The present invention relates generally to a method and apparatus for luminating a fluid. Specifically, the present invention relates to an apparatus and method that improves the efficiency and uniformity of irradiating a biological fluid, such as blood, containing a photosensitive material utilized to inactivate pathogens or the like therein.
In recent years there has been great interest in inactivating viruses such as Hepatitis B (HBV), Hepatitis C (HCV), Human T Lymphotrophic Retrovirus Type 3 (HTLV), Human Immunodeficiency Virus (HIV), and Lymphadenopathy Associated Virus (LAV) in blood and blood products. At present, methods for inactivating these viruses in blood and blood fractions include (1) treatment with a chemical disinfectant such as formaldehyde (see U.S. Pat. No. 4,833,165); and (2) treatment with photosensitizers. For example, U.S. Pat. No. 5,232,844 describes the use of phthalocyanines; U.S. Pat. No. 5,041,078 describes the use of sapphyrins; U.S. Pat. Nos. 4,169,204, 4,294,822, 4,328,239 and 4,727,027 describe the use of various furocoumarins (psoralens) and analogs thereof; Meruelo et al. [Proc. Nat. Acad. Sci. U.S., 85, 5230-5234 (1988)] have described the use of hypericin; Lambrecht et al. [Vox Sang. 60, 207-213 (1991)] have described the use of phenothiazine dyes (methylene blue and toluidine blue); and U.S. Pat. No. 4,915,683 describes the use of merocyanine dyes to inactivate viruses. According to these methods, an exogenous photosensitizer is added to the blood or blood fraction and the solution is irradiated with light of appropriate wavelengths to inactivate the virus.
Phenothiazine dyes are photochemicals that bind to nucleic acids. Under suitable activation conditions such as long-wavelength UV irradiation, phenothiazine dyes are believed to crosslink the DNA and RNA strands in viruses, thereby disabling uncoiling and replication. They also react with membrane structures and they induce the production of virucidal oxygen radicals from molecular oxygen. These characteristics of phenothiazine dyes form the basis of viral inactivation and certain photochemotherapies. [See PCT application WO 91/03933.]
Psoralens are in some ways similar to phenothiazines in that activation with long-wavelength UV irradiation crosslinks the DNA and RNA strands in viruses, thereby disabling uncoiling and replication. [See Anderson and Voorhees, Ann. Rev. Pharmacol. Toxicol. 20, 235-57 (1980).] More recently psoralens have been applied successfully to inactivate blood-born viruses. [See Rai, S. et al., xe2x80x9cDramatic Improvements in Viral Inactivation with Brominuted Psoralens, Naphthalencs and Anthracenes,xe2x80x9d Photochem. and Photobiol. 58:59-65 (1993).] The interaction mechanism of psoralens with DNA has been extensively studied and reviewed. A preliminary intercalation complex is formed between the psoralen and two base pairs of the duplex DNA via hydrophobic interaction. Subsequent exposure to UV-A irradiation then causes photoconjugation between the furocoumarin structure of the psoralen and one or two bases of the nucleic acid (to form mono- and bi-functional adducts, respectively). Pyrimidine bases, particularly thymine, have been identified as participants in these reactions. Subsequently, the mono-functional adduct may absorb a photon and react with a second base of the complementary strand of the DNA to form a covalent crosslink. [See Anderson and Voorhees op. cit. page 240.]
As use of photosensitizers increases, results are establishing that the effectiveness of such agents is dependent upon uniform irradiation of the fluids containing the agents. However, existing prior art methods and apparatus do not employ means that take into account this consideration and other factors for irradiating the photosensitizers. The teachings of the prior art do not sufficiently control defraction of the illumination source, do not adequately control extinction that occurs when irradiating an opaque material (e.g. red blood cells) and principally teach xe2x80x9copenxe2x80x9d systems where the integrity of a sealed blood system is not insured. Also, various pathogen inactivation agents such as phatholocyanine dyes, methylene blue, psoralens 2 hypericin, etc. are best activated by either ultraviolet, visible and infrared wavelength light components. For example, depending on the type of blood product desired to be irradiated, variations in the quantity of illumination must be adjustable in terms of luminance output and optical path length between fluid components due to the extinction factor. More opaque red blood cells require a sufficiently narrow space between each other to allow the blood cells at the end of the light path to receive a comparable quantity of illumination to those at the beginning of the path, without over-exposure which can damage the cells. Differently, platelet concentrates and plasma can be adequately and evenly illuminated with a much longer optical path length because they are less opaque than blood cells.
The deficiencies in the prior art are largely attributable to the failure to recognize that the optical path length between fluid components nearest an illumination source and those further away is critical to properly and effectively irradiate a fluid containing photosensitizers. Additionally, conventional means in the art of irradiating a fluid product do not provide mixing during the exposure period. Thus, uneven irradiation is problematic and more likely and the tendency to over-expose simply to achieve target levels of an activation throughout the fluid product often occurs.
A need exists for controlling the effective optical path length for irradiating a fluid. A further need exists to improve the efficiency and uniformity of biological fluid exposure to illumination. A still further need exists to reduce potential side effects to blood components due to overexposure. As will be described in greater detail hereafter, the method and apparatus of the present invention meets these needs and overcome the short comings of the prior art.
The present invention includes an apparatus for illuminating a fluid having photosensitive material therein comprising a surface. A roller is separated from the surface by a space and the space is adapted to receive a flexible container. The flexible container on the surface contacts the roller and is translated through the space. A light source is adapted to transmit light to the space to illuminate the fluid and react with photosensitive material therein as the flexible container translates through the space.
Another feature of the present invention may relate to a second roller juxtaposed from the roller and separated from the surface by a second space. In this way, the flexible container on the surface contacts the second roller after passing through the space and translates through the second space for further irradiation of the fluid, permitting successive irradiation using different wavelengths, if necessary, and benefiting the photo-chemical/blood component combination of interest.
Still another feature of the present invention may concern a second roller juxtaposed from the roller and a second support roller juxtaposed from a support roller. The second roller and second support roller are separated by a second space and the flexible container contacts the second roller and second support roller after passing through the space between the roller and support roller, for further irradiation of the fluid.
The invention also provides for a method of inducing a photoreaction of a photosensitive material within a fluid in a flexible container comprising: placing the flexible container into a well-defined space between a roller and a surface; translating the container between the roller and surface by squeezing the container through the space; and illuminating the fluid within the container as the container translates and is squeezed through the space by directing light towards the space thereby inducing photoreaction of the photosensitive material in the fluid within the container.
Yet another feature of the invention may include translating the container through a second space located between a second roller juxtaposed from the roller and the surface wherein the flexible container contacts the second roller after passing through the space and translates through the second space.
In accordance with the following it may be an advantage of the present invention to provide an adjustable optical path length for illuminating a fluid, such as the biological fluid or blood, for irradiating photosensitive material therein.
A further advantage of the invention may concern multiple locations and members for translating and illuminating a fluid in a flexible container such as a blood bag and providing efficient and uniform exposure of the fluid to the illumination source.
Yet a further advantage of the invention may concern providing sufficient mixing without having to compromise a closed system, unlike external pumping circuits and special thin-channel chambers intended to be the illumination cell. Also, mixing may be enhanced by repeated forward and reverse or reciprocating translation of a fluid container such a blood bag, and in particular for irradiation of opaque fluids such as red blood cells and the like.
Still a further advantage of the invention may include utilizing conventional biological liquid or blood collection containers, systems and methods. In this way the integrity and sterility of the collected liquid is less likely to be compromised. Also, utilizing conventional means lowers the cost of practicing the invention and simplifies use of the same.
USPTO Backgrounds
USPTO Backgrounds