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Transplantation Research

Organ transplantation creates a stressful environment for tissues and cells. During organ transplantation, the cells may undergo several modes of injury. Cold preservation is one of the major risk factors for organ dysfunction. Currently, solutions composed of electrolytes, carbohydrates, and buffers are added to the organs to prevent energy loss and increase the osmotic pressure of the solution. Tryptophan may be added as a cell membrane stabilizer. In addition, antioxidants may be added to suppress the deleterious effects of free radical generation.

P188 is at the center of an effective strategy to promote cell wound healing and improve preservation in the stressful environment of organ transplantation. P188 has been shown to be an effective cell membrane stabilizing agent. We have shown that P188 can seal cells against the loss of a fluorescent dye after electroporation (Lee et al. 1992). In the years following this initial finding, it has been demonstrated that P188 can also seal membrane pores in skeletal muscle cells after heat shock (Padanilam et al. 1994), enhance the functional recovery of lethally heat-shocked fibroblasts (Merchant et al. 1998), and decrease damage due to high ionizing radiation (Greenebaum et al. 2004). P188 has also been shown to protect embryonic hippocampal neurons against death due to a neurotoxin-induced loss of membrane integrity. The ability of these amphiphilic copolymers to repair cell membranes at millimolar concentrations distinguishes them from PEG, which requires molar concentrations to achieve the same goal. Furthermore, the diversity of cell types that P188 protects illustrates its versatility for multiple organ types.

Antioxidants, such as mannitol, are typically added to organ storage media. Polyethylene glycol, a major component of P188, has been shown to inhibit free radical production in a model of neuronal membrane damage.However, although there is tantalizing evidence that free radical scavengers and antioxidants may decrease cellular injury after trauma, clinical trials of antioxidant administration have mostly been negative to this point. As the extent of membrane damage due to free radicals becomes more evident, targeted membrane-sealing therapeutics will probably need to be included as an adjunct to the antioxidants, since antioxidants can only prevent, but not repair, irreversible injury.

There are several needs that must be met in order to translate basic science findings into workable solutions in the clinic. P188 satisfies several of these, namely that it can preserve cells and tissues with minimal structural and functional compromise from storage and processing, particularly for applications where immediate functional capacity is necessary, such as is the case with organ transplantation. P188 is also nontoxic and biocompatible and can therefore be added safely to any preservation fluid with the expectation that it will safely flush from the system following organ placement.