Growing old, staying young

The body regenerates itself constantly, but fails with age: can technology help?

Regenerative medicine is one of the great biomedical challenges of this century. The basic idea is to repair, reconstruct, or engineer tissues - and to regenerate organs - before they become completely and irreversibly dysfunctional. Does it seem far fetched to you? Well, it isn't, because it is already happening.

Recent medical technology seeks to regenerate parts of the human body lost due to trauma, disease, and genetic factors. The examples are many: tissue for the heart, bladder, pancreas, and liver; bio-artificial cartilages, bio-artificial cornea, bone fixing devices encouraging the formation of callus. One sort of tissue after another, medical technology constantly conquers new ground.

Ageing reduces the efficiency of all our bodily systems, but does not destroy it. From the moment of conception, there is a natural balance in the body between tissue being destroyed and tissue being repaired. The rate of aging depends on this relationship, with many organs becoming progressively dysfunctional as we all grow old.

Have you perhaps an 80-year aunt who recently broke her leg ? Or may be an uncle who is 65 and has a heart problem ? Are you concerned about your mom's hip, or your dad's condition? Do not feel alone. We live in a society with a growing number of elderly people: 25% of the Europeans are older than 60 years. The World Health Organization predicts that by 2050 seniors will make up one-third of the earth's population. The number of seniors beyond 65 will double to more than one billion by 2020. You yourself who are reading, may well live to be in that lot, to be 100 years old or more.

Tissue engineering makes fast progresses

"Let’s think for instance to the recurring incidence of thigh-bone fracture in elderly people. Tissue engineering has the means to change the perspectives of recovering from such trauma" says Maria Espinosa y Carretero, specialist in biomaterials and tissue engineering at the EPO. "Some say that 80% of women worldwide would be in need of an artificial hip, and research in regenerative medicine is crucial in this regard ¹ ".

"I give another example: artificial cardiac valves. They can be made either of natural or of artificial tissue. The tissue of pigs is very good to use, but bears a limited lasting time, while an artificial tissue will definitely last more. Therefore the researchers are working to obtain more lasting bioengineered tissue valves ² ", explains Maria Espinosa. The relevance of what she says comes strongly into perspective when we think that, according to the World Health Organisation, heart disease is the deadliest ailment in the world. Thousands of patients need new hearts annually, and most die waiting.

"Another area is the treatment for burnings. If a patient needs a new spot of skin, the epidermis can be engineered ³ . Still another important area is that of tissue engineered prostheses, which - when implanted into a mammalian host - can serve as a functioning repair, augmentation, or replacement body part, or tissue structure, and undergo controlled biodegradation along with remodelling by the host's cells. These prosthesis function as a substitute body part and as a remodelling template for the in-growth of host cells."

A post-human future?

These technologies are benign and exciting. Yet, future developments in tissue engineering might trigger intricate juridical and ethical problems.

Bert Gordijn, Editor-in-Chief of the European Journal Medicine, Health Care and Philosophy, says that "tissue and organs developed in the laboratory would probably in time cease to be distinguishable from their endogenous equivalents in appearance and function. Under the influence of tissue engineering the difference between ‘natural’ bodies – without any interventions of the type described – and ‘manipulated’ bodies – containing artificial subparts – would become increasingly blurred. In time it may even become non-existent. The features distinguishing a human being from a machine or an artifact would also become increasingly vague."

He also considers that "tissue engineering would be providing not only restitutio ad integrum (restitution of the integral body and its functions), but also an improvement in human constitution beyond the purely curative. The two traditional areas of medicine, namely ‘healing’ and ‘prevention’, would be extended to include a third area, ‘enhancement’."

Scaffolds for life

Key component of tissue engineering and regenerative medicine are synthetic scaffolds and their interactions with cells ⁴ . Without the development of effective scaffold technologies, many specialists doubt significant progress can be made.

A scaffold is an artificial or natural matrix that mimics the natural environment around cells in the body. This three-dimensional scaffold must deliver important signals to cells to induce their proliferation and differentiation into specific tissues and organs. To jump start the cells into the regenerative process, they are given initial cues through the scaffold. Once the cells are on the right track to regenerate a tissue or an organ, the artificial matrix can be programmed to disappear into nutrients as cells elaborate into a natural matrix.

Completely artificial scaffolds can be made of polymers compatible with the human body, and research is still concentrated to avoid as much as possible rejection when the materials are implanted into the body. The use of collagens has shown to help in a meaningful way this kind of compatibility. The scaffolds are being designed at the nano- or micro-scale enabling scientists to create smart objects that can reach small spaces in the body. A nanometre is roughly 100000 times smaller than the width of a human hair.

Equally important is developing a practical technology to deliver these scaffolds to the appropriate location in a patient. Most of the time this happens by surgical interventions, but implantation by injection has advantages over conventional procedures of surgical transplant, and is under study. A great share of research is focusing into the interaction between biomaterials and the human body in order to obtain ever advanced grafts.

The magic powers of regeneration

Natural examples of tissue regeneration, fascinating biological problems in their own right, may also provide clues to these biomedical issues. While humans display poor regenerative ability, other vertebrates are able to regenerate an amazing spectrum of organs and body structures. Salamanders are the champion regenerators among vertebrates, boasting a repertoire of limb, tail, eye, jaw, and heart regeneration. The adult zebra-fish is able to regenerate the fin and heart.

With time, besides current cardiovascular and orthopaedic applications, this research will see many other uses, because regenerative medicine encompasses also cell therapy, which is an implantation by injection of suspensions of cells or tissues in a physiological solution.

No one knows exactly how cell therapy works. Basically, cell therapy is a form of transplanting, but instead of actually transplanting a whole organ, one transplants the cells of an organ. Under some conditions the transplanted cells then somehow bring about the revitalization of their corresponding organs.

No one knows how progenitor cells being suddenly implanted into the adult environment can be expected to grow and reconstitute the complex function and pattern of the adult tissue—normally a result of intricate genetic programs and cell-cell interactions that originally spanned months and even years of development. Yet, it seems they do reconstitute complex functions.

From the perspective of patenting

Maria Espinosa y Carretero graduated in biology and specialized in biochemistry at the University of Madrid. She is a biochemist, with a strong background in genetics and molecular biology. After an experience of three years at the Spanish Patent Office, Maria Espinosa joined the EPO, where she currently works with a group of experts who examine patent applications concerning biomaterials and the procedures for their implantation.

“As far as it is the healthcare industry who mainly invest in research about tissue engineering, this can be seen as a business issue - says Maria Espinosa - but we are aware that these technologies relate to the health of people: a very serious subject. Every aspect is deeply scrutinized. The ultimate goal is the achievement of biocompatible and lasting tissues".
Market demand is pulling strongly, and biotechnology companies are investing with the aim of obtaining better and better materials. As materials and artefacts are developed, for instance endoprotheses, so are methods for treatment of the human body by surgery or therapy, based on these inventions.

"Some countries – underlines Maria Espinosa - allow patenting of the surgical and therapeutic methods, and some do not. In Europe, these methods cannot be patented, and there is much case law in this respect, while in the USA they are not excluded from patentability".

The international scientific community is mostly against patentability of medical methods, but a shift toward running medical practices like business make some believe the Hippocratic ethic to be naive and out of date. Besides, medical methods such as ex-vivo gene therapy break new ground, and put all over the world the borders between what is patentable and what isn't into question.

The pharmaceutical and biotechnology industries look at this issue very carefully, because they prosecute patents when they find new uses for existing prescription drugs: were new medical uses of therapeutic substances not patentable, this would seriously damage their business and would reduce the incentives to invest in new pharmaceutical products.

US legislation specifies that medical procedures can be patented, but medical practitioners are exempted from liability when they conduct these procedures in the course of their practice. On the other hand, in Europe, protecting these medical methods with patents would be perceived as creating an obstacle to cure or even save the life of people. This is unacceptable in Europe: there are no European patents on medical methods.

Patenting investments related to materials for grafts or prostheses or for coating grafts or prostheses grew strongly in last decade, and are still growing. Click on the chart to see an enlarged version. (click to enlarge)

March 2006, Siena

Journalist: Rosario Simone
Expert opinion: Maria Espinosa y Carretero and Berthold Rutz at the EPO; Bert Gordijn at the University of Nijmegen.
Chart: Silvio Endrizzi, EPO.
Research and Coordination: Leo Giannotti, EPO.

¹see for instance EP1494625 (materials for hip replacement prosthesis)
²see for instance EP0871415 or EP0276975 or EP1230901
³see for instance EP1375647 (artificial dermis), or EP1046402 (aged skin equivalent), or EP1314440 (cultured skin)
⁴see for instance EP1384489 (biocompatible scaffold)

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