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No. 65 Bones and Joints |
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Bone Substitutes Lars Lidgren Lund University Hospital, Lund Loss of bone due to surgery, accidents or normal aging very often entails a functional and/or cosmetic handicap. To heal a fracture, the bone-producing cells need a framework (matrix) both to grow on and to attach the produced bone minerals and proteins to. In a normal situation, blood clots and connective tissue fill out the fracture space, thus creating the necessary bridge for bone growth. However, if the defect is too large, the healing process is halted. To bridge over the lack of continuity between bone tissues and promote the bone-healing process in larger cavities, the best results are those obtained when transplanting the patientīs own bone (autograft), usually taken from the pelvic region and transferred to the target area. The demand of autografts widely exceeds the supply, mainly because it is only possible for a small sample of the patientīs own bone to be taken. Another major drawback is that postoperatively the patients very often suffer from painful sensations at the donor site. With the autograft procedure, the operation time is also prolonged considerably with increased costs and an increased risk for the patient. Artificial bone substitution would be able to solve several problems associated with transplantation, and biocompatible materials have thus been introduced to replace natural bone. Bone Grafts The global use of bone grafts in 2000 has been calculated to be about 1 million yearly, less than 15% being with synthetic material. The contributing factors for bone substitute incorporation are shown in figure 1. The gold standard is the autograft. For allografts (bone transplanted from another human) there is good evidence today for use mainly in joint prosthetic surgery. Xenografts (taken from animals) are mainly bovine apatite, sintered from cattle, collagen originating both from cattle or pigs, digested and then cross-linked, and sea coralline which is thermally converted into calcium carbonate. For these substances, evidence for use in humans is scarce, with definite drawbacks such as weak, unpredictable mechanical strength and structure, and a risk of transmisson of infection. An upcoming European regulation may even restrict their use.  Fig. 1. Factors contributing to the success of bone substitutes. As only living cells can produce new bone, the success of any bone-grafting procedure is dependent on having enough bone-forming or osteogenic cells in the area. An ideal bone substitute should be able to provide a framework for bone deposition (osteoconductivity). Osteoinductive growth factors, many of which are present in normal human bone, induce bone formation locally by stimulating stem cells or immature bone cells to grow and mature, thus forming healthy bone. Osteoinductive Factors Of the osteoinductive (bone-forming) substances, the growth factor family is the largest. Most important are the bone morphogenic proteins, BMPs. Good overviews on the subject have been presented in the last years by Lane et al. [1], and Keating and McQueen [2]. The drawbacks are that they are expensive and difficult to administer. For stem cell transplantation, immediate transfer after harvesting from the iliac crest (pelvic bone) is optimal. It has been shown that multiplying the stem cells by up to five times improves graft incorporation. Recently, systemic drug treatment with bisphosphonates has been reported to increase bone ingrowth in the early healing period, in joint prosthetic surgery. Animal studies have shown a similar positive effect of parathyroid hormone and BMPs in grafting procedures. The future strategy might be to combine synthetic grafts with systemic short-term osteoinductive drug treatment. Osteoconductive Synthetic Grafts The osteoconductive (bone-stimulating) synthetic grafts that are used fall mainly under the calcium sulphate and calcium phosphate groups. They can be used as preset and injectable materials. The use of calcium sulphates was first reported by Dressman from the Trendelenburg clinic in 1892 and then later by Peltier in the United States, who gained extensive clinical experience from the 1950s to the 1970s. There is now renewed interest in treatment of contained bone defects. The drawbacks of calcium sulphates are their weak mechanical strength and rapid resorption within 6–12 weeks. For clinical use, injectable osteoconductive grafts should ideally be biphasic with a compressive strength >25 Mpa. Their injection time should be between 2 and 6 min, with a setting time of less than 10 min. There are a number of phosphate substances which, with the addition of water and different accelerators, will set into solid phosphates. Of these, hydroxyapatite is the least soluble. So far, at least 25 phosphate compounds have been reported, but they are at best mouldable and not easily injectable, thus restricting indications. They often have very low strength, especially during the first few days, and no interconnecting porosity and, most importantly, are very expensive. Recently, polymer phosphate compounds have come into limited clinical use. The combination of polyethylene and apatite for middle ear implants is one example, but also degradable screws for fracture fixation, such as polylactic acid combined with tri-calcium phosphate, are used today. Development of Phosphate Cement The development of phosphate cement will be to improve the biological response and injectability. The graft should have a construct that creates interconnection porosity for bone ingrowth. We have added vitamin E, a radical scavenger and anti-oxidant, to improve fracture healing. A small amount of vitamin E also increases injectability and creates a certain porosity within the material (fig. 2). In an animal bone harvest chamber model, the composition of apatite and calcium sulphate has been studied. The sulphate is resorbed within a few weeks and replaced by bone ingrowth, providing very close contact between natural and synthetic bone (hydroxyapatite) (fig. 3).
Fig. 2. Left: Calcium sulphate + hydroxyapatite. Right: Calcium sulphate + hydroxyapatite + vitamin E.  Fig. 3. Histology at 6 weeks, showing bone ingrowth around the synthetic bone (HA). Indications for Bone Substitutes The main indications for bone substitutes will be in spinal fusion, bone defects, osteoporotic fractures, revision surgery and, recently, vertebroplasty (injecting a vertebra with synthetic material). Vertebroplasty using polymethylmethacrylate was first introduced in France more than 15 years ago by neurosurgeons, but its use is now spreading rapidly. This mini-invasive procedure for the treatment of vertebral fractures in osteoporosis can reinforce fractured bone, alleviate chronic pain and prevent further vertebral collapse. Vertebroplasty is performed under biplanar fluoroscopic control, CT or guided navigation (fig. 4). Constantz et al. [3] and Kopylov [4], in his thesis, studied fractures using an injectable bone substitute that sets to a carbonate (fig. 5). In general, the material has been working well, but with some handling difficulties, and histological studies have shown good bone contact.  Fig. 4. Schematic drawing of a vertebral body, on which synthetic bone grafting (vertebroplasty) is performed using the injection-suction method. Two needles are used, one for injecting the synthetic bone material and the other for developing an underpressure in the vertebral body. This method reduces the risk of leakage into vessels or the nerves in the spinal canal.  Fig. 5. Treatment of a wrist fracture with an injectable synthetic bone graft and internal fixation. From Kopylov [4], with permission. Outlook Today, bone grafts are widely used by orthopedic surgeons, plastic surgeons, oral and maxillofacial surgeons, and dentists – next to blood, bone is the second most transplanted tissue. The use of synthetic bone substitutes is increasing rapidly, and it is hoped that transplantation of bone from donors and animals will one day become obsolete. Careful evaluation of these innovative materials and methods is necessary to determine if they are safe and have the desired healing and mechanical characteristics. But the future holds great promise for the directed regeneration of bone damaged by trauma, disease or degeneration. The rapid advances in biomaterials research and tissue engineering that will continue to take place will supplement and enhance our potential to treat painful and disabling bone conditions. Lars Lidgren is Head of the Department of Orthopedics at the University Hospital in Lund, Sweden. He is Chairman of the Swedish National Knee Register and Spokesman for Biomaterials in the Nordic Orthopedic Society. Professor Lidgren initiated a Bone and Joint Decade Consensus Meeting in Lund in 1998, which led to the global Bone and Joint Decade campaign, and is Chairman of its International Steering Committee. References
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