Regenerative Medicine’s Auspicious Future
The manufacture of synthetic body parts to substitute damaged organs has been the vision of generations of scientists, and we are closer than ever to realizing that dream today.
It is hoped that this could provide a promising alternative to transplantation, which suffers from two critical issues: possible rejection by the patients’ immune system, and a shortage of donors.
This article surveys the historical breakthroughs made in this challenging yet fascinating field of medicine, and in particular the auspicious future of tissue engineering.
The 19th century brought many changes to the industrial landscape of Great Britain. Revolutions in the practice and scale of manufacturing fuelled the growth of an empire, and left lasting effects on Britain’s economy and urban areas which are still felt today. One of the most crucial advances was the concept of replaceable parts: by designing a product such that faulty parts could be substituted rather than requiring the entire product to be replaced. This allowed for greater consistency and longer product lifetimes, and the concept is now ubiquitous in modern product design.
This development was noted with interest by the medical community of the day, and it wasn’t long before the question emerged as to whether the same principle could be applied to humans; would it be possible to manufacture body parts to replace damaged originals? The possibilities of using ‘spare’ body parts had long been considered: accounts of Saint Damien and Saint Cosmas claim that they replaced a patient’s leg that had been lost to gangrene in the third century A.D. Later, Mary Shelley caught the imagination of the public with her novel Frankenstein, which explored the idea of creating a new living being composed of spare body parts.
The first step towards this goal was to show that organs from a donor could be transplanted into a patient such that their function was retained in the new environment. While this had been attempted in animals and in some humans, the often fatal issue of rejection meant that this method would not become routine until the 1970s after the discovery of the immunosuppressant drug cyclosporine.
The second crucial problem of transplantation remained: for every organ recipient there must be a donor, and the shortage of willing and able donors continues even to the present day. While living donors can be used in the case of some organs (such as the kidneys or liver), many organs for transplantation must be harvested from recently deceased donors, further limiting availability. This restriction means that transplantation cannot be a widespread intervention technique for diseased organs, and waiting lists are long and dispiriting; for example, there are currently 250,000 adults in the UK with congenital heart defects, yet only 131 heart transplants were performed in 2010/11; at an average cost to the NHS of £40,000 per transplant. Any increase in this number would also have a significant impact on public health budgets.
The dream of manufactured body parts therefore remains a priority goal for modern medicine. Approaches based on stem cells and other ‘living’ materials have advanced significantly in recent years but remain far from clinical use; this is due in part to the difficulty in organising an amorphous group of cells into the higher-order structures required to form a working organ.
on stem cells (…)
remain far from
clinical use; this
is due in part
to the difficulty
an amorphous group
of cells into the higher-
required to form a
Bridging the gap between the micro-scale of the cell and the macro-scale of body tissue remained a thorn in the side of attempts to grow replacement organs until the early 1990s. The answer came from the decidedly inorganic field of engineering: if cells cannot organise themselves, why not guide them with a pre-organised material, like a train along tracks? By taking materials with a defined framework to act as a ‘scaffold’ and seeding it with cells, biological structures suitable for replacing organic tissue could be grown.
This new approach has yielded success: the first implant of artificial tissue in a human patient occurred in 1991. In this procedure, an artificial polymer scaffold was seeded with cartilage cells taken from the patient’s own tissue, and successfully inserted to replace his missing sternum. With this breakthrough, similar procedures followed quickly: a new thumb constructed using a scaffold based on porous coral was implanted in 1998, and shortly afterwards, replacement pulmonary arteries were produced by researchers in Japan.
By taking materials with
a defined framework to
act as a ‘scaffold’ and
seeding it with cells,
suitable for replacing
organic tissue could be
This new field of medicine was fully established, and became known as tissue engineering. Despite its successes, the scale of the challenges yet to be faced soon became apparent. The scaffold material had to be very carefully selected so as to direct cell formation correctly, and successfully growing a large number of cells from small sample sizes proved to be a significant problem. Defects in the scaffold structure or a misshapen scaffold could lead to uneven cell growth making them unsuitable for implantation. Reliable methods for obtaining artificial tissue were (and remain) hard to come by, and the length of time taken to grow enough tissue (given that multiple attempts may be required) was a serious consideration for patients.
Even when enough suitable tissue for replacement could be produced, it was by no means guaranteed that the body would develop an adequate blood supply after implantation. And such an intensive, individual process is far from cheap; expanding its use beyond a handful of isolated cases remains problematic.
Nevertheless, the progress of tissue engineering has led to intensive research into suitable scaffolds. The list of requirements for such materials is long: they must be non-toxic, structurally and mechanically similar to the target tissue, allow interactions with seeded cells, and, ideally, cheap to produce. Depending on the target tissue, factors such as porosity, transparency, and injectability may also be important.
One class of materials which have emerged as frontrunners in fulfilling these needs are synthetic polymers: plastics. They are non-toxic, have properties that can be easily tuned to the specific requirements of the implant, and are inexpensive. Indeed some polymers were already being used for other medical applications before the advent of tissue engineering, and so any effects on human tissue are well documented.
Polymers such as poly(ethylene glycol) (PEG) and poly(vinyl acetate) (PVA) have been most widely applied due to their suitable properties and characteristics. They must be modified to mimic natural biological processes of development in order to be effective. Without these modifications, they are unable to send the chemical signals that cause cells develop, and so the scaffold is ineffective for organ growth.
Similar polymers have been invaluable in the creation of replica bone. Bone has been the target of much research due to its relatively simple anatomical structure and rigidity, which can be more easily replicated by synthetic materials. It is also an important target, as bone complaints are commonplace: over 200,000 spinal fusions are performed annually in the US alone, and these require painful and expensive bone grafting. By creating a carefully-designed mixture of polymers, and incorporating proteins to promote cellular growth and biocompatibility, researchers at Nottingham were able to create an injectable substance which hardens in the body into a rigid but porous structure. This ‘injectable bone’ was then an excellent scaffold to promote stem cell growth into new bone in the patient.
Research carried out at Imperial College by Prof. Molly Stevens has been critical in this context. Her work focuses on developing in vivo bone tissue growth through a ‘bone bioreactor’. Rather than grow the bone tissue in a laboratory and then surgically implant it, the bone bioreactor works by creating a space in the body into which regeneration of the patient’s own bone is directed. The ‘bioreactor space’ is kept open with a biocompatible polymer gel, which dissolves to make way for the growth of the new bone. After tests in rabbits, clinical trials of the process in humans are under way, and, if equally successful, could lead to a major clinical breakthrough.
Polymers (…) must be
able to mimic natural
biological processes of
natural development in
order to be effective
Polymers have also found applications that require biodegradability. Some plastics, mostly those linked by amide or ester bonds, are particularly susceptible to hydrolysis in the body, i.e. they are degraded and removed from the tissue site. While this would be a problem in cases where the scaffold is intended to remain part of the final structure, it is beneficial for the development of softer tissue and organs as it eliminates the need for surgical removal. The rate of degradation can be carefully designed through control of the synthesis and blending of polymer mixtures such that it neither disappears too quickly nor lingers too long in the body. The most advanced research is looking to match the rate of scaffold degradation to the rate of new tissue growth.
The Search Goes On
Despite its novelty, the potential offered by the scaffold method has led many researchers in the field to set ambitious goals. After the successful implantation of a tissue-engineered bladder by researchers in North Carolina, other soft tissues have become targets for replication: attempts to make an artificial pancreas using a scaffold of synthetic fibres and cells from the patient are underway, as are efforts towards a bioartificial liver using a collagen scaffold (intended as a short-term solution until a suitable transplant becomes available). Most recently, researchers at MIT have created a carbohydrate glass scaffold for liver tissue which also concurrently grows a network for blood supply, potentially solving a major problem in the production of large organs. Bone marrow, blood vessels and even erectile tissue are also in researchers’ sights.
While the idea of organs-to-order may seem to fall under the banner of science fiction, the achievements already made by researchers in this field certainly imply that this goal may be achievable in years to come. The use of highly artificial materials such as polymers is an unexpected but beautiful example of the interaction between seemingly distant fields, and a reminder of the value of scientific collaboration in the continuing development of medicine.
Stephen McCarthy is a recent Chemistry graduate, with an interest in polymers and the medicinal applications of chemistry.