There is today no harmonized EU regulatory framework for the marketing of products such as tissue engineered cartilage, bone and skin substitutes. This constitutes a considerable obstacle to improving patient access to these innovative medical technologies. The European Commission has proposed a draft Regulation, but some products may well be left out of its scope...
The development of human tissue engineering, and, in a wider sense, regenerative medicine, will change medical practice profoundly, offering better more cost-effective treatment, enhanced quality of life of patients and, in the future, a solution to overcome the shortage of donor organs for transplantation. The potential world-wide market for this cutting-edge sector has been evaluated at up to €400 billion[1].
The European Parliament is currently examining the draft Regulation on Advanced Therapy Medicinal Products published by the European Commission in November 2005. This legislation will establish harmonized rules for marketing human tissue engineering products as well as gene therapy products and somatic cell therapy products in the European Union. The aim is to close the current regulatory gap that exists for human tissue engineered products in particular. Indeed, gene therapy and somatic cell therapy products are classified as 'medicinal products' and already regulated under the Medicinal Products Directive (2003/63/EC).
The Commission proposal is to regulate the evaluation and authorization of all these products by building on the existing medicinal products legislation. However, as it stands, the draft Regulation could leave a number of human tissue engineered products unregulated - those that do not act as medicines, i.e. whose principal mode of action is neither pharmaceutical, nor metabolic, nor immunologic.
Demineralized bone products are a typical example: a bone powder or strip can be used to fill the hole left by an abscess in a patient's jawbone, for example. Such products can also be used to repair small defects in other bones and in the spinal vertebrae. They provide a support on which the patient's own bone cells can grow and repair the defect in a permanent way.
In the same way, some tissue engineered cartilage products manufactured ex-vivo serve as a supporting structure (nose, ear) or as a protective cushion (knee joint). Their mode of action also appears to be primarily physical/mechanical (neither pharmacological, nor immunological, nor metabolic).
Tissue engineered skin products consist of a sheet-like matrix (made of e.g. collagen, biodegradable synthetic or semi-synthetic polymers) and skin cells (usually extracted from the patient) grown ex vivo. The wounds are protected with this product, which allows the tissues underneath to recover in a fully biocompatible environment. As the original skin, the tissue engineered skin serves as mechanical defence and desiccation barrier during wound repair.
Some have argued that these products could actually be covered by the Medical Devices Directive 93/42/EC, if a number of adjustments to this legislation are made. According to the EU Joint Research Centre report "Human tissue-engineered products - Today's markets and future prospects" (October 2003), "Some tissue-engineered products might act primarily in a structural way (e.g. bones, cartilage), thus resembling medical devices. Also, they might act like pharmaceuticals (e.g. bioartificial liver or pancreas), or in both ways".
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Click here to view the Eucomed Tissue Engineering Vademecum
Click here to view the Eucomed position on the Advanced Therapy Products Regulation
Every year, thousands of people undergo aesthetic or reconstructive surgery, mainly wound treatment, breast enlargement or reduction, skin lifting and liposuction. Thanks to advances in medical technology these interventions have become available and affordable. Despite the development of increasingly safer procedures and better results, these are serious interventions which are not entirely risk free. But continuous research into medical technology has led to an ever increasing rate of success and satisfaction.
The number of deaths arising from burn injuries has decreased considerably in the last decades[3] thanks to a better knowledge of thermal injuries and their systemic consequences, innovation in medical technology and improved surgical techniques. However, although mortality rates are declining, patients that survive are often left with physical and emotional scars, and reduced functionality such as uncontrollable muscle contractions or loss of facial expression.
Burn injuries occur in three levels of severity: first, second and third degree burns. A first degree burn only affects the epidermis. The affected skin turns red and becomes painful. After a few days, the injury has completely healed without any scarring. In second degree burns, not only the epidermis, but also the underlying layer of skin is affected, resulting in painful blisters. The healing process takes a few weeks and scarring sometimes occurs. Third degree burns are characterised by dark, cardboard-like skin. The patient feels no pain since all skin layers, including the nerves, are charred. For people suffering from third degree burns, reconstructive surgery can be a life altering solution.
The effectiveness of burn treatment largely depends on correct diagnosis and appropriate wound management. As infection remains the leading cause of death in burn wound patients, immediate care is a vital part of the healing process and considerably determines the final outcome. In the case of second degree burns, the method of choice is debridement, a very painful but necessary procedure to avoid bacterial infections and other complications, and to stimulate the healing process, whereby damaged or dead tissue is removed surgically, autolytically, enzymatically or mechanically[4]. In the case of deep second or third degree burns, excision - removing layer after layer of dead skin until living tissue is exposed - is necessary to prepare the wound for a skin replacement operation.
To protect a severe burn wound from infection and possible scarring during recovery (skin around untreated burn wounds contracts), skin grafting is a commonly used procedure which can function as temporary wound covering or permanent skin replacement. New, healthy skin is "shaven" off part of the patient's body such as the stomach or buttocks and draped over the wound, being held in place by surgical staples, stitches or a pressure dressing. If new blood vessels start growing within the first 72 hours after the operation, the procedure will most likely be successful. This procedure is also know as an autograft (skin is taken from the patient's body to minimize chances of rejection). The donor site, the part of the body from which the skin was taken, usually heals within 2 weeks, depending on the thickness of the layer of skin that was taken. Grafts can be divided into two categories according to their thickness: split-thickness grafts (containing only the epidermis and part of the dermis) and full-thickness grafts (containing the entire epidermis and dermis). In cases where the surgeon opts for a split-thickness graft, the skin attaches more quickly to the wound and the donorsite heals more quickly, increasing the survival rate of the graft. From a functional and aesthetic perspective however, the best results are achieved with a thick graft[5]. In cases where the number of donorsites is limited, the graft will be expanded to a mesh graft. This allows for tissue from the patient's own body to be expanded to up to 9 times its original size.[6]
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Tissue engineered skin is often the only chance of survival for very severe burn patients, as large quantities of skin substitute can be generated rapidly in vitro. Cells extracted from the patient are cultured in vitro on a supporting biomaterial sheet-like matrix (collagen or biodegradable polymers). The surgeon covers the wounds with the product, which acts as a mechanical defence against infection, a dessication barrier and an aid to natural wound repair. As the tissue is grown from the patient's own cells it is not rejected by the immune system.
Tissue engineered skin is also used to treat chronic wounds (diabetic wounds or pressure ulcers, for example) and for plastic surgery. It can serve for testing in toxicology, pharmacology and cosmetics. However there are considerable difficulties with reimbursement by national health insurance schemes of treatments based on tissue engineered skin products. This tends to limit access to "self-payer" patients (mostly expensive aesthetic surgery applications)[7]. It is expected that the establishment of a harmonized EU regulatory framework will greatly contribute to disseminating this technology.
Burns are assessed in terms of total body surface area (TBSA), which is the percentage affected by partial thickness or full thickness burns (superficial thickness burns are not counted). The rule of nines is used as a quick and useful way to estimate the affected TBSA.
No matter how well the burn injury was treated, chances are high the patient will be left with some scars. There are, however, two major procedures that can help to mask them.
The two major surgical procedures commonly used today are dermabrasion and laser resurfacing. Dermabrasion, or skin planing, is a surgical procedure in which the top layers of the skin are surgically scraped off to soften the effects of scarring. Though dermabrasion smoothes the surface of the scar it will not remove the scar. Scars are permanent but their appearance will improve over time. As this procedure in fact wounds the skin, dermabrasion is a very painful operation usually requiring full anaesthesia and several weeks to heal. The healed skin generally has a smoother appearance. People undergoing dermabrasion can usually return to their daily activities after two weeks of recovery.
A recent development in the treatment of scars is laser resurfacing, sometimes called "laser peel," whereby a carbon dioxide (CO2) laser is used to remove areas of damaged or wrinkled skin, layer by layer. The procedure is not only useful for the treatment of scars after (burn) injuries, but also to minimize the appearance of wrinkles, especially around the mouth and the eyes. Although it is still a very new procedure, it has been shown that in a considerable number of cases, this surgical method produces less bruising and post-operative discomfort than is typically seen with other resurfacing methods. Other advantages of this innovative procedure include more precision when treating small areas, and less (or no) bleeding during the operation.
Burns are assessed in terms of total body surface area (TBSA), which is the percentage affected by partial thickness or full thickness burns (superficial thickness burns are not counted). The rule of nines is used as a quick and useful way to estimate the affected TBSA.
| COMPARISON CRITERIA | KELOID SCARS | HYPERTROPHIC SCARS | CONTRACTURES |
| Most common complexion | Dark | Light | N/A |
| Extends beyond original wound | Yes | No | Yes |
| Respond to treatment | Sometimes | Yes | Yes |
| Raised scarring | Yes | Yes | Yes |
| Common to burn injuries | No | Yes | Yes |
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Keloid scars are very similar to hypertrophic scars and are characterized by raised and ill defined growth of skin in the area of damaged skin. The main difference with hypertrophic scars is that keloids grow beyond the wound area, do not occur after burn injuries and are more likely to appear in people with highly pigmented skin.
A contracture scar is a permanent shortening of the skin, affecting underlying tendons and muscles and producing deformity. It occurs when normal elastic skin tissue is damaged and replaced by fast-growing, non-elastic tissue. Contracture scars hence limit movement of the affected skin area. If physical exercise does not improve the effects of the scarring, surgery may be required. Current treatments consist of excision, skin grafting and skin flapping. Alternatively, the surgeon can propose a new technique called Z-Plasty (a procedure in which the direction of the scar is rotated to reduce its contracture, making it more comfortable and less visible).
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[1] Report from the Institute for Prospective Technological Studies and Joint Research Centre of the European Commission, EUR 21000, October 2003.
[2] New organization of the European Commission Scientific Committees: click here
[3] 1 million reported burn injuries in the US alone - American Burn Association. Burn Incidence and Treatment in the US: 2000 Fact Sheet, August 2000. http://www.ameriburn.org
[4]http://www.wounds1.com/care/procedure20.cfm/19 [5] Joseph J. Disa, M.D., Himansu R. Shah, M.D., and Gordon Kaplan, M.D. Surface Reconstruction Procedures. ACS Surgery: Principles and Practice, WebMD, 2003
[6]http://www.brandwonden.be
[7] "Human tissue-engineered products - Today's markets and future prospects" (October 2003), the EU Joint Research Centre
