operational flexibility and safety due to its unique construction. 
         [0004]    The invention further relates to both method and apparatus for irradiating blood with blue radiation, and more particularly to such method and apparatus for extracorporeal radiation of blood from both humans and animals with stored blood or blood circulated outside the patient and returned to the patient after treatment. 
         [0005]    This invention also relates generally to the treatment of neonatal hyperbilirubinemia (jaundice) and related conditions, such as Crigler-Najjar Syndrome, and more specifically it relates to phototherapy treatment methods and apparatus. 
         [0006]    This invention also relates generally to a method and system for medical treatment of a living mammal, and more specifically relates to a method for treating the blood supply of a living subject by irradiating the blood for the purpose of photo-isomerizing bilirubin to reduce high levels in the blood stream. 
         [0007]    The present invention further relates to an apparatus for treating blood or plasma by extracorporeal circulation and processes for manufacturing and using the apparatus. 
         [0008]    This invention further relates generally to methods and systems for medical treatment of the human body, and more specifically relates to a method and system usable in treating the blood supply of a human subject for the purpose of reducing high levels of bilirubin in the blood supply of such subject. 
       BACKGROUND OF THE INVENTION 
       [0009]    Jaundice is a condition experienced by many newborn babies as well as adults stricken with certain diseases where abnormally high levels of bilirubin have accumulated in their body. Its most pronounced symptom is yellow coloring of the skin and eyes. Jaundice is also known as hyperbilirubinemia. 
         [0010]    Bilirubin is primarily a byproduct of the death and decomposition of red blood cells. Normally, bilirubin is conjugated with glucuronic acid in the liver so that it can be eliminated from the body through the bile. However, several of the proteins and enzymes that perform this function are not present at the necessary levels in newborns and in certain adult diseases. This leads to a rise in bilirubin levels in their blood. Since the bilirubin is not water-soluble it tends to accumulate in body tissues, thereby causing the yellow coloration. The danger of high levels of bilirubin is that it can be neurotoxic. If levels get too high there can be nerve damage, or even death. 
         [0011]    In most cases, newborn jaundice is not very severe and disappears within a few weeks as the baby&#39;s body develops to a point where it is better able to rid itself of the bilirubin. However, if bilirubin levels are too high when the baby is still very young, then treatment may be necessary to prevent possible nerve damage. The most common treatment for jaundice is phototherapy. 
         [0012]    Phototherapy is comprised of shining light onto skin. The light penetrates the skin to a certain degree and interacts with bilirubin. Bilirubin has the chemical structure shown in  FIG. 1A . The carboxyl groups form hydrogen bonds with nearby nitrogen atoms, which hides the hydrophilic moieties and increases the molecule&#39;s overall hydrophobicity. Bilirubin&#39;s hydrophobicity makes it dangerous because it will readily absorb into tissue. 
         [0013]    Phototherapy light can cause two distinct and important changes of bilirubin. The first is a configurational isomerization where intramolecular hydrogen bonds within bilirubin are broken. This change exposes a carboxyl group and helps makes bilirubin water-soluble for a limited time. Water-soluble bilirubin is safer because it cannot easily enter tissues or penetrate the blood-brain barrier; it is slowly eliminated through the bile. In this manner, phototherapy reduces the amount of total bilirubin that can potentially cause damage by about 20% during phototherapy. The second change is a structural isomerization of bilirubin to lumirubin. This change is irreversible and exposes one of the carboxyl groups, thereby making lumirubin more hydrophilic than bilirubin. The liver easily eliminates lumirubin through the bile. The amount of lumirubin produced by phototherapy is dependant on the intensity of the light. Higher light intensities generate more lumirubin. The quick elimination of lumirubin may account for the majority of total serum bilirubin reduction provided by phototherapy. 
         [0014]    Phototherapy is considered to be extremely safe. The only potential risk is damage to a baby&#39;s eyes by the intense light. Therefore, it is highly recommended that the baby&#39;s eyes be covered appropriately during phototherapy. Otherwise, no significant side effects of phototherapy have been documented. 
         [0015]    The appropriate wavelength of light varies within the available literature. The most appropriate wavelength for treating jaundice is 450 nm, which is the most efficient wavelength for the isomerization of bilirubin. It is likely that wavelengths that fall within the range of 400 nm-500 nm, and more specifically 445 nm-475 nm, will have a beneficial effect. In addition, a light intensity of at least 6 microWatts per square centimeter per nanometer of light wavelength is also needed. This intensity is equivalent to 2.7 milliwatts per square centimeter of 450 nm wavelength light. 
         [0016]    Hyperbilirubinemia, an elevation in bilirubin circulating in the blood, can arise from both acute and congenital circumstances. Bilirubin is a natural byproduct of the metabolism of hemoglobin derived from aged or injured red blood cells. Infant hyperbilirubinemia (neonatal jaundice) is common but easily treated by placing the infant under blue lights. Unmanaged hyperbilirubinemia, however, leads to kernicterus (brain damage, ataxia) and early mortality. Solitary bilirubin is insoluble in the blood and cannot be efficiently excreted in this form. It is therefore conjugated and solubilized by the enzyme uridine diphosphate glycosyltransferase 1-A1 (UGT1A1), allowing excretion through the feces and urine. Unconjugated hyperbilirubinemia is a hallmark of Crigler-Najjar Syndrome (CNS) Type 1, a genetic deficiency of UGT1A1. The current standard treatment for CNS is phototherapy, which is conducted within a bed or chamber fitted with blue lights (wavelength of approximately 450 to 530 nm). Light of this wavelength initiates a photo-isomerization reaction which converts unconjugated bilirubin into an isomer known as lumirubin, which is water soluble and readily excreted. However, the onset of puberty is characterized by thickening and pigmentation of the skin, accompanied by a decrease in the body&#39;s surface area:volume ratio. These changes represent barriers to light penetration into circulating blood (which contains the majority of bilirubin). Therefore, the efficacy of phototherapy decreases substantially following puberty. Consequently, CNS life expectancy is 30 years of age even with regular phototherapy, in the absence of liver transplantation. Exchange transfusion and exchange plasmapheresis have been used as emergency measures prior to life-saving liver transplantation. 
         [0017]    As already mentioned above, bilirubin is a byproduct of the natural turnover and destruction of red blood cells, which releases hemoglobin into the blood. Breakdown of hemoglobin releases a heme group which is further catabolized into bilirubin. At physiological blood pH (around pH 7.4), bilirubin&#39;s hydrophilic domain is masked by hydrogen bonding, reducing its solubility. However, bilirubin is conjugated to glucuronic acid in the endoplasmic reticulum of hepatocytes by the enzyme uridine diphosphate glycosyltransferase 1-A1 (UGT1A1), disrupting the hydrogen bonds. The resulting configurational and structural changes facilitate bilirubin solubilization and excretion through the liver, kidneys, and intestines. Crigler-Najjar Syndrome (CNS) Type 1 patients lack UGT1A1 activity due to a genetic abnormality and suffer from chronic unconjugated hyperbilirubinemia. While the normal level of unconjugated bilirubin in the blood is 0.2-0.9 mg/dL, CNS patients have ≧20 mg/dL of bilirubin in their blood. Young CNS patients sleep under beds fitted with long fluorescent blue lights, a treatment known as phototherapy. Phototherapy provides an alternative mechanism for disruption of bilirubin&#39;s hydrogen bonds (i.e. light absorption), allowing for conversion of unconjugated bilirubin into soluble, excretable lumirubin isoforms even in the absence of UGT1A1 activity ( FIG. 1 ). 
         [0018]    However, phototherapy requires several hours of blue light exposure per day. Furthermore, the efficacy of phototherapy decreases in childhood as thickening and pigmentation of the skin interferes with penetration of blue light into the bloodstream. Effectiveness of phototherapy decreases further during puberty as the body&#39;s surface area:volume ratio decreases, such that CNS patients still die early despite regular phototherapy. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0019]      FIG. 1  shows the conversion of bilirubin into lumirubin. 
           [0020]      FIG. 2  illustrates the irradiation chamber used for the extracorporeal photo-isomerization of circulating bilirubin. 
           [0021]      FIG. 3  describes the device used to control the fluid flow rate. 
           [0022]      FIG. 4  illustrates the use of the apparatus of the invention for bilirubin photo-isomerization. 
       
    
    
     SUMMARY OF THE INVENTION 
       [0023]    The invention is an apparatus for the extracorporeal (i.e. outside the body) photo-isomerization of circulating bilirubin and could serve as a replacement for the aforementioned transfusion and plasmapheresis emergency measures mentioned in the background section of this application. Using the apparatus, the direct irradiation of bilirubin in body fluid will improve photo-isomerization and decrease duration of treatment as compared to traditional phototherapy. Furthermore, extracorporeal photo-isomerization is applicable to any case of unconjugated hyperbilirubinemia, both acute and chronic, independently of cause. 
         [0024]    The invention provides an extracorporeal photo-isomerization apparatus for treating mammals having diseases associated with abnormal levels of bilirubin, said apparatus comprising: (a) means for drawing body fluids from said mammal; (b) means for pumping said body fluids through flexible and clear sterile tubing; (c) optional means for oxygenating said body fluids; and (d) an extracorporeal irradiation chamber for exposing said fluids to blue light. 
         [0025]    The invention described also concerns an apparatus for extracorporeal irradiation of a liquid containing bilirubin, with subsequent photo-isomerization of bilirubin. The invention further covers a process for improving bilirubin clearance in a human being. 
         [0026]    The invention further provides a closed loop method for reducing high levels of bilirubin in the blood of a patient comprising: (a) removing blood from the patient; (b) pumping said blood through an irradiation chamber thereby photoisomerizing said bilirubin in said blood; and (c) returning the irradiated blood to the patient. 
         [0027]    The invention also provides a closed loop method for reducing harmful levels of bilirubin in the blood supply of a mammal, comprising the steps of: (a) withdrawing whole blood from said mammal; (b) forming said whole blood into an extracorporeal stream; (c) flowing said stream through flexible and clear sterile tubing housed in an irradiation chamber; (d) irradiating said withdrawn whole blood in said irradiation chamber with blue light radiation to effect photoisomerization of bilirubin, thereby reducing the harmful levels of bilirubin; and (e) returning the irradiated whole blood to said mammal. 
       DETAILED DESCRIPTION OF THE INVENTION 
       [0028]    As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. The figures are not necessarily to scale; some features may be exaggerated or minimized to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for the claims and/or as a representative basis for teaching one skilled in the art to utilize the present invention. 
         [0029]      FIG. 1  shows the conversion of bilirubin into lumirubin. Bilirubin (left) contains a hydrophilic domain that is masked by hydrogen bonds, shown by dotted lines (A). Photo-isomerization, indicated by the arrow, disrupts the hydrogen bonds (B) and converts bilirubin into the water-soluble lumirubin. 
         [0030]      FIG. 2  illustrates the extracorporeal photo-isomerization of the circulating bilirubin. The patient&#39;s body fluid is passed through sterile tubing  1  in direct proximity to blue lights in the bottom of the irradiating chamber  2  which irradiate at a wavelength between 450 to 530 nm  4 . A solid clear layer  3  resides over the blue lights and provides support for the tubing. The photo-isomerization device has a reflective, hinged lid  5   a  which can be lowered  5   b  to cover the apparatus and to contain and focus the light waves in the direct proximity of the bodily fluid. The body fluid is routed continuously and unidirectionally through the tubing and exits out of the irradiation chamber device  6  to ultimately return to the patient. 
         [0031]      FIG. 3  is a pump that controls the fluid flow rate. A peristaltic pump as shown in  FIG. 3 , is one example of a mechanism to regulate the flow of a patient&#39;s body fluid. The fluid is drawn toward the pump  1  by the unidirectional rotation of the pump&#39;s spindle  2 . Body fluid is then subsequently propelled away from the pump  3 . 
         [0032]    In the bilirubin photo-isomerization apparatus shown in  FIG. 4 , body fluid is drawn from the patient&#39;s peripheral vein  1  into sterile tubing (shown as a thick black line), routed toward the photo-isomerization irradiation chamber device by a peristaltic pump  2 , passed through an optional oxygenation antechamber  3 , exposed to blue lights within the photo-isomerization irradiation chamber  4 , then returned to the body  5 . 
         [0033]    The direct exposure of circulating bilirubin to blue light as described in the instant invention, therefore, would improve the efficacy of the photo-isomerization reaction ( FIG. 2 ). 
         [0034]    The apparatus and method of the invention can be used in conjunction with other equipment requiring vascular access to which a patient may already be connected; for example, dialysis or transfusion equipment. The invention can be integrated in-line with existing equipment by using the same sterile tubing to pass bodily fluids directly from existing equipment into the instant invention (or vice versa). 
         [0035]    The invention is further exemplified in more detail in connection with each component as follows: 
       Extracorporeal Photo-Isomerization Device 
       [0036]    The aforementioned extracorporeal bilirubin photo-isomerization device draws body fluid (especially blood) from the patient into flexible sterile tubing, exposes bilirubin-containing body fluid to blue light within an extracorporeal irradiation chamber, then returns the fluid to the body (See  FIG. 2 ). The body fluid within the tubing is propelled mechanically, for example by a peristaltic pump (See  FIG. 3 ). The tubing passes across the irradiation chamber&#39;s clear horizontal surface, under which the blue lights reside. The flow rate is typically in the range of 100 to 500 ml/min. In liver support therapy this rate is preferably 300 ml/min. The body fluid feed unit can be, for example, a pump such as peristaltic pump. 
         [0037]    The blue lights are chosen for light emission wavelengths of approximately 450 to 530 nm, which is the optimal range of absorption for bilirubin. Lights that emit within approximately 450 to 530 nm are commercially available as fluorescent tubes as well as newer LED (light-emitting diode) bulbs. LED bulbs hold the advantages of lower operational temperatures, reduced power consumption, and long operational lifespan. Current LED bulbs offer an emission intensity of &gt;12 μW/cm 2 /nm. Indeed, LED exposure (410-490 nm wavelength range) has been shown to be sufficient for bilirubin photoconversion in experimental assays. A pediatric study has suggested that increasing the intensity of blue light exposure will expedite the bilirubin photoconversion reaction, which will shorten the necessary treatment duration. It is recommended that exposure of the skin to blue light surpasses 30 μW/cm 2 /nm for neonatal hyperbilirubinemia (jaundice). Unlike neonatal bilirubin phototherapy units, however, the present invention places body fluid in close proximity to blue light, allowing direct penetration of light into the circulating bilirubin. Therefore, even low intensity blue bulbs are likely to be sufficient for bilirubin photo-isomerization in the context of the invention. 
         [0038]    The blue lights sit in the bottom of the irradiation chamber, beneath a clear horizontal surface, for example plexiglass, glass or other plastic that is clear and suitable for use. The material is chosen to ensure it does not restrict the passage of light rays from blue bulbs toward the body fluid in the tubing (See  FIG. 2 ). For example, commercially available glass allows ˜90% transmission of visible light. The body fluid will pass through clear, light-transmissive medical grade tubing. The tubing passes back and forth multiple times across the horizontal surface, maximizing the dwell time of the body fluid within the irradiation chamber and thereby increasing exposure of circulating bilirubin to blue light. The irradiation chamber will also have a hinged lid at the top with a reflective coating on the lid&#39;s lower surface (See  FIG. 2 ). When the lid is closed it will rest atop the tubing (without compressing the tubing), and the reflective surface will focus the light rays onto the bilirubin-containing fluid in the tubing. The body fluid travels within a closed loop, providing an unbroken sterile environment and minimizing the need for junctions and/or couplings in the tubing (See  FIG. 4 ). Junctions may be susceptible to damage or leakage which would compromise sterility of the tubing&#39;s contents, so elimination of junctions is desirable. 
         [0039]    Another common feature of the apparatus of the invention is that it comprises a blood compartment provided with two accesses, in which, during the treatment the patient&#39;s blood is circulated. To do this, a blood withdrawal line is connected between a blood vessel of the patient and an access, employed as entry, of the blood compartment; a blood return line is connected between the other access of the blood compartment, employed as exit, and a blood vessel of the patient; and the patient&#39;s blood is circulated in this extracorporeal circuit looped onto the patient, by means of a pump, usually placed in the withdrawal line. 
         [0040]    In the practice of the present invention, blood is retained within sterile tubing the entire time and therefore there is no need for extra couplings and junctions and therefore reduces risk of blood contamination. 
       Vascular Access 
       [0041]    For patients with recurring hyperbilirubinemia, regular treatment with the extracorporeal photo-isomerization apparatus of the invention may be necessary to maintain curative bilirubin conversion and subsequent excretion. Patients expected to require regular extracorporeal photo-isomerization treatment are fitted surgically with vascular access mechanisms which are designed to provide frequent access to the patient&#39;s blood. Some examples of these mechanisms are venous catheter, arteriovenous graft and arteriovenous fistula; a common example of their use is for kidney failure patients who require several hemodialysis sessions per week, at 3 to 4 hours per session. Of the current mechanisms, the arteriovenous fistula (AV) is considered the best candidate for long-term use and can be generated in up to 90% of candidate patients. These vascular access mechanisms will provide long-term, reusable access points at convenient locations for the patient, facilitating recurring circulation of body fluid through the photo-isomerization chamber. 
         [0042]    An AV fistula has proven to be the best kind of vascular access for people whose veins are large enough, not only because it lasts longer but it is also less likely than other types of access to form clots or become infected. 
         [0043]    Surgery to create an arteriovenous fistula is usually conducted using a local anesthetic, injected at the site of the proposed fistula. The procedure is performed in a hospital or one-day surgery center and can usually be performed on an outpatient basis if the patient is not already hospitalized. After cleaning and sterilizing the site, the surgeon will make a small incision in the forearm sufficient to allow the permanent joining together of a vein and an artery in the arm. The blood vessels will be appropriately blocked to stop blood flow for the procedure and incisions will be made to join them. Silk sutures, just as those used in other types of surgical incisions, will be used to close incised areas as needed after the vein and artery have been joined. Once joined, blood flow will increase, the vein will become thicker, and over a period of months the connection will become strong and develop into the fistula that will allow permanent vascular access. 
       Oxygenation of Body Fluid 
       [0044]    The apparatus and method of the invention is enhanced by an (aerobic) oxygenated environment which makes the bilirubin photo-isomerization process more efficient. More specifically, decay of unconjugated bilirubin is faster and production of lumirubin is concomitantly enhanced. Therefore, oxygenation of bilirubin-containing bodily fluid expedites and/or enhances the bilirubin photo-isomerization capability of the present invention. One example of an oxygenation strategy is to use oxygen-permeable medical tubing and an external oxygen source (such as an oxygen tank). In this embodiment, the tubing containing body fluid would pass through a small antechamber containing pressurized oxygen before reaching the irradiation chamber (See  FIG. 4 ). The oxygen in the antechamber will therefore diffuse through the tubing into the body fluid before the body fluid undergoes the photo-isomerization reaction in the irradiation chamber. The embodiment is compatible with the single, unbroken length of sterile tubing as described above in the Extracorporeal Photo-isomerization device section. 
         [0045]    In another embodiment for increasing the oxygen concentration of the body fluid prior to photo-isomerization, the patient is fitted with an oxygen mask before and/or during the treatment time with the extracorporeal apparatus of the invention. 
       Disease Applications for the Extracorporeal Bilirubin Photo-Isomerization Device 
       [0046]    Hyperbilirubinemia typically arises from a variety of causes involving hemolysis, liver dysfunction, or problems with the gallbladder or bile duct. The apparatus of the invention is useful for the treatment of unconjugated hyperbilirubinemia arising from any cause. Any disorder that causes hyperbilirubinemia can be treated with the apparatus and method of the invention. 
         [0047]    Increases in bilirubin levels result from excessive erythrocyte decomposition, liver dysfunction or impaired hepatic excretion of bile. When bilirubin levels exceed glucuronidation and the subsequent excretion into bile, the result is hyperbilirubinemia, in which nonconjugated bilirubin (i.e. that bound to albumin) is elevated in plasma. Bilirubin concentrates in the phospholipid membranes of cells and, in sufficiently high concentrations, can pass through the blood-brain barrier (kernicterus). An increased risk of neurotoxic effects exists at a serum-bilirubin concentration of 20 mg/dl and up. The normal range of blood-bilirubin concentration in adults and children is less than 1 mg/dl. In patients with Crigler-Najjar syndrome type 1, the range is between 20 to 50 mg/dl. 
         [0048]    Exemplary disorders that can treated using the apparatus and method of the invention include: 
         [0049]    (1) Sickle cell anemia: exchange transfusion is typically indicated for intrahepatic cholestasis (SCIC), an uncommon but potentially fatal complication of sickle cell disease which can lead to hyperbilirubinemia. The severity of hyperbilirubinemia also depends on the patient&#39;s UGT1A1 genotype. The instant invention represents a potential alternative to exchange transfusion. 
         [0050]    (2) Hereditary spherocytosis (HS): this is the most common inherited hemolytic disease in people of Northern European descent and can lead to neonatal hyperbilirubinemia severe enough to require exchange transfusion. 
         [0051]    (3) α- and β-Thalassemia: variable status of the UGT1A1 gene affects bilirubin concentrations in both α- and β-thalassemia heterozygotes. The long-term increase in red-cell turnover causes hyperbilirubinemia and bilirubin-containing gallstones. 
         [0052]    (4) Crigler-Najjar Syndrome (CNS) Type 1 is also treated with the method and apparatus of the instant invention. 
         [0053]    The content of all references cited and/or introduced in the future for the record by an IDS by Applicant in connection with the instant specification of this invention and all cited references in each of those references are incorporated in their entirety by reference herein as if those references were denoted in the text. 
         [0054]    While the many embodiments of the invention have been disclosed above and include presently preferred embodiments, many other embodiments and variations are possible within the scope of the present disclosure and in the appended claims that follow. Accordingly, the details of the preferred embodiments and examples provided are not to be construed as limiting. It is to be understood that the terms used herein are merely descriptive rather than limiting and that various changes, numerous equivalents may be made without departing from the spirit or scope of the claimed invention.