Patent Description:
Smyczynski suggested in <CIT> that light radiation at <NUM> nanometers (nm) and/or <NUM> could be used to treat CO poisoning by photodissociating COHb in blood passing through an extracorporeal gas exchanger. The treatment system of Smyczynski involves removing and recirculating anticoagulated blood from a patient through an extracorporeal oxygenator. The blood passing through the extracorporeal oxygenator is irradiated with light from a laser at either <NUM> and/or <NUM>. The extracorporeal oxygenator is designed such that the blood-light contact surface is as large as possible because the <NUM> and/or <NUM> light does not penetrate deeply into the blood stream before becoming completely absorbed. The <NUM> and <NUM> light wavelengths are chosen by Smyczynski because these wavelengths align with peaks in the COHb absorption spectra.

<CIT> discloses an artificial lung in which carbon monoxide in blood of a patient can be easily replaced by oxygen by forming a light source part to radiate light of a specified wavelength to dissociate carbon monoxide from hemoglobin in blood to be provided inside the artificial lung in such a way that this light is continuous radiated during gas exchange by the artificial lung. <CIT>discloses a mass transfer device having a microporous, spirally wound hollow fibre membrane. <CIT> discloses an extracorporeal photodynamic blood illumination (irradiation) for the treatment of carbon monoxide poisoning.

The present disclosure provides systems and non-claimed methods for extracorporeal CO removal using phototherapy. In particular, systems and non-claimed methods are provided for a extracorporeal phototherapy system that emits light onto opposing sides of an oxygenator that includes a plurality of microporous hollow fiber membranes arranged in layers to photodissociate CO from Hb.

In one aspect, the present disclosure provides an extracorporeal phototherapy system for removing carbon monoxide from whole blood. The extracorporeal phototherapy system includes an oxygenator having a plurality of membrane layers each with a plurality of microporous hollow fiber membranes. The plurality of microporous hollow fiber membranes each include an external surface and an internal channel. Each of the plurality of microporous membrane layers is rotationally offset with respect to an adjacent layer. The oxygenator further includes a gas inlet port in fluid communication with a first end of the internal channels, a gas outlet port in fluid communication a second end of the internal channels, a blood inlet port in fluid communication with the external surfaces, and a blood outlet port in fluid communication with the external surfaces. The extracorporeal phototherapy system further includes a light source configured to output light and arranged to emit the light output by the light source onto at least one surface of the oxygenator.

In one aspect, the present disclosure provides an extracorporeal phototherapy system for removing carbon monoxide from whole blood. The extracorporeal phototherapy system includes an oxygenator having a plurality of membrane layers, a gas inlet port configured to provide fluid communication through internal channels formed in each of the plurality of membrane layers and to a gas outlet port, and a blood inlet port configured to provide fluid communication around external surfaces defined by each of the plurality of membrane layers and to a blood outlet port. The extracorporeal phototherapy system further includes a first light source configured to output light and arranged to emit the light output by the first light source onto a first side of the oxygenator, and a second light source configured to output light and arranged to emit the light output by the second light source onto a second side of the oxygenator opposite to the first side.

In one aspect, the present disclosure provides a non-claimed method of removing carbon monoxide from whole blood. The method includes flowing whole blood over a plurality of microporous hollow fibers arranged within an oxygenator, flowing oxygen through the plurality microporous hollow fibers, and emitting light from a light source onto opposing sides of the plurality of microporous hollow fibers to photodissociate carboxyhemoglobin in the whole blood.

The foregoing and other aspects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration a preferred embodiment of the invention. Such embodiment does not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention.

Such detailed description makes reference to the following drawings which may not be drawn to scale.

The term "visible light" as used herein refers to a portion of the electromagnetic spectrum, generally bound between wavelengths of approximately <NUM> nanometers (nm) and approximately <NUM>, that is visible to the human eye. One of skill in the art would recognize that the wavelength range of visible light will vary from person to person depending on one's vision. Thus, the range from <NUM> to <NUM> is a generally accepted range and is not meant to be definitively limiting in any way.

Carbon monoxide intoxication is a leading cause of poisoning related deaths and results in more than <NUM>,<NUM> visits to emergency departments in the United States each year. Exposure to carbon monoxide is often associated with inhalation of other chemicals and particulates, which can damage the airways and alveoli, resulting in acute lung injury and respiratory failure. In soldiers and firefighters, acute respiratory distress syndrome (ARDS) secondary to trauma and burns can be present. Whenever CO poisoning is associated with impaired gas exchange in the lungs, treatment with either normobaric or hyperbaric oxygen might be less effective or noxious.

<FIG> and <FIG> illustrate one non-limiting example of a extracorporeal phototherapy system <NUM> according to the present disclosure. In general, the extracorporeal phototherapy system <NUM> may include at least one light source arranged to emit light at a surface of an oxygenator <NUM> to promote photodissociation of carboxyhemoglobin (COHb). In the illustrated non-limiting example, the extracorporeal phototherapy system <NUM> may include a first light source <NUM> and a second light source <NUM> arranged on opposing sides of the oxygenator <NUM>. That is, the first light source <NUM> may be arranged to emit light onto a first side <NUM> of the oxygenator <NUM> and the second light source <NUM> may be arranged to emit light onto a second side <NUM> of the oxygenator <NUM>.

In some non-limiting examples, the first light source <NUM> and the second light source <NUM> may be configured to emit coherent light. In some non-limiting examples, the first light source <NUM> and the second light source <NUM> may be configured to emit non-coherent light. In some non-limiting examples, the first light source <NUM> and the second light source <NUM> may each be in the form of an array of one or more light emitting diodes (LEDs). In some non-limiting examples, the first light source <NUM> and the second light source <NUM> may each be configured to output light at with a wavelength in the visible spectrum. In some non-limiting examples, the first light source <NUM> and the second light source <NUM> may each be configured to output light at with a wavelength greater than <NUM> nanometers (nm). In some non-limiting examples, the first light source <NUM> and the second light source <NUM> may each be configured to output light at with a wavelength between than <NUM> and <NUM>.

As described herein, the use of red light (e.g., light with a wavelength generally between <NUM> and <NUM>) may provide increased penetration depth into the oxygenator <NUM> as well as result in less heating of the blood flowing through the oxygenator <NUM>, when compared to irradiation with light of a lower wavelength (e.g., <NUM> or <NUM>). The increased penetration depth of the red light may provide increased CO elimination from the blood in the oxygenator <NUM>, when compared to irradiation with light of a lower wavelength.

In the illustrated non-limiting example, the oxygenator <NUM> includes a plurality of membrane layers <NUM> enclosed within a housing <NUM>. The plurality of membrane layers <NUM> each include a plurality of microporous hollow fiber membranes <NUM> that are arranged in a planar shape and parallel to one another. In general, the plurality of microporous hollow fiber membranes <NUM> may be fabricated from a material that provides a high diffusion coefficient for CO and oxygen (O<NUM>). For example, a silicone material may define a CO diffusion coefficient that is too low to enable effective removal of CO from the treated blood in a single pass. In some non-limiting examples, the plurality of hollow fiber membranes may be fabricated from a microporous polypropylene or a polymethylpentene material, which provide efficient CO removal and oxygenation.

In the illustrated non-limiting example, each of the plurality of membrane layers <NUM> may be rotationally offset with respect to an adjacent layer. For example, each of the plurality of membrane layers <NUM> may be rotated ninety degrees with respect to the adjacent layers. In this way, for example, the plurality of microporous hollow fiber membranes <NUM>, which extend generally parallel to one another within a respective one of the plurality of membrane layers <NUM>, may define a generally checkered pattern. That is, one layer of the plurality of microporous hollow fiber membranes <NUM> may extend in a first direction and an adjacent layer, either above and/or below, may extend in a second direction perpendicular to the first direction.

Each of the plurality of microporous hollow fiber membranes <NUM> may include an external surface <NUM> and an internal channel <NUM>. The internal channels <NUM> may extend axially along each of the plurality of microporous hollow fiber membranes <NUM>. In general, the plurality of microporous hollow fiber membranes <NUM> may be designed to allow diffusion of O<NUM> and CO between blood flowing over the external surfaces <NUM> and gas flowing (e.g., O<NUM>) through the internal channels <NUM>.

With reference to <FIG> in particular, the oxygenator <NUM> may be designed to provide efficient phototherapy for photodissociation of COHb in CO-poisoned blood (e.g., whole blood). In conventional oxygenators, an air gap may be formed between the first layer of membranes and a treatment surface <NUM> (e.g., top and bottom surfaces of the oxygenator <NUM> from the perspective of <FIG>). During operation, a blood layer may form in this air gap and, since this blood layer is not flowing over a membrane layer, the efficiency of phototherapy to eliminate CO from the blood may be significantly reduced. That is, although the phototherapy may aid in photodissociating COHb, oxygenation and removal of the CO, which are facilitated by the plurality of microporous hollow fiber membranes <NUM>, must be provided to prevent rebinding of the CO to hemoglobin. As such, the oxygenator <NUM> may be designed to reduce or eliminate an air gap A formed between a treatment surface <NUM> (i.e., an incident on which the first light source <NUM> and the second light source <NUM> emit light) and the layer of the plurality of membrane layers <NUM> adjacent to the treatment surface <NUM>. The air gap A may be at the top and the bottom. In this way, for example, the oxygenator <NUM> may ensure that the emitted light is emitted onto blood flowing over one of the plurality of microporous hollow fiber membranes <NUM>.

In some non-limiting examples, to further increase the efficacy of the phototherapy elimination of CO from blood in the oxygenator <NUM>, the oxygenator <NUM> may be designed with a thickness T that ensures that the light emitted by the first light source <NUM> and the second light source <NUM> may penetrate through to all of the plurality of membrane layers <NUM>. In general, a number of layers in the plurality of membrane layers <NUM> may define the thickness T (e.g., via an outer diameter defined by the external surfaces <NUM>). As such, in some non-limiting examples, the oxygenator <NUM> may be designed with a predetermined number of layers in the plurality of membrane layers <NUM> to achieved a desired thickness T. In some non-limiting examples, the thickness T may be less than <NUM> millimeters (mm). In some non-limiting examples, the thickness T may be less than <NUM>.

In general, the oxygenator <NUM> may be configured to exchange CO and O<NUM> via diffusion through the plurality of microporous hollow fiber membranes <NUM> in blood flowing over the external surfaces <NUM>. To facilitate blood flow and gas flow through the oxygenator <NUM>, the housing <NUM> may be provided with one or more ports to facilitate connections to flow devices (e.g., pumps, gas tanks, etc.) arranged externally from the oxygenator <NUM>. Alternatively or additionally, one or more of the oxygenators <NUM> may be placed in parallel (see, e.g., <FIG>) or in series (see, e.g., <FIG>).

With reference to <FIG> in particular, in general, the oxygenator <NUM> may be separated into a blood compartment <NUM>, a gas inlet compartment <NUM>, and a gas outlet compartment <NUM>. In some non-limiting examples, an adhesive (e.g., a silicone adhesive) may be applied to seal the blood compartment <NUM> from the gas inlet compartment <NUM> and the gas outlet compartment <NUM>. The seal between the blood compartment <NUM> and the gas inlet compartment <NUM> may allow a first end <NUM> of the plurality of microporous hollow fiber membranes <NUM> to protrude into gas inlet compartment <NUM>. The seal between the blood compartment <NUM> and the gas outlet compartment <NUM> may allow a second end <NUM> of the plurality of microporous hollow fiber membranes <NUM> to protrude into the gas outlet compartment <NUM>. In this way for example, the first ends <NUM> and the second ends <NUM> of the plurality of microporous hollow fiber membranes <NUM> may be sealed from the blood compartment <NUM> to allow gas flow through the internal channels <NUM> and prevent blood from flowing into the internal channels <NUM>. A remainder of the plurality of microporous hollow fiber membranes <NUM> not sealed off by the gas inlet compartment <NUM> and the gas outlet compartment <NUM> may be arranged within the blood compartment <NUM>. Thus, the blood compartment <NUM> may provide a sealed compartment within which blood may flow over the external surfaces <NUM> of the plurality of microporous hollow fiber membranes <NUM>.

In the illustrated non-limiting example, the housing <NUM> may include a gas inlet port <NUM>, a gas outlet port <NUM>, a blood inlet port <NUM>, and a blood outlet port <NUM>. The gas inlet port <NUM> may be arranged within the gas inlet compartment <NUM> and may be in fluid communication with the first ends <NUM> of the internal channels <NUM>. The gas outlet port <NUM> may be arranged within the gas outlet compartment <NUM> and may be in fluid communication with the second ends <NUM> of the internal channels <NUM>. The blood inlet port <NUM> and the blood outlet port <NUM> may be arranged within the blood outlet compartment <NUM>. In general, an arrangement of the gas inlet port <NUM>, the gas outlet port <NUM>, the blood inlet port <NUM>, and the blood outlet port <NUM> may provide gas flow and blood flow in a common direction (e.g., diagonal from upper left to lower right from the perspective of <FIG>). In this way, for example, the oxygenator <NUM> may aid in preventing or minimizing a rebinding rate of COHb.

In some non-limiting examples, the gas inlet port <NUM> may be in fluid communication with a fluid source configured to supply gas to the gas inlet port <NUM> at a predetermined flow rate. In some non-limiting examples, the fluid source may be configured to supply <NUM>% O<NUM> to the gas inlet port <NUM>. Using <NUM>% oxygen and <NUM>% CO2 may be desirable in some settings. If removing CO2 with the extracorporeal device, removal of CO from the lungs will be impaired based on breathing, with a null effect on overall CO removal rate as a result. Providing the device with some CO2 (<NUM>%) will not materially affect arterial PCO2, respiratory drive and the like. In some non-limiting examples, the fluid source may be configured to supply air to the gas inlet port <NUM>. In general, the blood inlet port <NUM> may be in fluid communication with a pump, or another fluid flow device, that is configured to draw whole blood from a patient or a reservoir connected to the patient (e.g., via cannulas inserted into one or more veins of the patient). The whole blood removed from the patient may flow through the oxygenator <NUM> over the external surfaces <NUM> of the plurality of microporous hollow fiber membranes <NUM> to the blood outlet port <NUM>. The blood outlet port <NUM> may be in fluid communication with the patient (e.g., via one or more cannulas inserted into one or more veins of the patient). As such, the whole blood may be recirculated through the oxygenator <NUM> and the patient.

In general, the gas flow rate supplied to the gas inlet port <NUM> may be higher than a blood flow rate supplied to the blood inlet port <NUM>. In some non-limiting examples, a ratio between the gas flow rate supplied to the gas inlet port <NUM> to the blood flow rate supplied to the blood inlet port <NUM> may be greater than <NUM>:<NUM>. In some non-limiting examples, a ratio between the gas flow rate supplied to the gas inlet port <NUM> to the blood flow rate supplied to the blood inlet port <NUM> may be greater than <NUM>:<NUM>. If the ratio between GAS and BLOOD flow rates is appreciably elevated, an undesirable air gas embolism can be introduced into blood. Up to <NUM> times higher gas flow than blood flow can be used as a rule of thumb. For example, <NUM>/min blood flow can be used with <NUM>/min gas flow, <NUM>/min blood flow can be used with <NUM>/min gas flow and the like. Of course, other parameters will work beyond this rule of thumb. In some non-limiting examples, the gas flow rate provided to the gas inlet port <NUM> may provide a partial pressure of O<NUM> (PO<NUM>) between <NUM> millimeters of mercury (mmHg) and <NUM> mmHg. The high gas flow rates compared to the blood flow rates aid the oxygenator <NUM> in reducing COHb rebinding rates and provide needed ventilation to expel photodisassociated CO.

During operation, it is important to design the oxygenator <NUM> to ensure that blood covers the a substantial portion of the blood compartment surface area. In this way, for example, the surface area for treatment may be expanded to encompass the entire or a substantial portion of the blood compartment <NUM>. <FIG> illustrates one non-limiting example where the housing <NUM> includes an blood inlet channel <NUM> connected to the blood inlet port <NUM> and a blood outlet channel <NUM> connected to the blood outlet port <NUM>. The blood inlet channel <NUM> extends along one side of the blood compartment <NUM> and the blood outlet channel <NUM> extend along an opposite side of the blood compartment <NUM> in a direction that is general parallel to the blood inlet channel <NUM>. In this way, for example, blood may be distributed from the blood inlet port <NUM> along one side of the blood compartment <NUM>. With the blood distributed along one side of the blood compartment <NUM>, the blood may flow along the blood compartment <NUM> to the opposing side and into the blood outlet channel <NUM>. The blood inlet channel <NUM> and the blood outlet channel <NUM> may aid in distributing the blood over the entire surface area, or a substantial portion of the surface area, of the blood compartment <NUM>.

In the illustrates non-limiting examples of <FIG> the oxygenator <NUM> defines a generally planar shape (e.g., a thin rectangular prism). In other non-limiting, comparative examples, the oxygenator <NUM> may be designed in alternative shapes while maintaining the principles and characteristics described herein. <FIG> illustrates one non-limiting, comparative example of the extracorporeal phototherapy system <NUM> where the oxygenator <NUM> defines a generally cylindrical shape. Similar to the planar design of the oxygenator <NUM>, the cylindrical design of the oxygenator <NUM> may enable phototherapy to be applied onto two opposing surfaces of the oxygenator <NUM>. In the illustrated non-limiting example, the first light source <NUM> may define a generally annular shape that extends concentrically around an outer surface of the oxygenator <NUM>. The second light source <NUM> may be define a generally rectangular prism shape and may be arranged within an internal surface of the oxygenator <NUM>. In other non-limiting examples, the second light source <NUM> may define alternative shapes (e.g., cylindrical).

In the illustrated non-limiting example, a flow of cooling fluid <NUM> (e.g., water) may be provided to the second light source <NUM> arranged within the oxygenator <NUM>. In this way, for example, cooling may be provided to the blood flowing through the oxygenator <NUM>. The cooling system may be a heat exchanger with cold water that cools entering inlet blood a few degrees Celcius.

In some non-limiting examples, as illustrated in <FIG>, a cooling device <NUM> (e.g., a heat exchanger, a photoelectric cooler, an evaporative cooler, etc.) may be placed in fluid communication with the blood outlet port <NUM> to selectively provide cooling to the blood flow leaving the oxygenator <NUM> and flowing toward, for example, a patient. The cooling device <NUM> may be configured to cool the blood flowing from the blood outlet port <NUM> to a predetermined temperature (e.g., around body temperature). In some non-limiting examples, the cooling device <NUM> may be in communication with a controller that is configured to monitor an outlet temperature of the blood flowing from the blood outlet port <NUM> and control the cooling device <NUM> to maintain the blood temperature flowing from the cooling device <NUM> to the predetermined temperature.

One non-limiting example of operation of the extracorporeal phototherapy system <NUM> will be described with reference to <FIG>. In general, the extracorporeal phototherapy system <NUM> may provide removal of CO from blood in a patient having CO poisoning. For example, the extracorporeal phototherapy system <NUM> may provide sufficient removal of CO to allow the treatment of CO poisoning in environments where medical care is not easily accessible and breathing O<NUM> is not helping treat the CO poisoning. Typically, to treat a patient having CO poisoning the blood inlet port <NUM> may be connected to a pump, which is configured to remove whole blood from a patient, and the blood outlet port <NUM> may be connected to the patient (e.g., via a cannula inserted into a vein of the patient). The gas inlet port <NUM> may be connected to a gas supply configured to flow, for example, <NUM>% O<NUM> through the internal channels <NUM> of the plurality of microporous hollow fiber membranes <NUM> to the gas outlet port <NUM>.

With the gas and blood flows connected the oxygenator <NUM>, the flow of whole blood and oxygen may begin, for example, with the gas flow rate being approximately <NUM> times greater than or equal to the blood flow rate, or approximately <NUM> times greater than or equal to the blood flow rate. While the blood and gas are flowing through the oxygenator <NUM>, the first light source <NUM> and the second light source <NUM> may emit light onto opposing sides of the oxygenator <NUM>, specifically, onto treatment surfaces <NUM> arranged on opposing sides of the blood compartment <NUM>. The light emitted by the first light source <NUM> and the second light source <NUM> may penetrate through the plurality of membrane layers <NUM>, for example, due to the thickness T defined by the plurality of membrane layers <NUM> and the penetration capabilities of the light emitted by the first light source <NUM> and the second light source <NUM>. The photons emitted by the first light source <NUM> and the second light source <NUM> may be absorbed by COHb in the blood and photodisassociate the COHb into CO and Hb. The first light source <NUM> and/or the second light source <NUM> may be arranged inside of or outside of the oxygenator and/or can also be located on a cooling device <NUM>.

Since the partial pressure of oxygen flowing through the internal channels <NUM> of the plurality of microporous hollow fiber membranes <NUM> is much greater than in the blood flowing over the external surfaces <NUM>, oxygen may diffuse through the plurality of microporous hollow fiber membranes <NUM> to bind to deoxygenated Hb. The CO may diffuse into the plurality of microporous hollow fiber membranes <NUM> and the gas flow may expel the CO from the oxygenator <NUM>. As such, the design and properties of the extracorporeal phototherapy system <NUM> may facilitate efficient and effective removal of CO from whole blood in a patient having CO poisoning.

Of note the average human or rat has a blood volume of <NUM>-<NUM>% of body weight or for a <NUM> human that is about <NUM> liters total blood volume. To clean out most of the CO and replace with <NUM>, one must treat <NUM> to remove <NUM>% of the CO. As a non-limiting example, if one can process vein-to-vein blood extracorporeally at <NUM>/min to remove <NUM>% of CO on a single phototherapy pass, a liter can be processed every <NUM> minutes.

The following examples set forth, in detail, ways in which the extracorporeal phototherapy systems described herein may be used or implemented, and will enable one of skill in the art to more readily understand the principles thereof. The following examples are presented by way of illustration and are not meant to be limiting in any way.

A membrane oxygenator was built with a configuration suitable for blood phototherapy and tested the device in an in vitro model of veno-venous extracorporeal blood circulation. The in vitro circuit for blood circulation consisted of an open reservoir (<NUM> syringe), a roller pump (NE-<NUM>-G, Farmingdale, NY), silicone tubing and a membrane oxygenator. Blood entering and exiting the CO photo-remover was collected while the CO photo-remover was perfused with deoxygenated blood and ventilated with <NUM>% oxygen at <NUM>/min. For each pair of samples, the actual oxygen transfer and the maximum oxygen transfer were calculated as following:
<MAT> <MAT>
Where:
<MAT> <MAT> <MAT><MAT>.

In all equations 'C' refers to content of oxygen in blood, `pre' refers to blood entering the oxygenator and 'post' refers to blood exiting the oxygenator.

To create a membrane oxygenator (CO photo-remover) with optimal characteristics for both oxygen transfer, CO removal and venous blood light exposure, a microporous polypropylene membrane for gas exchange was enclosed within and a clear plexiglass case to allow light penetration. The polypropylene membrane was obtained from a disassembled cardiopulmonary bypass oxygenator and cut into 7x7 cm sections as shown in <FIG>. Eight sections were placed on top of each other, with each layer rotated <NUM> degrees relative to the one below as shown in <FIG>. The edges of the membranes were sealed with silicone rubber adhesive and enclosed in a clear plexiglass case with ports formed therein to provide a blood inlet <NUM>, a blood outlet (not shown), a gas inlet <NUM>, and a gas outlet (not shown) as shown in <FIG>. The configuration of the device was such that two sealed compartments were obtained: a compartment for blood flowing around the hollow fibers, and a compartment for oxygen flowing into the hollow fibers as shown in <FIG>. The size of the chamber containing the hollow fibers and the blood was <NUM> centimeters (cm) wide, <NUM> long, and <NUM> in height. Within the chamber, the priming volume for blood was <NUM>, while the remaining volume was occupied by the hollow fibers. The surface area for gas exchange was <NUM><NUM> and the total surface area for phototherapy was <NUM><NUM>.

To determine the in vitro oxygenating performance of the CO photo-remover, deoxygenated whole blood was circulated through the CO photo-remover at various flow rates while the device was "ventilated" with <NUM>% oxygen (see <FIG>). In commercially available extracorporeal membrane oxygenation devices, the partial pressure of oxygen in blood (PO<NUM>) exiting the membrane lung is between <NUM> and <NUM> mmHg (see, e.g., <FIG>). The PO<NUM> of the blood entering and exiting the CO photo-remover was <NUM>±<NUM> and <NUM>±<NUM> mmHg, respectively. The actual oxygen transfer was similar to the maximum oxygen transfer (R2=<NUM>, Slope=<NUM>, P<<NUM>, see <FIG>) and the oxygen transfer increased linearly with increasing blood flow rate (R2=<NUM>, P<<NUM>, see <FIG>). These results indicate that the CO photo-remover has an oxygen transfer performance equivalent to a commercial device used for cardiopulmonary bypass and extracorporeal membrane oxygenation.

To test whether the newly developed CO photo-remover was an effective approach to treating CO poisoned blood in vitro, human blood was circulated through the device using a roller pump while the membranes were ventilated with <NUM>% CO in nitrogen. After <NUM>-<NUM> minutes, <NUM>-<NUM>% of hemoglobin was saturated with CO. The CO photo-remover was then ventilated with <NUM>% oxygen at <NUM>/min and was exposed to LEDs generated blue (<NUM>), green (<NUM>), red (<NUM>) or no light. The developed light sources are shown in <FIG>. Light emitting diodes (LEDs, Mouser Electronics, Mansfield, TX), with a maximum power of <NUM> mW, were used to produce green (<NUM>), red (<NUM>) or blue (<NUM>) light. During ECCOR with phototherapy (ECCOR-P), the CO photo-remover was irradiated using a total of <NUM> LEDs, four on each side of the membrane oxygenator. The irradiance of phototherapy (the light power over the surface area of exposure) was approximately <NUM> mW/cm<NUM>. LEDs were attached to heat sinks, which were ventilated with small fans to dissipate the heat produced during phototherapy (see, e.g., <FIG>).

Serial samples of blood were collected to measure COHb and to calculate COHb half-life (COHb-t<NUM>/<NUM>), while CO concentration exiting the CO photo-remover was measured continuously. During circulation of CO poisoned blood through the CO photo-remover, while the device was ventilated with <NUM>% oxygen but was not treated with phototherapy (control), the COHb-t<NUM>/<NUM> was <NUM>±<NUM>. Compared to control (no exposure to light), addition of either blue or green light reduced COHb-t<NUM>/<NUM> by approximately <NUM>% (to <NUM>±<NUM> and <NUM>±<NUM> for blue or green light, respectively, each with p<<NUM> compared to control, see <FIG>). Exposure of the device to red light reduced COHb-t<NUM>/<NUM> to <NUM>±<NUM>, reflecting a <NUM>% reduction compared to no light (p<<NUM>) and <NUM>% reduction compared to blue or green light (p<<NUM> for each comparison). The CO exiting the photo-remover during phototherapy with light (and exposure to <NUM>% oxygen) was greater than during treatment with <NUM>% oxygen alone. Exposure of the CO photo-remover to red light resulted in greater CO elimination than blue or green phototherapy (see <FIG>). These results show that phototherapy increases the rate of CO elimination from blood in vitro and that red light is more effective than blue or green light at enhancing the rate of CO removal.

All animal experiments were approved by the Subcommittee on Research Animal Care of the Massachusetts General Hospital, Boston, Mass. Anesthetized and mechanically ventilated Sprague Dawley rats weighing <NUM>-<NUM> were tested. Rats were anesthetized with Isoflurane <NUM>% in oxygen for <NUM>-<NUM> minutes in a plexiglass chamber. Following a tracheostomy, rocuronium (<NUM>•kg-<NUM>) was injected (i. ) to induce muscle relaxation and rats were mechanically ventilated (Inspira; Harvard Apparatus, Holliston, Mass). Volume-controlled ventilation was provided at a respiratory rate of <NUM> breaths•min-<NUM>, a tidal volume of <NUM>•kg-<NUM>, positive end expiratory pressure (PEEP) of <NUM> cmH<NUM>O. Anesthesia was maintained with <NUM>-<NUM>% isoflurane and continuous muscle relaxation was provided with rocuronium (<NUM>-<NUM>•kg-<NUM>•h-<NUM>). Airway pressure was continuously monitored, as well as end tidal CO<NUM> (ETCO<NUM>) which was measured by a capnometer (PhysioSuite, CapnoScan End-Tidal CO<NUM> Monitor, Kent Scientific, Torrington, Conn).

The right carotid artery was cannulated with a PE20 catheter for blood sampling and arterial blood pressure monitoring. A bolus of heparin (<NUM> UI•kg-<NUM>) and subsequent continuous infusion at <NUM> UI•kg-<NUM>•h-<NUM> was administered for blood anticoagulation. A custom-made <NUM>-hole, <NUM>-gauge cannula was placed in the right femoral vein and a <NUM>-gauge cannula (Introcan Safety, B Brown Medical Inc. , Irvine, CA) was placed in the right jugular vein. Fluid resuscitation was maintained infusing <NUM>% Saline at a rate of <NUM> to <NUM>•kg-<NUM>•h-<NUM>.

To determine whether the CO photo-remover was able to increase the rate of CO elimination from blood in vivo, the device was tested in a rat model of CO poisoning (see <FIG>). Anesthetized and mechanically ventilated rats were poisoned by breathing <NUM> ppm CO in air for <NUM>. All animals underwent veno-venous extracorporeal blood circulation with blood flow rate ranging from <NUM> to <NUM>/kg/min (which corresponds to approximately <NUM>-<NUM>% of the rat's cardiac output) and were treated by breathing <NUM>% oxygen while the CO photo-remover was provided with: <NUM>) neither gas nor light (control); <NUM>) gas flow (<NUM>% O<NUM> and <NUM>% CO<NUM>) but no phototherapy (ECCOR); <NUM>) gas flow and phototherapy with combined green and blue light (ECCOR-P-Green/Blue); <NUM>) gas flow and phototherapy with red light (ECCOR-P-Red).

In control animals, neither gas flow nor light was applied to the CO-photo-remover. No CO was eliminated by the device (see <FIG>) and the COHb-t<NUM>/<NUM> was <NUM>±<NUM>. Addition of gas flow, but no light, to the CO photo-remover (ECCOR) reduced COHb-t<NUM>/<NUM> by <NUM>% (<NUM>±<NUM> vs. <NUM>±<NUM>, p<<NUM> see <FIG>). As illustrated in <FIG>, irradiation of the device with green and blue light produced a <NUM>% reduction in COHb-t<NUM>/<NUM> compared to controls (<NUM>±<NUM> vs. <NUM>±<NUM>, p<<NUM>) and a <NUM>% reduction in COHb-t<NUM>/<NUM> compared to ECCOR with gas, but without light (<NUM>±<NUM> vs. <NUM>±<NUM> p<<NUM>). Red light produced a <NUM>% reduction in COHb-t<NUM>/<NUM> compared to control (<NUM>±<NUM> vs. <NUM>±<NUM>,p<<NUM>) and a <NUM>% reduction in COHb-t<NUM>/<NUM> compared to ECCOR with gas but without light (<NUM>±<NUM> vs. <NUM>±<NUM>, p<<NUM>). These results show that the extracorporeal removal of CO using phototherapy increases the rate of blood CO elimination in vivo.

Because the CO eliminated by the CO photo-remover during phototherapy (ECCOR-P-Green/Blue and ECCOR-P-Red) was significantly higher than the CO eliminated without phototherapy (ECCOR - only gas flow), there was less CO remaining to be exhaled from the lungs of treated animals compared to control rats (see <FIG>). Taken together, these results show that the extracorporeal removal of CO using phototherapy increases the rate of blood CO elimination in vivo.

To determine whether the faster reduction of COHb observed with the combination of ECCOR and phototherapy has a beneficial effect on tissue oxygenation after CO poisoning, a more severe model of CO poisoning was developed. Rats were anesthetized and poisoned by breathing <NUM> ppm CO in air for <NUM> minutes and developed tissue hypoxia and lactic acidosis. During CO poisoning, mean arterial pressure (MAP) decreased from <NUM>±<NUM> to <NUM>±<NUM> mmHg (p<<NUM>) and heart rate (HR) increased from <NUM>±<NUM> to <NUM>±<NUM> beats per minute (p<<NUM>). Arterial levels of COHb increased to <NUM>±<NUM>% at the end of the CO poisoning period, while venous PO<NUM> decreased from <NUM>±<NUM> to <NUM>±<NUM> mmHg (p<<NUM>). Lactate concentration increased from <NUM>±<NUM> before CO poisoning to <NUM>±<NUM> mmol/L (p<<NUM>) at the end of <NUM> minutes and produced acidosis, as suggested by a decreased arterial base excess (from <NUM>±<NUM> to -<NUM>±<NUM> mmol/L, p<<NUM>).

After poisoning, animals were treated by breathing air so as to mimic a situation of reduced arterial oxygenation, as may occur in a patient with acute lung injury (ARDS) and impaired gas exchange. All animals were treated with veno-venous extracorporeal blood circulation with blood flow rates ranging from <NUM> to <NUM>/kg/min. In control animals the device was provided with neither gas flow nor phototherapy and the COHb-t<NUM>/<NUM> was <NUM>±<NUM> (<FIG>). Treatment with ECCOR and gas flow, but no phototherapy, reduced COHb-t<NUM>/<NUM> by <NUM>% (<NUM>±<NUM> vs. <NUM>±<NUM> p<<NUM>). Treatment with ECCOR, gas flow and combined green and blue light (ECCOR-P-Green/Blue) reduced COHb-t<NUM>/<NUM> by <NUM>% compared to control animals (<NUM>±<NUM> vs. <NUM>±<NUM>, p<<NUM>). Treatment with ECCOR gas flow and red light (ECCOR-P-Red) reduced COHb-t<NUM>/<NUM> by <NUM>% compared to controls (<NUM>±<NUM> vs. <NUM>±<NUM>, p<<NUM>) and by <NUM>% compared to treatment with ECCOR-P-Green/Blue (<NUM>±<NUM> vs. <NUM>±<NUM>, p=<NUM>).

At the beginning of the treatment period, the elimination of CO from the lungs of CO-poisoned animals was similar in all four groups (<FIG>). In later phases of the treatment period, the CO exhaled from the lungs of control animals was higher than in treated animals, as a greater amount of COHb remained in the circulation and more CO was available to be removed by the lungs. The elimination of CO from the CO photo-remover was significantly greater using ECCOR with red light than with ECCOR alone or with ECCOR with green and blue light (see <FIG>).

Animals treated with ECCOR-P-Red or ECCOR-P-Green/Blue had a faster return of venous PO<NUM> to baseline (see <FIG>) compared to control animals (for which neither gas flow nor phototherapy was applied to the device). Lactate clearance was also faster in ECCOR-P-treated animals (see <FIG>), resulting in a more rapid return of base excess to baseline values and correction of metabolic acidosis (see <FIG>).

Taken together, these results show that in CO-poisoned rats breathing room air, veno-venous extracorporeal removal of CO using phototherapy dramatically increases the rate of CO elimination and that red light is more effective than the combination of green and blue light in removing CO from the blood of CO poisoned rats. The faster removal of CO from circulating blood is associated with improved tissue oxygenation, as well as faster clearance of systemic lactate and correction of metabolic acidosis.

In rats that were poisoned with CO, the use of ECCOR-P-Red doubled the rate of CO elimination compared to rats breathing <NUM>% oxygen and produced a five-fold increase in the rate of CO removal in rats breathing room air. It was hypothesized that ECCOR-P-Red would be particularly beneficial in a situation of limited gas exchange, such as may occur in patients with acute lung injury. An intravenous injection of oleic acid was used to produce a rat model of acute lung injury and impaired gas exchange (see <FIG>). This model has a high degree of reproducibility and the histopathological and physiological changes caused by oleic acid are similar to those seen in patients with ARDS. After oleic acid injection, animals were poisoned with <NUM> ppm CO for <NUM> minutes. All of the control animals, treated with <NUM>% oxygen but no extracorporeal circulation, died within <NUM> minutes after the initiation of treatment. In contrast, all animals treated with <NUM>% oxygen ventilation and ECCOR-P-Red (initiated after the poisoning) survived until the endpoint of the study (<NUM> minutes after the initiation of treatment; see <FIG>). The severity of the acute lung injury and the CO poisoning level was comparable in the two groups: <NUM>) The ratio between PaO<NUM> and FiO<NUM> (P/F ratio) and the respiratory system compliance (Crs) were significantly reduced at the end of the CO poisoning (and beginning of treatment) in both groups (see <FIG>); <NUM>) Arterial pH, PO<NUM> and O<NUM>Hb levels similarly decreased during lung injury and CO poisoning (see <FIG>). The partial pressure of carbon dioxide (PaCO<NUM>) initially increased due to lung injury, and then decreased during CO poisoning, likely due to reduced CO<NUM> production in the setting of tissue hypoxia (see <FIG>); <NUM>) Prior to treatment, mean arterial pressure, heart rate and the arterial blood lactate levels were similar in both groups (see Figs. <NUM>-<NUM>).

In oleic acid treated and CO poisoned rats ventilated with <NUM>% oxygen, the circulating COHb levels decreased faster in rats treated with ECCOR-P-Red than in rats that were treated with <NUM>% oxygen alone. (COHb-t<NUM>/<NUM>: <NUM>±<NUM> vs. <NUM>±<NUM>, p=<NUM>, see Fig. <NUM>). Compared to control rats, rats treated with ECCOR-P-Red had significantly higher pHa and O<NUM>Hb levels and lower levels of PaCO<NUM> during the treatment period. These results show that, in rats with acute lung injury and CO poisoning, treatment with the veno-venous extracorporeal removal of CO using phototherapy markedly increased the rate of CO elimination and improved overall survival.

To assess whether the efficacy of CO removal by veno-venous ECCOR-P is altered by changing the rate of blood circulating through the device, rats were poisoned with <NUM> ppm CO in air and then treated with <NUM>% oxygen and ECCOR-P-Red at different blood flow rates. Treatment with ECCOR-P-Red increased the rate of CO elimination at blood flows ranging from <NUM> to <NUM>/kg/min (see <FIG>). The relationship between COHb-t<NUM>/<NUM> and the veno-venous extracorporeal blood flow rate is described by an exponential decay curve (Y=(Y<NUM>-Plateau)•exp(-K•X)+Plateau, (Figure 6A, R<NUM>=<NUM>). When the blood flow was greater than <NUM>/kg/min (which corresponds to approximately <NUM>-<NUM>% of the rat's cardiac output), a CO removal plateau was reached (COHb-t<NUM>/<NUM> plateau = <NUM>), indicating that a further increase in the blood flow rate did not increase the rate of CO elimination.

To investigate whether ECCOR-P is effective at a wide range of blood flow rates in animals breathing a lower concentration of oxygen, rats were poisoned with <NUM> ppm CO in air and then treated by breathing air instead of <NUM>% oxygen. The rats were treated with ECCOR-P-Red at different blood flow rates. ECCOR-P-Red was effective at blood flows ranging from <NUM> to <NUM>/kg/min, with a COHb-t<NUM>/<NUM> plateau of <NUM> (see <FIG>, R<NUM>=<NUM>).

At each blood flow rate, the performance of the CO photo-remover was assessed by measuring the amount of CO in the blood entering the device and the amount of CO in the gas effluent. At high blood flow rates, approximately <NUM>% of the CO entering the device was eliminated. In contrast, at lower blood flow rates, up to <NUM>% of the CO entering the device was eliminated (see <FIG>). These results show that the extracorporeal removal of CO using phototherapy is highly effective at a wide range of blood flow rates, and that at low blood flow rates more CO is eliminated per unit of blood entering the CO photo-remover.

The rat-sized CO photo-remover developed as described above was tested to assess the effect of wavelength on blood temperature at the blood outlet port. The size of the blood compartment was <NUM> × <NUM> and <NUM> layers of gas exchange membranes were used. The gas exchange area was <NUM><NUM>. The CO photo-remover was illuminated with <NUM> LEDs from the top and at the bottom. Blood volume = <NUM>, Hb concentration = <NUM>-<NUM>/dL, blood flow = <NUM>/min, gas flow = <NUM>/min.

As illustrated in <FIG>, the use of no phototherapy resulted in the blood temperature slightly decreasing over time, while all of the phototherapy tests resulted in an increase in blood temperature. However, the use of red light resulted in the lowest increase in blood temperature, when compared to the use of green light and blue light, which further demonstrates the efficacy of using ECCOR-P treatment with red light to eliminate CO from blood.

The rat-sized CO photo-remover developed as described above was tested and in vitro COHb-t<NUM>/<NUM> was measured during treatment of blood with <NUM>% O<NUM>, with or without red phototherapy, with a CO photo-remover having <NUM>, <NUM>, or <NUM> layers of membranes. As illustrated in <FIG>, red phototherapy is still effective at CO removal when increasing the blood compartment from <NUM> layers to <NUM> layers. The greatest reduction in COHb-t<NUM>/<NUM>, when comparing no red phototherapy to with red phototherapy, is seen for the <NUM> layer configuration. This is likely due to the ability of the red light to fully penetrate all of the layers of the CO photo-remover. It is hypothesized that there is a maximum thickness where the phototherapy effect diminishes and the light is no longer able to sufficiently penetrate to reach the blood layers. In some non-limiting examples, the number of layers may define a thickness that is less than <NUM>.

Experiments were performed with a modified-commercially available oxygenator (LivaNova®). The heat exchanger and the blood inflow part were removed from the inside of the oxygenator. A self-made blood inflow part at the other side of the oxygenator was constructed. With these modifications, the oxygenator may be illuminated from the inside and at the outside with red high-power LEDs. The LEDs which are illuminating the inside of the oxygenator are placed on a self-made aluminium box through which cold water runs through. By this, the heat is removed from the oxygenator and the blood does not heat up.

As illustrated in <FIG>, red light at <NUM> was effective at removing CO from the human-sized oxygenator over all of the blood flow rates tested (see <FIG>). The gas flow rates during the experiments were ten times greater than the illustrated blood flow rates.

As illustrated in <FIG>, blood temperature increase was measured using red phototherapy at <NUM> and may be lowered to a medically manageable extent. The results illustrated that blood temperature increase is generally lowered with increasing blood flow rate. However, this trend would need to be balanced with the decreasing CO removal as blood flow increases as discussed herein. In some non-limiting examples, a cooling device may be placed in communication with the blood outlet port to selectively cool the outlet blood to a predetermined temperature.

A flat human-sized CO photo-remover was constructed (see <FIG>). The blood compartment was made with a different gas exchange membrane compared to the previous results (Celgard X30-<NUM> from the company <NUM>®). Wall thickness = <NUM>, outer diameter = <NUM>, internal diameter = <NUM>. The size of the blood compartment was <NUM> × <NUM>. As illustrated in <FIG>, the human-sized CO photo-remover was effective at significantly reducing COHb-t<NUM>/<NUM> during treatment of blood with <NUM>% O<NUM> with red phototherapy. Hb = <NUM>/dl, blood volume= <NUM>, blood flow = <NUM>/min, gas flow = <NUM>/min. Gas exchange area = <NUM><NUM>.

Within this specification embodiments have been described in a way which enables a clear and concise specification to be written, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the invention. For example, it will be appreciated that all preferred features described herein are applicable to all aspects of the invention described herein.

Thus, while the invention has been described in connection with particular embodiments and examples, the invention is not necessarily so limited, and that numerous other embodiments, examples, modifications and departures from the embodiments, examples are intended to be encompassed by the claims attached hereto.

Claim 1:
An extracorporeal phototherapy system (<NUM>) for removing carbon monoxide from whole blood, the extracorporeal phototherapy system comprising:
an oxygenator (<NUM>) including:
a plurality of membrane layers (<NUM>) each including a plurality of microporous hollow fiber membranes (<NUM>) each having an external surface and an internal channel, wherein each of the plurality of membrane layers is rotationally offset with respect to an adjacent layer;
a gas inlet port (<NUM>) in fluid communication with a first end (<NUM>) of the internal channels;
a gas outlet port (<NUM>) in fluid communication with a second end (<NUM>) of the internal channels;
a blood inlet port (<NUM>) in fluid communication with the external surfaces;
a blood outlet port (<NUM>) in fluid communication with the external surfaces;
a light source (<NUM>, <NUM>) configured to output light and arranged to emit the light output by the light source onto at least one surface of the oxygenator;
wherein the oxygenator includes a housing (<NUM>) enclosing the plurality of membrane layers; and
wherein the housing and the plurality of membrane layers define a planar shape.