Perpetuation of the species requires that some minimum number of individuals survive to reproductive maturity. Individual survival in the face of environmental insults and entropic processes requires a mechanism that can maintain the functional integrity of tissues. That mechanism is regeneration. Regeneration maintains or restores the original structure and function of a tissue by recapitulating part of its embryonic development. Some tissues, such as blood and epithelia, undergo continual turnover and thus must replace themselves continually, a process called maintenance, or homeostatic regeneration. These tissues, as well as a number of others, also regenerate on a larger scale when damaged, a process called injury-induced regeneration. The relationship among regeneration, life, and death has been concisely summed up by one of the great masters of regenerative biology, Richard J. Goss, in the following words. "If there were no regeneration there could be no life. If everything regenerated there would be no death. All organisms exist between these two extremes. Other things being equal, they tend toward the latter end of the spectrum, never quite achieving immortality because this would be incompatible with reproduction" (Goss, 1969). In other words, we are in a constant battle that pits our ability to locally reverse the second law of thermodynamics (regenerate) against inexorable entropic processes, a battle that we ultimately lose as individuals, but win as a species through reproduction.
Nature has provided us with another mechanism for injury-induced repair, fibrosis, which patches a wound with scar tissue whose structure is quite different from the original tissue structure. Repair by fibrosis maintains the overall integrity of the tissue or organ, but at the expense of reducing its functional capacity. Fibrosis is the result of an inflammatory response to injury that produces a fibroblastic granulation tissue that is then remodeled into a virtually acellular collagenous scar.
Mammalian tissues that do not regenerate spontaneously are repaired by fibrosis. Even tissues capable of regeneration may repair by fibrosis if they suffer wounds of a size that exceeds their regenerative capacity. Furthermore, chronic degenerative diseases can promote fibrotic repair, neutralizing inherent regenerative ability. Prominent examples of tissues that undergo repair by scar tissue when injured are the dermis of the skin, meniscus and articular cartilage, the spinal cord and most regions of the brain, the neural retina and lens of the eye, cardiac muscle, lung, and kidney glomerulus. It is not that these tissues have no ability to regenerate. Many, if not all, initiate a regenerative response to injury, but the response is overwhelmed by a competing fibrotic response.
The cost of tissue damage due to regenerative deficiency is enormous in terms of health care (estimated to exceed $400 billion/yr in the United States alone), lost economic productivity, diminished quality of life, and premature death. In the United States, the health care costs of spinal cord injuries alone exceed $8 billion per year and $1.5 million per patient over a lifetime. Diabetes, heart, liver, and renal failure, chronic obstructive pulmonary diseases such as emphysema, macular degeneration and other retinal diseases, diseases of the nervous system such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's, Huntington's, and Alzheimer's, arthritis, burns, and traumatic injuries that damage skin, muscles, bones, ligaments, tendons, and joints are other major contributors to these fiscal and human costs. Thus, medical science seeks ways not only to prevent and cure underlying disease, but also to restore the structure and function of tissues and organs damaged by disease or traumatic injury.
There is currently great excitement over the possibility of replacing damaged body parts through the new field of regenerative medicine. What tends to be forgotten, however, is that regenerative medicine cannot develop its potential without a fundamental understanding of the biology of regeneration, driven by
FIGURE 1.1 Autotransplant of forehead skin flap to reconstruct the nose, described by Sushruta ~1000AD. The flap was cut to conform to the outline of a nose, peeled down and twisted 180° at the stalk (arrows). It was then positioned over the nasal area with the dermal side down and held in place with wooden rods until healed.
advances in molecular, cell and developmental biology, and information science and systems biology. This understanding is far from complete. Thus, I call this new field of tissue restoration regenerative biology and medicine to emphasize that understanding the biology of regeneration is prerequisite to establishing and practicing a regenerative medicine. The objective of regenerative biology is to understand the cellular and molecular mechanisms of regeneration where it occurs naturally and how these mechanisms differ from the mechanism of fibrosis. Regenerative medicine then seeks to use this understanding to devise therapies that will stimulate the functional regeneration of damaged human tissues that do not regenerate spontaneously, or whose regenerative capacity has been compromised.
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