This application claims priority from U.S. Provisional Application No. 61/499,983, filed Jun. 22, 2011, the contents of which are incorporated herein by reference.
FIELD OF INVENTION
This invention relates to systems, processes, and methods for ex vivo organ preservation, maintenance, repair, and/or assessment. This invention also relates to preserved, maintained, repaired and/or assessed organs provided by the systems, processes and methods described herein.
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Organ transplantation is lifesaving for patients. For example, lung transplants can be lifesaving for individuals with end-stage lung diseases; however, the number of patients waiting for lung transplants greatly exceeds the number of available donors. On average, 15% of lungs from multi-organ donors are used for transplantation and the rest are typically considered unsuitable.
Currently, the use of static hypothermia is widely accepted for preserving organs after removal. There are drawbacks to this method, however, such as drawbacks related to keeping an organ in a hypothermic state for a period of time. For example, the inhibition of cellular metabolism as a result of hypothermia can make it difficult to repair an organ or assess its suitability or condition during the preservation period.
In addition, many organs are considered injured or too “high risk” to be transplanted in a human. For example, more than 80% of donor lungs are considered too high risk for reasons including lung injury that typically occurs after brain death and/or complications associated with treatment in intensive care units.
Although non-optimal donor organs, such as lungs with suboptimal gas-exchange function or infiltrates visible on chest radiographs, have been used with success, increased primary graft dysfunction (an acute lung injury typically occurring within 72 hours after transplantation) has been reported in some studies. These injuries can affect early outcomes and can be associated with an increased risk of chronic graft dysfunction.
The techniques currently used to assess an organ for transplant suitability cannot adequately identify every suitable organ because of hypothermic preservation conditions and time constraints. As a result, clinicians tend to be highly conservative when selecting donors, and because of the relatively small number of organs that are deemed to be acceptable, mortality in patients awaiting transplantation is high. Furthermore, current preservation and maintenance procedures do not allow for the possibility of repairing and/or improving a suitable or high risk organ.
Having an increased number of suitable organs, such as lungs, available to transplant is a promising means of augmenting the number of organ transplants and thereby saving more lives. Accordingly, there is a desire for a system that will adequately preserve and maintain an organ for a period of time and in such a condition that it can be assessed, repaired, and/or improved in order to give the transplant recipient the best chance for recovery.
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An aspect of the present invention is a repaired ex vivo organ suitable for transplantation in a human, said repaired ex vivo organ having undergone ex vivo organ perfusion for a maintenance period, wherein said organ had been assessed as being unsuitable for transplantation into a human before the maintenance period and was determined to be suitable for transplantation after the maintenance period. The repaired ex vivo organ can be a lung having a best ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of more than 350 mm Hg. In some embodiments, the lung may have been assessed as being unsuitable for transplantation because its best ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen was less than 300 mm Hg. The maintenance period of time can be at least 24 hours, 8 hours, 3 hours, or 1 hour.
In some embodiments, the repaired ex vivo organ can also undergone ex vivo perfusion for a treatment period. According to some embodiments, the repaired ex vivo organ is a lung and may have been assessed as being unsuitable for transplantation because it had pulmonary edema, pneumonia, or inflammation. In embodiments where the organ is a lung and was assessed as having injury or pulmonary edema, it may have been subjected to antibiotics, hyper-perfusion techniques, beta-agonists, anti-inflammatory agents, or flow techniques during the treatment period. In embodiments where the lung was assessed as having pneumonia, it may have been subjected to antibiotics or steroids during the treatment period. In embodiments where the lung was assessed as having inflammation, it may have been subjected to gene therapy, stem cells, or anti-coagulants during the treatment period. In some embodiments, the repaired ex vivo organ can be a lung, liver, heart, kidney, or pancreas.
Another aspect of the invention is a donor organ system for repairing and/or improving a donor organ so that the donor organ is suitable for transplantation into a human. The donor organ system comprises the steps of (i) determining the status of the organ by evaluating pre-selected criteria; (ii) subjecting the organ to an acellular perfusate at normothermic temperatures for a maintenance period; and (iii) determining improvement and/or repair of the organ by re-evaluating the pre-selected criteria. In some embodiments, the maintenance period can within the range of 1 to 10 hours, 1 to 7 hours, or 1 to 3 hours. In some embodiments, step (i) can be performed concurrently with step (ii). In some embodiments, the organ can be a lung, liver, heart, kidney, or pancreas.
The donor organ system of the present invention can further comprise the step of treating the organ with a suitable medical treatment for a treatment period after step (ii). In some embodiments, the treatment period is within the range of 1 to 10 hours, 1 to 7 hours, or 1 to 3 hours.
Another aspect of the invention is a method of improving an ex vivo organ, the method comprising the steps of (i) determining the status of the organ by evaluating pre-selected criteria; (ii) subjecting the organ to an acellular perfusate at normothermic temperatures for a maintenance period; and (iii) determining improvement of the organ by re-evaluating the pre-selected criteria. In some embodiments of the invention, the organ can be a lung, liver, heart, kidney, or pancreas. In an embodiment where the organ is a lung, the pre-selected criteria can include the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen. In some embodiments the preselected criteria can show an improvement of at least 10%, at least 20%, or at least 40% between steps (i) and (iii).
BRIEF DESCRIPTION OF DRAWINGS
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For a better understanding of embodiments of the organs, processes, systems, and methods described herein, and to show more clearly how they may be carried into effect, reference will be made by way of example to the accompanying drawings in which:
FIG. 1 is a representation of the donor organ systematic process according to an embodiment of the present invention;
FIG. 2 is a schematic drawing of the ex vivo organ perfusion system according to an embodiment of the present invention;
FIGS. 3A, 3B, 3C, and 3D are graphs showing ex vivo lung function according to an embodiment of the present invention;
FIG. 4 is a representation of the process of selecting lungs for ex vivo lung perfusion according to an embodiment of the present invention;
FIG. 5 is a chart showing preservation times of lungs subjected to ex vivo lung perfusion according to an embodiment of the present invention; and
FIGS. 6 A, B, C, and D are graphs showing lung function of lungs subjected to ex vivo lung perfusion according to an embodiment of the present invention.
DESCRIPTION OF INVENTION
It will be appreciated that for simplicity and clarity of illustration, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements or steps. In addition, numerous specific details are set forth in order to provide a thorough understanding of the embodiments described herein. However, it will be understood by those of ordinary skill in the art that the embodiments described herein may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the embodiments described herein. Furthermore, this description is not to be considered as limiting the scope of the embodiments described herein in any way, but rather as merely describing the implementation of the various embodiments described herein.
The present invention generally provides a systematic process for preserving, maintaining, repairing, and/or improving an organ isolated from a donor. The process also provides a method for assessing the organ to determine whether it is suitable for transplantation into a human. Organs subjected to this process can be improved candidates for transplantation compared to organs subjected to current transplantation protocols.
The improved process of providing an organ suitable for transplantation into a human is set out in FIG. 1 as process 100. Process 100 begins with donor organ 102. Donor organ 102 has been isolated from the donor by suitable procedures and is considered to be an ex vivo organ. Organs suitable for the present invention include any organ suitable for transplantation, including one or both lungs, liver, heart, kidney, pancreas, or a composite tissue, such as a face or hand. One or both lungs are preferred. Once donor organ 102 has been isolated from the donor, it can be subjected to standard evaluation 104. Standard evaluation 104 methods include methods traditionally used by the skilled person to assess whether an organ is suitable for transplantation. For example, clinicians often assess suitability based on factors such as the rate of change of the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (PO2 or PaO2/FIO2), pulmonary vascular resistance, peak inspiratory pressure, or dynamic compliance, bronchoscope findings, radiologic assessment, and direct examination of the lung during procurement. In addition, lungs that are obtained from donors without a heartbeat are often not considered suitable for transplantation as their function is more unpredictable.
If donor organ 102 is deemed to be an injured organ 108 by standard evaluation 104, it will be categorized according to treatment protocols. An injured organ is one that is deemed sub-optimal or too high risk to be successfully transplanted into a human. For example, an injured organ may have be indicated as such because of the presence of pneumonia, edema, or inflammation. Also, the injured organ may have an injury such as a disruption of the blood-alveolar barrier, a severe injury, such as a mechanical injury, or an injury that is difficult to determine, such as a non-specific injury. In addition, or in other cases, the injured organ may have sub-optimal physiologic criteria, such as sub-optimal PaO2/FIO2, pulmonary vascular resistance, peak inspiratory pressure, or dynamic compliance. Categorization of injured organ 108 can occur as part of standard evaluation 104, or as a separate step once donor organ 102 has been determined to be an injured organ 108. Categories of injury of injured organ 108 include, but are not limited to, severe injury 112, pneumonia 114, edema 116, inflammation 118, and non-specific injury 120. Generally, any organ that is considered “high risk” for transplantation into a human can fall under a category of injury.