Work in the Dental School of the University of Dundee has led to identification of a cell activation factor named Migration Stimulating Factor, which works in concert with appropriate tissue matrices and matrix molecules in regeneration of normal tissue (contact a.m.schor@dundee.ac.uk for more details)

Many people in the world are walking around with tooth defects filled with amalgam, a mouldable metal mixture containing mercury. There is increasing concern about possible toxicity from this mercury. Several projects funded by EC's Brite-EuRam programmes in the current network and in previous R&D Frameworks have worked on replacement materials with polymeric, glass ionomeric and other types of material for tooth repairs (see BE-3042, BE-3721, BE-6062). A Swedish company Dentronic has developed a zirconium dioxide based material to replace amalgam but maintain the hardwearing characteristics of the alloy. However, the material is not malleable and cannot be moulded in situ. Dentronic has worked with a UK computer aided design and manufacturing company to allow scanning of a cavity cast and translation into instructions for machining the implant material to the correct shape, followed by cementing into the cavity. Specialised ceramic materials are obtained from the French company Norton Desmarquet. Dentronic's Denzir® was launched in 1999. Development and commercial agreements were considerably assisted by the EC-supported Innovation Relay Centre in Umeå, Sweden. Denzir is now CE-marked and is undergoing FDA approval. Further details from Dentronic AB, anders.sundh@dentronic.se

Members of the team for project BE97-4329, in the European Biomaterials Network, report their work on membranes for cultivation of kidney epithelial cells in Biomaterials Vol 21. Polyacrylonitrile and polysulfone membranes have been constructed that provided good substrates for both proximal and distal tubule cells in vitro. The aim is to generate bioartificial organs that will maintain high detoxifying efficiencies using living cells.

There is a considerable amount of effort going into coating of metal implants for better stability and osteointegration. Conventional methods include plasma spraying of surfaces with hydroxyapatite. Workers at the Lawrence Berkeley National Laboratory and University of California have reported production of stable enamel coating of titanium alloy with silicate-based glasses, in which either Bioglass® or hydroxyapatite particles were embedded. The glass composition was geared to the thermal expansion coefficient of the titanium alloy, and the enamelling temperatures used were relatively low (800°C).

Chitosan, derived from fungal mycelium or invertebrate exoskeletons, is an interesting biomaterial with intrinsic activity in promoting wound healing and tissue normalisation. Researchers at two Korean Universities (Seoul National and Ewha Womans) have used chitosan sponge as the delivery matrix for platelet-derived growth factor BB, and shown that this accelerates bone healing in vivo, in the rat calvarial model. At North Carolina State University, a new type of wound dressing has been tested, consisting of layers of chitosan, synthetic polymers and surgical gauze. The chitosan and polymer are absorbed into the skin as wounds heal. Studies in pigs skin explants have been successful, but in work on pigs, the dressing proved to allow the wounds to dry out too quickly.

Collagen is normally regarded as a biodegradable polymer, but Tissue Science Laboratories, in collaboration with Dundee University Scotland, has developed Permacol™, using porcine collagen as a base. The collagen, derived from skin, is cell-free and has been cross-linked in such a way that it provides a permanent scaffold, with the shape and support functions that implies.

The physical environment of cells may be important to their normal development and function, and failure to account for this could hinder tissue-engineering attempts. Current work on generation of engineered tendons and ligaments at Queen Mary & Westfield College, London UK, uses cyclic axial tension on the support matrix to encourage cells to form functional tendon material. Workers at Duke University have produced bioartificial porcine blood vessels with desired mechanical properties by growing vessel muscle cells on biodegradable polymer tubes and pulsing growth medium through the tubes, to mimic the pressure changes occurring in the circulation in nature. The muscle cells migrated through the matrix, establishing a muscular layer within the tubes, allowing establishment of an endothelium using bovine cells. Collagen production was stimulated by manipulation of the culture medium. Bioartificial vessels were then implanted into pigs - those that had been subjected to pressure pulses remained functional and clot-free, compared with un-pulsed vessels.

Concerns about osteointegration for orthopaedic implants and cell or platelet reactions from 'soft' implants and devices has driven coating and surface modification R&D. Silver-impregnated catheters are available that claim to suppress or reduce risks from bacterial colonisation and tracking. The US company Datascope last year announced that it had obtained a CE mark for a silver-impregnated vascular graft, InterGuard. The company is targeting the risk of infection following grafting, which may reach 5% of procedures and lead to amputation or death. STS Biopolymers, of Henrietta New York, is developing biocompatible coatings for a variety of medical devices, including catheters, cannulae, needles, stents, implants and fibre-optics. The BiodivYsio stent, manufactured by UK company Biocompatibles, has recently undergone an extensive trans-European trial, SOPHOS, with positive results of fewer adverse reactions, less revascularisation and an apparently lower restenosis in small-diameter vessels. Biocompatibles will be seeking to CE-mark a small-vessel stent for 2-2.5 mm blood vessels, based on the data. The BiodivYsio stent is coated with phosphorylcholine, to mimic cell phospholipid layers and enhance biotolerance.

Attention is also being paid to proteins and glycoproteins as coatings, because of the role of sugar residues in cell surface molecules and messaging. Desmos, of San Diego California, uses extracellular matrix proteins to manage cell-implant interactions. In collaboration with Baxter, the antibacterial abilities of such coatings are being investigated for peritoneal dialysis catheters and in a Guidant-funded study, the impact of coatings on restenosis of stents is being evaluated.

In an interesting twist on protein-coating, researchers at the Engineered Biomaterials Center of the University of Washington have received a National Science Foundation Grant to explore tailored coatings that recognise specific cell surface proteins or messengers and aid cell-implant adhesion and normal cell and tissue healing. If fluoropolymers are deposited by gas-phase plasma onto a smooth surface on which the desired protein and appropriate sugar moieties have been layered, and the entire layer is removed and the protein dissolved out, the polymer coating remains with protein-specific surface cavities lined by the sugars. The Center team hopes to prepare coatings that attract and activate specific tissue proteins, such as osteopontin, important for avoiding heart valve calcification.

Infection-resistant biomaterials rely mainly on incorporation of antibacterial substances such as silver and antibiotics. The US company, CardioTech International, based in Woburn Minnesota, has recently received a grant to develop such materials. The study, supported by the National Heart, Lung and Blood Institute, is aimed at cutting down the infection rates from catheters, cannulae and stents, using quinolone-impregnated polyurethanes. CardioTech has already developed polyurethane vascular grafts for cardiac and other vessel surgery. Work is underway at the University of Seattle on polyurethane-polyethylene glycol copolymer materials containing ciprofloxacin, coated with butyl methacrylate. The BMA is intended to allow plasma to flow into the copolymer, dissolving the polyurethane component and releasing ciprofloxacin to diffuse into the plasma. In August 1999, the American Medical Association reported that the use of catheters impregnated with chlorhexidine and silver sulfadiazine reduced the incidence of catheter-related bloodstream infections from up to 7% to 3%, whilst reducing length of hospitalisation and costs of care. Since death occurs in 10-25% of cases of bacteraemia despite treatment, prevention has a considerable knock-on effect on deaths and costs, as well as improving the quality of life of catheterised patients. Direct medical costs of the impregnated catheters were given as $336 per catheter, compared with $532 for conventional catheters.

AorTech, one of the UK's bright hopes as far as innovative devices are concerned, has successfully obtained patent filings for an improved version of its trileaflet totally synthetic heart valve. The material used is a polyurethane copolymer, named Elast-Eon by the company, licensed for this purpose from the Australian company Elastomedic. Clinical trials will start in 2000.

The options for bioengineered tissues and organs for human treatment include autogenous cells, harvested from the patient, grown in culture and re-implanted in a suitable matrix, standardised allogeneic human cells, perhaps derived from tissue banks or from immortalised cell lines, or xenogeneic cells from species such as primates, mice or pigs. Workers at the Medical College of Virginia have used healthy human liver cells, stored frozen in liquid nitrogen, to seed damaged livers in adult patients with acute liver failure and infants with genetic liver defects, with good effects. In spite of the current concerns over disease risks from pig cells, these are still seen as a viable option for liver and kidney support systems. The US company Circe Biomedical is testing its bioartificial liver and has demonstrated significant benefits in liver-failure patients. Researchers at the University of Michigan, Ann Arbor, have implanted pig kidney cells into a conventional multifibre dialysis cartridge, as part of a kidney support system. They have shown good function in vitro and plan to test the device in patients suffering from otherwise fatal acute kidney failure. CryoLife is using porcine heart valves and implanting these with human cells, as bioartificial replacements for diseased valves in humans. The valves, SynerGraft™, have performed well in experimental sheep for over 5 months and gave successful results in the first two clinical cases implanted during later 1999.

Encelle, based in Greenville North Carolina, is working on bioartificial pancreases and has found that a type of polymer used to coat its Encellin XP islet-cell implant appears to stimulate new blood vessel growth. Encelle is now looking to develop this for use in diabetic foot ulcers, wound healing and vascular disease.

St Jude Medical has obtained a $2m grant from the National Institute of Science and Technology to develop an entirely bio-engineered heart valve, a prosthesis within which fibroblasts will be implanted, and on which endothelial cells will colonise to form a layer. The aim is also to obtain a bio-responsive prosthesis that will change as the patient grows, for example.

The Dutch company IsoTis is developing a range of bioartificial and tissue-engineered materials, including new skin, new bone and biomimetic implant coatings (Biskin™, PolyActive™, Rainbow™), as well as the in vitro techniques required to ensure good culture of cells and interaction with support matrices. IsoTis is the co-ordinator of one of the projects in the European Biomaterials Network.

Protein-based surgical adhesives have shown good results in managing difficult graft procedures, such as coronary artery repair. CryoLife's BioGlue is being developed for use in minimally-invasive heart surgery. BioGlue has been CE-marked for use in pulmonary surgery and in blood-vessel repair.

An exciting advance that may prevent post-operative stenosis of vessel grafts is being trialled in USA. Saphenous vein grafts are dipped into a solution of DNA that blocks receptors on endothelial cells and prevents them from overgrowing in response to endothelial growth factors. In early clinical trials with 33 patients, 17 with the treated grafts, 16 with conventional grafts, 3/17 treated grafts became blocked, compared with10/16 conventional ones. A pivotal study has started, which will recruit 2000 patients at several sites within the US.

Organogenesis is working with bioartificial vessels, made by cross-linking tubes of bovine-origin collagen within tubes of porcine-origin collagen and coating the inner layer with heparin, to prevent platelet adhesion. In vivo, the tubes withstand normal physiological conditions and are gradually invaded by normal vascular, endothelial and smooth muscle cells so that they resemble normal arteries. Explanted tubes responded in the same way as normal arteries to a variety of pharmacological stimuli. The Cambridge Massachusetts tissue engineering company Reprogenesis is developing a polymer matrix vessel in which allogeneic endothelial cells are seeded, and is using a $2m grant from the National Institute of Standards and Technology to reach Phase 1 trials in the next 12 months.

In addition to developments from Sulzer Medica, utilising various growth factors, Genentech & DePuy are collaborating on trials of transforming growth factor (TGF) b1 for non-unions, hip prosthesis revisions and other orthopaedic problems. Stryker has already launched a combination of bone morphogenetic protein OP-1 with collagen.

Smith+Nephew is developing a biodegradable polymer that behaves like liquid crystals when extruded at over 150°C, forming aligned chains that are twice as stiff as conventional biodegradable polymers, with a modulus within the range of bone (compared with that of metal implants, 8-20 times higher than bone). Smith+Nephew plan to make bone screws and, eventually, support pins from the material.

Dentsply has obtained FDA approval for its bioengineered bone graft material PepGen P-15. This consists of a synthetic peptide covalently bonded to a bovine-origin matrix, which accelerates fracture repair and reduces requirements for further treatment. The material is intended for use to repair the bone defects caused by periodontitis.

Corin Medical, one of UK's burgeoning devices SMEs, is developing a femoral implant in which the stem is non-metallic, consisting of an epoxy resin matrix reinforced with carbon-fibre. The Young's modulus of the polymer-fibre combination matches bone stiffness better than steel or titanium, thus avoiding stress shielding, bone resorption and loosening seen with metallic hip implants. The device has been developed in collaboration with the University of Keele, Staffordshire UK and AEA Technology Harwell, in a project funded by the UK DTI's LINK medical implants programme.

Although many companies and R&D teams are investigating the use of bone substitutes, bioartificial bone materials or bone growth factors for repair of hard tissues, others are developing biomechanical or electromechanical approaches. RayMedica, based in Minneapolis USA, is working on its PDN (prosthetic disc nucleus) devices, that are inserted in pairs via an endoscope into the intervertebral space, then injected with a hydrogel that swells, to take pressure off prolapsed IV discs.  This has now been CE-marked. Medical Bracing Systems, an Israeli company, is using electromagnetic pulses to stimulate healing of fractures in limb bones. Electrical stimulation of muscles and percutaneous stimulation of muscles is also being developed by the company. IGEA, an Italian company that at one time was a local branch of Howmedica, has also developed an electromagnetic pulse device for treatment of cartilage degeneration and synovial inflammation. IGEA also makes and sells an ultrasound monitor for osteoporosis. Orthofix International converted its minority stake in Neomedics Inc into ownership during 1999, gaining full access to implantable electromagnetic stimulators for vertebral fusion.

New developments in microtechnology may counteract muscle problems, such as those following cerebrovascular accidents, nerve damage and other disorders. Researchers at University of Southern California have created microelectrodes for implantation into diseased muscle, to stimulate contraction and movement. The electrodes are 2mm in diameter and can be injected directly via a standard syringe and needle. The 'BIONs' are activated by the patient, by radio signal from an induction coil. The intramuscular implant avoids percutaneous electrodes and wires that could provide a conduit for infection. The electrodes have a maximum output of 30 milliamps for less than 0.5 milliseconds and their use is reported to produce nothing more than a mild tickling sensation.

Electrodes are also an essential component of the new generation of cochlear implants, designed to fit into the acoustic nerve itself, as in the 'Nuclear 24RCS' under study at New York University Medical Center, or into the acoustic nucleus in the brain stem, as in an EC-funded development collaboration between the UK company Cochlear and the University Clinic of Navarra in Spain. The latter is intended for patients who no longer have a functioning acoustic nerve, and in a clinical trial of almost 50 patients with auditory tumours, nearly all were helped by the device.

Developments in microtechnology and microsystems also require an understanding of materials science and biocompatibility. There will be considerable potential for new materials and adaptation of existing materials. Micropumps are already available for use in human medicine and it is conceivable that microreactors might be implanted to take over body physiology and biochemistry. The UK-based technology transfer company, BTG, has recently taken a licence to a new micropump developed by Impella Cardiotechnik, based in Aachen Germany. The pump is implanted in the hepatic portal vein to enhance blood flow in cases of liver cirrhosis. Japanese researchers at Hokkaido University have created a micromotor that works by releasing alcohol from polystearile acrylate gel through holes in the opposite faces of a tiny strip of polymer. The effect of alcohol escaping from these holes when the strip is place in an aqueous environment is to cause rotation at up to 400 revolutions per minute. When tiny magnets were attached at each end of the strip, it was possible to produce a power output of 0.2 mwatts via an induction coil. Researchers at the Medical School of John Hopkins University, Baltimore, have used a minute MRI coil to visualise damaged parts of the heart wall of dogs. The MRI coil is based on one approved in September 1999 by the FDS for visualising the human oesophagus, Surgi-Vision's EEMRI. The intracardiac coil will be useful in procedures such as atrial fibrillation ablation.

Columbia University reports some microtechnology in the latest issue of Biomedical Frontiers (biofrontiers@columbia.edu) - Dr Mehmet Oz of the Surgery department has invented a tool for minimally-invasive repair of defective cardiac mitral valves, based on a suturing technique developed in Italy by O Alfieri. The tool is passed through the pulmonary vein, grasps the two leaflets of the mitral valve, then inserts a small threaded screw into them in order to eliminate the gap at relaxation that causes the problem. Ultimately, the grasper tool and the screw will be visualised using echocardiography. The device has been licensed to The Foundry, a small US company dedicated to minimally-invasive surgery.

We are now one step nearer a totally artificial heart. Arrow International has started clinical implants of a permanent heart replacement, powered transdermally using a transmitter. Abiomed is also using a transdermally-powered in situ pump device. The Jarvik 2000 minipump, developed by Dr Robert Jarvik, previously used as a bridge treatment, will also be implanted as a permanent heart replacement during 2000.,

Motorola has invested in Clinical Micro Sensors, a California-based bio-chip company, to exploit Clinical Micro Sensor's DNA capture chips in electronic devices. Dr Ingrid Fritsch and co-workers at the University of arkansas have created a microanalyser on a silicon chip, that is small enough to investigate a single cell or piece of DNA.

In 1997, the Japanese Science and Technology Agency predicted how artificial organs and tissues would come on-stream over the next 25 years: by 2010-2015, active cochlear implants in the clinic, total artificial hearts and kidneys in development, biohybrid endocrine glands in development and clinical use of tissue-engineered organs were foreseen; by 2020, long-term extracorporeal liver systems, in-vitro foetus-placenta culture, clinical use of implantable artificial kidneys, development of retinal implants and artificial muscles were forecast, and beyond came the bioengineering of repair tissues from differentiated cells. This view of the future should be compared with a more recent report, at the first Techvest investors' conference in New York, where Professor M Sefton of University of Toronto Canada predicted development of the tissue components of a bioartificial heart within 4 years, animal tests within 6 years and management of rejection of 'foreign' hearts achieved in 7 years. An international group of researchers has been assembled under the LIFE project to develop the fully-artificial heart.

The Institute for Medicine and Engineering at University of Pennsylvania and the University of Minnesota report their discovery of polycarbonate microcapsules, generated from a film deposited on a wire then blown off as 10-35 m capsules by adding water and generating steam from an electric current passed down the wire. The researchers plan to encapsulate purified haemoglobin, other oxygen-carrying materials, gene therapies and drugs for targeted delivery.

Although it often seems that the focus on new materials is on polymers or coatings, new metallic materials are not being entirely neglected. A start-up company Davitech, based in Tennessee, has the rights to a new titanium alloy, with molybdenum and hafnium, which has mechanical properties closer to bone than conventional titanium and Ti alloys and appears to withstand corrosion and micromovement stress better. Hafnium imparts increased hardness and wear-resistance without significantly reducing flexibility or increasing stress-shielding effects.

The Controlled Release Society has a Committee focusing on Veterinary Products, and intends to establish a Vet Interest Group, more details from www.controlledrelease.org/vetforum/ (membership details may be required). Vet activities are co-ordinated by Michael J Rathbone, InterAg, mjr@interag.co.nz

Spider silk has long exerted a fascination, for its tensile properties and flexibility, as much as for the astonishing way in which it is formed in vivo. DuPont uses transformed bacteria and transgenic plant cells to produce silk proteins, that it intends to use in textiles and clothing for its wearability and maintenance benefits; Nexia Biotechnologies Inc of Montréal (www.nexiabiotech.com) is using transgenic goats to secrete the proteins into milk, and plans to use its spider-silk product, BioSteel® Medical, for wound closure, vascular grafts, haemostatic devices and matrices for drug release.

Electrosols Ltd, a UK company based in Haslemere, has developed a spray consisting of biocompatible, biodegradable polymer such as poly-L-lactic acid, mixed with ethanol and given an electric charge in a semiconducting delivery vessel. If the vessel is brought close to the skin, the charged liquid is attracted to it and, by passing the liquid through fine nozzles, a mat of fine fibres, each 5 m in thickness, covers the sprayed area. The intention is to cover wounds and provide a scaffold that fibroblasts can colonise easily, thus aiding wound healing. The system has yet to be tested in animals or humans.

One hurdle for gene technology is how to get genes targeted to the defective area for a long-enough period of time. At the University of Michigan, studies in rats revealed that a polymer sponge containing genes for platelet-derived growth factor acted as a slow-release implant and stimulated wound healing and neovascularisation, something that gene injection failed to do. This kind of technique will also have an impact on functional bioartificial implants that might be required to change their behaviour over a period.

The US National Institutes of Health may found a special NI for Biomedical Imaging and Bioengineering, following introduction of legislation in the US Senate in mid-1999.

Synthetic Blood International has an oxygenating fluid blood replacer, Oxycyte™, based on a perfluorocarbon material. SBL has developed this for use in angioplasty, tumour oxygenation, open heart surgery and trauma management. Its Fluorovent, a pure perfluorocarbon material, is used for patients with respiratory difficulties.

Vascular stents that do not cause break-up of atheromatous plaque and further embolism, artificial eyes, improved corneal replacements, matrices and composites for maxillofacial surgery, arteriovenous access grafts and urinary catheters were all topics of a recent conference organised in London UK by the Biomaterials Partnership, to highlight 'Neglected Areas of Disease Treatment' and the role that new biomaterials and devices might play in dealing with these.

A long-standing material used in many devices, latex, has come under increasing pressure as the numbers of unacceptable allergic reactions have grown. The latex proteins found in the natural sap from the Hevea rubber tree are responsible. Washing processes were developed that removed most of the proteins but also reduced the antiviral barrier effects. Although it is now possible to preserve the barrier properties and at the same time wash out the proteins, this is expensive and many people are still potentially at risk to anaphylaxis if they meet an unwashed latex product. A Mexican silverweed Parthenium argentatum, or guayule, has been shown to contain a non-allergenic latex, with necessary antiviral barrier properties and superior strength to Hevea latex and a company has been sent up in Philadelphia USA, Yulex, to commercialise this.

At Baylor College of Medicine in Texas, a gene has been found that is associated with a cell surface receptor in skin cells that triggers follicle development, and a protein that binds to this receptor or similar ones has also been isolated. The possibility that new hair may be stimulated by altering the gene or applying the protein has yet to be investigated.

Gait analysis, a computer-based technique used to assess relationship between the anatomy of joint surfaces, the shape of joint movements and the interaction on overall limb movement and gait, is useful in planning how to compensate in surgical positioning for any peculiarities in gait in patients requiring orthopaedic prostheses, and in monitoring progress after surgery. This technique is used extensively by a partner in one project in the network, BE-3242, in developing new prostheses. It may also have a use in analysing video clips of crimes, since each person has a characteristic gait, still visible even if the face or body of the criminal has been disguised or covered. This is under investigation at Southampton University UK.