Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or... – Including perfusion; composition therefor
Reexamination Certificate
2000-07-28
2002-12-10
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
Including perfusion; composition therefor
C435S002000, C514S832000
Reexamination Certificate
active
06492103
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to organ preservation and hypothermic blood substitution. This invention particularly relates to compositions, processes and systems for organ and tissue preservation and/or hypothermic blood substitution.
2. Description of Related Art
Hypothermia is the bed rock of all useful methods of organ and tissue preservation, and has proven to be most effectively applied by controlling the extracellular environment of cells directly, and the intracellular environment indirectly, during cold exposure. Control of the extracellular environment of cells to optimise preservation is based upon different strategies that include either static cold storage (or flush preservation), or low temperature continuous perfusion. These different strategies call for different approaches to interventional control of the extracellular environment in order to optimize preservation, and hence different design elements for the solutions used to effect these strategies.
In principle, cold flush storage or preservation is based upon the premise that temperature reduction to near but not below the ice point (0° C.) precludes the need to support metabolism to any significant extent, and that the correct distribution of water and ions between the intracellular and extracellular compartments can be maintained by physical rather than metabolic means. During the period that metabolic pumps are inactivated, the driving force for transmembrane ion flux is the difference in ionic balance between intracellular and extracellular fluid. The driving force for water uptake (cell swelling) is the impermeant intracellular anions. Thus changes can be prevented or restricted by manipulating the extracellular environment to abolish chemical potential gradients. On this basis, a variety of flush, or organ washout, solutions have been devised and evaluated for cold storage. These solutions are often referred to as “intracellular” solutions due to their resemblance, in some respects, to intracellular fluid.
The principle design elements of the “intracellular” flush solutions has been to adjust the ionic balance (notably of the monovalent cations) and to raise the osmolality by including an impermeant solute to balance the intracellular osmotic pressure responsible for water uptake. However, the most important factor for the efficacy of cold flush solutions may be the prevention of cellular edema by inclusion of impermeant solutes since it has been established that ionic imbalances, especially potassium depletion, are readily and rapidly reversible.
Prior to 1988, the standard solution for clinical preservation of abdominal organs, principally the kidney, was Collins solution, which consists predominantly of potassium phosphate. magnesium sulfate and glucose. In recent years, however, this has been superseded either by a modified version called “EuroCollins” in which the magnesium sulfate is omitted, or more extensively by the University of Wisconsin solution (UW solution) in which much of the phosphate anion has been replaced with lactobionate, and in which glucose has been replaced with raffinose. These larger molecules provide better protection against adverse effects of cell swelling during hypothermic storage. The choice of solutions for heart preservation has been strongly influenced by the previous experience of cardiac surgeons with cardioplegic solutions in open-heart surgery. In this case the primary objective has been to produce rapid cessation of the heartbeat, and solutions were designed more with this in mind than with protection of the cells during preservation in mind. In particular, early studies suggested that the very high potassium levels (>100 mM) found in organ preservation solutions might be harmful to the heart. In fact, the solution most often used was St. Thomas's (Plegisol) with a potassium content of only 16 mM.
The choice of solution for cardioplegia and myocardial preservation remains controversial and widely varied. While UW solution has emerged as the industry standard for kidney, liver and pancreas, no such standard has been adopted for heart preservation. Moreover, the development of the variety of preservation solutions for organ storage has emphasized the need for careful optimization in relation to the specific characteristics of the tissue to be preserved.
Attention to biophysical properties of “intracellular” flush solutions, to restrict passive diffusional processes, has unquestionably led to the development of techniques that have provided the basis of clinical organ preservation during the past 30 years. Nevertheless, it is recognized that further optimization of cold flush solutions can be achieved by inclusion of biochemical and pharmacological components that will be effective in counteracting the deleterious effects of ischemia and reperfusion injury. To a limited extent this approach has been incorporated in the design of the University of Wisconsin organ preservation solution (UW solution marketed as “Viaspanrm”; DuPont) which has become the most widely used solution for cold flush preservation of kidneys, livers and pancreases. With due consideration for the effects of ischemia, hypoxia, hypothermia and reperfusion injury on cells, coupled with the proven efficacy of various existing organ preservation solutions, a general consensus of the most important characteristics in the design of hypothermic storage solutions has emerged. These include: minimizing of hypothermically induced cell swelling; preventing expansion of the interstitial space (especially important during perfusion); restricting ionic imbalances; preventing intracellular acidosis; preventing injury from free radicals; and providing substrates for regeneration of high energy phosphate compounds during reperfusion.
In continuous hypothermic perfusion preservation, the desirable properties of hypothermic solutions listed above are also applicable to controlling the extracellular environment by way of continuous perfusion techniques. In contrast to static cold storage, continuous perfusion is usually controlled at around 10° C. and is based upon a different principle: it is generally assumed that a moderate degree of cooling will reduce metabolic needs but that continuous perfusion is required to support the suppressed metabolism and remove catabolic products. Because it is assumed that sufficient metabolic activity remains to actively regulate a near-normal cell volume and ionic gradients, the perfusates are generally acellular, isotonic, well oxygenated solutions having a composition that more closely resembles plasma than intracellular fluid. Such perfusates are therefore designated as “extracellular” solutions, and are perfused through the vascular bed of an organ at a pressure sufficient to achieve uniform tissue distribution (typically 40-60 mm Hg). To balance this applied hydrostatic pressure and prevent interstitial edema, oncotic agents such as albumin or synthetic macromolecular colloids are incorporated into the perfusates. Substrate support of the remaining metabolism at ~10° C. is also an important consideration and it has been shown in several organs that high energy adenine nucleotides can be synthesized during hypothermic perfusion preservation.
In addition to the principal objective of supporting metabolism, continuous perfusion also provides other advantages over flush preservation. These include the wash out of accumulated lactate and protons, thereby removing the metabolic block on glycolysis; this is thought to be especially beneficial for organs that have suffered prior warm ischemia. Perfusion also facilitates the removal of erythrocytes from the microcirculation and helps to maintain vascular patency during prolonged storage. Continuous perfusion has been shown to provide the best means of achieving prolonged hypothermic preservation (e.g., 3-7 days for kidneys), but concerns for damage to the vascular endothelium during prolonged perfusion may be a limiting factor.
Although it has been experimentally verified that cell
Oliff & Berridg,e PLC
Organ Recovery Systems, Inc.
Weber Jon P.
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