Sunday, December 3, 2023
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"Various new technologies, including stem cells, tissue engineering, xenotransplantation, and organogenesis, all have potential for replacing or augmenting organ function," Jeffrey L. Platt, MD, Director of Transplantation Biology at the Mayo Clinic in Rochester, Minnesota, told Medscape (personal communication, 2/12/03). "These technologies have significant overlap. Organogenesis, the de novo development of organs, may use xenotransplantation as a way of producing organs in the future, that is, human organs developed in animals." However, biological and immunologic obstacles may delay application of these technologies.[1] In addition, the government and the public have voiced ethical objections to studying stem cells, because of their capacity to become embryos.
The best approach to organ replacement depends on the organ system involved and may change over time. In heart failure, for example, xenotransplantation initially seemed like the best solution, but Platt says that progress in implantable mechanical assist devices and cellular therapy to augment myocardial function now makes these approaches more practical. Using stem cells from the affected patient confers the advantage of avoiding the immune response to donor cells, but carries the theoretical disadvantage of limited proliferative potential. On the other hand, the more complex structure and function of the kidney and the lung limit potential progress in implantable devices or cellular therapy as a replacement for these organs. Cellular therapy is more effective when the structure of the failing organ is relatively simple, and when disease is localized rather than diffuse.
How then can we replace structurally complex organs? One potential solution is organogenesis, the growing of an organ from primitive cells or stem cells. Tissue engineering could assist organogenesis by providing a substrate to protect a small organoid and allow it to grow. The most obvious drawback of this approach is that the internal environment of a sick person is not likely to be conducive to in vivo organ regeneration or growth. Even if organogenesis is possible, it could take months or even years, Platt says, necessitating other therapies in the interim.
While contributing to the development of organogenesis, xenotransplantation combined with genetic engineering could deliver specific gene products to replace those that are defective or to promote tissue growth. Before xenotransplantation can be considered clinically practical, however, the problems of human immunologic responses to the xenograft and the possibility of transferring infectious agents from the donor to the host must be addressed.
Technologies for organ replacement can be complementary rather than competing, agreed David E.R. Sutherland, MD, PhD,[2] of the Department of Surgery at the University of Minnesota in Minneapolis. "It is unlikely that the current approach of major surgery and immunosuppression to treat end-stage disease will prevail for the duration of human existence," he said.
Alternatives to organ replacement therapy and the accompanying need for immunosuppression include prevention of disease in the first place, mechanical devices that replace lost function, and induction of repair or regeneration of the affected organ. Ultimately, future alternatives could include generation of a new organ. Disease prevention is a noncompeting technology, which should reduce the need for organ replacement. Screening of blood products may prevent liver failure caused by hepatitis C, and tight glycemic control has lowered the risk of diabetic nephropathy.
For end-stage heart, lung, and liver disease, most of the existing mechanical devices would have to be greatly improved to seriously compete with organ transplantation as the treatment of choice, but they may buy valuable time during the search for suitable donors. The mechanical devices most likely to supersede organ or cell transplantation are for all intents and purposes pumps: the artificial heart pumps blood, and the artificial beta cell pumps insulin.
A major drawback of artificial devices is that regulation of output and physiologic feedback mechanisms now rely on the human brain, which Sutherland described as "brilliant, but not as brilliant in every area as an idiot savant, which is how I look at the beta cell. It does only one thing, but it does it perfectly, while the brain has to guess, like the brain trying to adjust the temperature of a room using a fireplace and trying to guess how many logs to use."
As more feedback mechanisms are incorporated, Sutherland hopes that mechanical devices will improve, but organs such as the liver are difficult to fabricate, and others may be difficult to implant. The beta cell pump, however, is "simply a glucostat" that could be primed with an inexhaustible supply of Escherichia coli insulin. "I envision an artificial beta cell as becoming truly competitive with beta cell transplantation," he told Medscape. "However, a mechanical liver that can do the myriad of metabolic and excretory functions of an organ afflicted by structural disease seems remote."
