Measuring and testing – Gas content of a liquid or a solid – Of a liquid
Reexamination Certificate
2000-03-24
2001-08-07
Williams, Hezron (Department: 2856)
Measuring and testing
Gas content of a liquid or a solid
Of a liquid
C073S064470, C600S323000, C600S364000
Reexamination Certificate
active
06269679
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a system and method for the characterization of gas transport properties, and applications therefore.
BACKGROUND
The world-wide need for donated blood is enormous. It was recently estimated that there is a world-wide shortage of donated blood in the area of 200 million units per year. While approximately 11 million units of blood are transfused in the United States each year, the number would be larger were it not for the concern about the transmission of infectious disease. Even with the extensive screening that is now performed on all donated blood, patients and their physicians still fear a repeat of the events of the 1980's, when many people were infected by HIV-contaminated blood. Approximately two-thirds of the donated blood in the U.S. is used during surgery, while the remainder is used in cases of emergency and for people with chronic anemia and other blood related ailments.
While the market remains essentially undeveloped in the U.S., a safe, effective and inexpensive blood substitute product could replace two-thirds of the transfusions, specifically in cases of surgery. Past research has demonstrated that the properties of surface-modified hemoglobin substitutes can be manipulated to provide improved blood flow to organs. See for example, U.S. Pat. No. 5,814,601, of Winslow, et al., which discloses a blood substitute with an oxygen-carrying component, the disclosure of which is incorporated herein by reference. However, in spite of the availability of blood substitutes, as yet, an inexpensive and reliable means for evaluating the properties of such blood substitutes has not been available.
Blood serves a duel function in the process of gas exchange within the body. It is responsible for the transport of oxygen to cells and tissue for aerobic metabolism. Secondly, blood functions to remove carbon dioxide, a by-product of aerobic metabolism, through the lungs. Failure to adequately perform these functions would result in eventual and inevitable cell death. In order for blood to successfully provide much-needed nutrients, as well as remove waste products from within the body, certain hemodynamic properties must be present. Fluid without the proper physicochemical properties will not function in the cardiovascular system.
Hemoglobin is the fundamental molecule for oxygen transport by blood. Hemoglobin is composed of four subunits, each subunit possessing an iron-containing heme group which is responsible for oxygen binding. With these four subunits, one hemoglobin molecule is capable of binding four oxygen molecules. Analysis of the hemoglobin-oxygen interaction is facilitated by plotting numerical blood saturation values against oxygen partial pressure, resulting in an oxygen equilibrium curve (OEC). The shape of the OEC is an important indicator of the ability of a blood sample to transport and deliver oxygen properly. Oxygen delivery needs to be precise. Early release will waste oxygen, and delivery of too much oxygen is believed to have detrimental effects on the vascular system including vasoconstriction and free radical production. In the design and evaluation of blood substitutes, the ability to emulate the precise delivery of oxygen by red blood cells is an important function that must be taken into consideration.
Successful and efficient gas transport is the first design consideration when developing a blood substitute. In natural blood systems, O
2
and CO
2
are transported by both convection and diffusion processes. Traditionally, analyses of hemoglobin-based oxygen carriers (HBOCs) have been done at equilibrium, thereby relying on the specific OEC. Further, these analyses have shed light on how HBOC effect vasoactivity in arterioles. The transfusion of HBOC into animal models have produced complex results but the dynamic properties of the cardiovascular system has made the analysis of gas transport properties difficult to obtain. Accordingly, a need remains for a method to analyze oxygen delivery by hemoglobin-based blood substitutes which simulates the physiological properties of the cardiovascular system while being completely removed from that system.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a system and method for the characterization of the diffusional gas transport properties of a fluid.
Another object of the present invention is to provide a system and method to characterize the gas transport properties of hemoglobin-based oxygen carriers.
Still another object of the present invention is to provide a method for the evaluation of gas transport properties of cell-free hemoglobins with respect to their ability to augment diffusive oxygen transport.
The artificial capillary testing apparatus (ACTA) of the present invention is designed to evaluate the gas transport/exchange properties of HBOC in isolation from physiological systems, while retaining the dynamics of convection and diffusion inherent in blood-gas transport systems.
Yet another object of the present invention is to provide a method to evaluate the amount of oxygen delivered by any given cell-free hemoglobin as a function of diffusion, hemoglobin concentration, and parameters defining any hemoglobin OEC, i.e., Adair constants.
In an exemplary embodiment, an artificial capillary testing apparatus (ACTA) is provided for evaluation of gas transport/exchange properties of a fluid. A sample fluid, having a known or measured partial gas pressure, is introduced from a gas-tight dispenser into an artificial capillary of known diameter located within an exchange chamber containing a flowing exchange gas. The artificial capillary is formed from a permeable material which permits gas exchange between the interior and exterior of the capillary. After exit from the artificial capillary, the effluent fluid is collected in a gas-tight collection cell, then removed from the apparatus to a gas analyzer to measure partial gas pressure. The dispenser, exchange chamber and collection cell are all enclosed within a temperature controlled cabinet. Monitoring of the environmental conditions within the exchange chamber is performed to confirm purity of the exchange gas. Flowmeters and other measurement devices can be inserted along the pathway upstream and/or downstream of the artificial capillary for monitoring or to provide additional data.
The amount of target gas transferred out of the capillary for a given length is calculated as a function of the gas diffusion constant, the partial gas pressure gradient, the capillary radius, the flow rate, and the distribution of gas in its various phases.
For use in measurement of oxygen transport properties of hemoglobin in blood or blood-substitutes, the apparatus is maintained at body temperature (37° C.) by providing temperature monitoring and controlling apparatus within the cabinet. The fluid is introduced using a gas-tight syringe after equilibrating the solution with humidified air, and calculating the partial oxygen pressure from the barometric pressure minus the water vapor pressure at 37° C. The fluid is pumped into the capillary at a predetermined flow rate to provide a specific residence time, initially with an air-equilibrated environment in the exchange chamber to confirm equal PO
2
at the entry and exit points. Humidified nitrogen at 37° C. is then admitted into the exchange chamber until no oxygen is detectable within the exchange chamber according to standard methods of measurement. The collection cell is purged of the initial set-up fluid. The sample fluid is then pumped through the artificial capillary so that the oxygen can diffuse through the capillary wall, and the sample is collected in the a gas-tight withdrawal syringe. The removed sample is tested using a blood gas analyzer or any other electrode system to measure PO
2
, PCO
2
, and pH. Total oxygen present in the fluid and transferred out of the capillary is calculated as a function of the diffusion constants for O
2
and HbO
2
, the difference in partial O
2
pressure inside and outside the capillary, the gr
McCarthy Michael R.
Vandegriff Kim D.
Winslow Robert M.
Brown Martin Haller & McClain LLP
Cygan Michael
The Regents of the University of California
Williams Hezron
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