MATERIAL MATTERS COLUMN
The repair process
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Hippocrates is reported to have said, “Healing is a matter of time, but sometimes it is a matter of opportunity.” In medical technology we are often faced with the requirement to assist in the healing process. This requirement may be based on social or economic pressures, including the perceived need to enhance the speed of recovery after sporting injuries. The question inevitably arises as to whether we are able to influence the former, that is, the rate of healing, or the latter, the repair process itself with the use of an increasing number of “opportunities.” It is also relevant to consider whether we can influence the overall quality of the healing, taking into account the varied nature of individuals and their different responses to injury. There are many technologies that may come into play here, including those that rely on mechanical means such as sutures, clips, plates and wires; those that involve some form of electrical or electromagnetic stimulation; and those that are based on a molecular intervention such as with a pharmaceutical agent.
Before we can assess just how good these technologies are, we should consider what the healing process involves and how, mechanistically, we could conceivably influence it. In this context, I will confine myself to healing processes that take place following trauma rather than disease. It is well known that adult humans have a limited capacity to heal injured tissues through the generation of new tissue that is identical to the tissue that has been damaged. It is obvious that skin can heal spontaneously through the generation of new skin tissue and that this can happen quickly, over a matter of days. Even here, however, there are significant limitations because rarely will the new skin exactly replicate the epidermal/dermal structure and it usually displays collagen rich scar tissue. In this way, the tissue is repaired and is a functional barrier and in most cases the deficiency is largely aesthetic. Bone is the other major tissue that can repair spontaneously. It is able to do so with the replication of structure that is identical to, and indistinguishable from, surrounding normal bone. However, it will take many weeks.
In the majority of the remaining tissues of the body, the ability of the body to repair itself is different. In soft connective tissue, the microvasculature can regenerate, as can extremely small nerves, but tissue largely heals through the formation of collagenous scar that is not able to replicate the properties of specialised tissues. Most nerves, when they are severed and displaced are not normally able to repair with new nerve tissue. Muscle usually reunites with scar tissue and so on.
Facilitating nature
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Professor David Williams DSc, FREng
is Professor of Tissue Engineering at the University of Liverpool and Director of the UK Centre for Tissue Engineering located in the Universities of Liverpool and Manchester. He is Editor-in-Chief of Biomaterials, the leading journal in the biomaterials field. He is Scientific Director of STEPS, the European Commission Framework VI Programme on a Systems Approach to Tissue Engineering Products and Processes. Professor Williams is also a Managing Partner of Morgan & Masterson LLC, a consulting partnership that focusses on global health-care issues. |
Thus, the properly functional generation of new tissue in the healing process is limited. When it does occur, however, the process of repair follows well established time-courses and mechanisms that involve inflammation and the signalling of cells through a variety of mediators so that they proliferate and express the new extracellular matrix. In general, and in otherwise healthy individuals, these processes cannot be speeded up, and healing is really a matter of time. There are no reliable medical technologies that speed up this natural pace of healing. What can be done, however, is to facilitate the repair process by providing a better environment for the healing to take place and possibly for producing a better quality of healed tissue. In essence, evolution has provided us with effective healing mechanisms and we should mainly be concerned with facilitating nature not trying to improve it.
The main method of facilitating nature is to mechanically bring together the surfaces of tissues that have been cut or broken. Well-established sutures, clips, fracture plates and other medical devices have been in use, highly successfully, for many years for this purpose. Even here, however, we can get it wrong through inappropriate mechanical intervention. Tissues require an optimal pattern of mechanical forces and under- or over-protection of the repair zone can delay the process or produce inferior results. Mechanical devices to facilitate wound apposition should do just that and no more; it is easy to offend the natural process and make matters worse. Of considerable importance here is the recent tendency to use biodegradable components for tissue repair, especially in bone repair. There is an obvious theoretical advantage in having a device that provides fixation or adaptation during the early phases of healing, which is then degraded and resorbed so that there is no long term presence of a medical device within the tissues. In spite of many years of development and clinical use, there are still problems with the optimisation of biodegradable polymers for these applications. These problems are primarily associated with an often adverse effect on the tissues by the products of the degradation process, especially in its late stages.
The role of intervention
Medical interventions may have a role to play in increasing the opportunities for healing, although this is nearly always in patients that are compromised in some way. Mention was made earlier about the healing process in otherwise healthy individuals. We do have differing abilities to heal: age is a common determinant, but also some disease states such as diabetes compromise healing ability. It is with bone, however, that the major interests lie. Non-union of fractures or extensively delayed union has been a significant concern in orthopaedics for many years. This occurs in some patients, often without any obvious underlying cause and any technology to produce a healing response would be enormously beneficial here. Electrical or electromagnetic stimulation has been attempted on these patients in various trials over the past few decades, whereby bone cells are provided with an electromagnetic stimulus to encourage osteoblast activity and/or mineralisation. The results have been varied, but in recent years there have been some indications that a significant number of previously non-union patients do eventually heal. Similarly, low intensity ultrasound has been used experimentally with some success.
The alternative to stimulus bone repair may well reside with biologically active molecules. Bone morphogenetic proteins are naturally occurring growth factors that stimulate bone formation. These molecules, derived naturally or made by recombinant means, have been found to improve bone regeneration under some circumstances. They may be incorporated into materials such as calcium phosphates and degradable polymers to stimulate bone formation. It is not only bone healing that may be facilitated by active molecules. The scar formation that occurs in skin may well prove to be controllable by the use of another molecule, the transforming growth factor TGFβ3, which is currently undergoing clinical trials for this application.
With tissue healing, therefore, it is not so much a case of using medical technology to enhance a natural, effective process under normal conditions, but rather its judicious use to facilitate the repair process that has been compromised, where nature cannot live up to our normal expectations. I like to think of the methods of intervention in the treatment of injury and disease as being those of repair, regeneration or replacement. Medical device technology is most obviously associated with replacement procedures and has a growing involvement in regeneration, as in tissue engineering. It is important to place the role of intervention in the repair category in the right perspective.
David Williams, Clinical Engineering Department, Royal Liverpool University Hospital, Liverpool L69 3BX, UK, tel. +44 151 706 5606, fax +44 151 706 5803, e-mail: dfw.ce@liverpool.ac.uk.
