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Bone Grafts And Bone Substitutes Basic Science And Clinical Applications


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Autogenous bone graft is the gold standard bone graft material. However, due to limitations of supply and morbidity associated with autograft harvest, various bone substitutes have been considered. This article aims to review the properties of the bone graft and various bone substitutes currently available in orthopedic surgery.


Synthetic bone substitutes consist of hydroxyapatite, tricalcium phosphate, calcium sulfate, or a combination of these minerals. Synthetic porous substitutes share several advantages over allografts, including unlimited supply, easy sterilization, and storage. However, they also have some disadvantages, such as brittle properties, variable rates of resorption, and poor performance in some clinical conditions. Recently, attention has been drawn to osteoinductive materials, such as demineralized bone matrix and bone morphogenetic proteins.


Despite tremendous efforts toward developing autograft alternatives, a single ideal bone graft substitute has not been developed. The surgeon should understand the properties of each bone graft substitute to facilitate appropriate selection in each specific clinical situation.


Bone graft procedures have been increasingly used in traumatology, tumor surgery, spine surgery, infection, and revision arthroplasty. In the US, approximately 500,000 bone graft procedures are performed annually [1]. These numbers easily double or triple on a global basis, resulting in a shortage in the availability of donor tissue conventionally used in these bone reconstruction procedures [1]. In terms of bone healing, autogenous bone graft exhibits the best osteogenic potential and is still considered to be a gold standard by many authors. Recently, another source of autogenous cancellous bone from intramedullary canal is developed. The reamer/irrigator/aspirator (RIA) technique was first developed to prepare long bones for intramedullary nail fixation [2, 3]. However, the autogenous bone graft itself is an additional operation, and complications related to bone harvesting have been reported in up to 20.6% of cases [4,5,6,7]. Disadvantages of RIA include cortical perforation, eccentric reaming, articular perforation, and intra- and peri-operative fracture [2]. Allograft has several advantages, including easy use, improved safety profiles, time advantages, availability in diverse sizes and shapes, and no donor-site morbidity. For these reasons, it is a typical alternative to autogenous bone. However, in the process of sterilization and storage, the biological and mechanical properties change, which results in loss of osteoinduction and osteogenic capability. With more demands for spinal fusion, revision surgery of arthroplasty, and joint fusion, there is a relative deficiency in allogeneic bone donors. Due to these disadvantages of autogenous bone or allograft, the necessity of bone substitutes is increasing [1].


Bone substitutes have a diversity of composition, mechanical strength, and functional biological mechanisms. Since each bone substitute has its own unique advantages and disadvantages, the relationship between various aspects of biological properties and bone healing should be understood. In this review, we will focus on the properties of bone graft and various bone substitutes currently available in orthopedic surgery.


The reason why the bone union rate following incorporation of allograft might be low is because the allograft has no osteogenesis and weak osteoinductivity and the process of sterilization and storage influence osteoconductivity and osteoinductivity [19,20,21]. Freezing or freeze-drying processes reduce the risk of an immune response of a bone graft after surgery, but sterilization itself weakens the mechanical property of a grafted bone up to approximately 50%. Furthermore, given that a large amount of gamma irradiation or ethylene oxide gas considerably decreases the osteoinductivity of bone graft, the necessity of synthetic bone substitutes has emerged to avoid adverse effects.


Allogeneic bone is available in many preparations, including morselized and cancellous, corticocancellous, cortical graft, osteochondral, whole bone segment, and demineralized bone matrix. The integration process of allogeneic bone is similar to that nonvascularized autogenous bone graft normally undergoes, but the size of allograft influences the time of incorporation. This feature is partially related to a lack of cells in the donated region for bone healing and immune reaction arising in the integration process of allogeneic bone [18, 22, 23]. In most clinical cases, allogenic cancellous bone is used to treat the partial bone defect rather than a segmental bone defect or whole-bone defect because allo-cancellous bone has no mechanical stability. Clinically, it is commonly used to reinforce spinal fusion and pack the bone defect in revision arthroplasty in particular. Two well-known types of ossification reactions, intramembranous ossification and the enchondral ossification, occur on the surface of a graft bone. An external callus is created around allogeneic bone with bridging enchondral bone formation, and resorption and creeping substitution of cortical bone occur simultaneously. Thus, the two bones are attached as if welded [24]. In addition, fusion occurs only on the junction, and dead bone trabecular mostly remains in the innermost part of a grafted bone for several years [25]. At this time, bone strength is the weakest at the 3rd to 6th month and slowly recovers during the 1st to 2nd year [24, 26].


Although bone minerals are eliminated from allogenic bone, DBM is able to provide a 3-dimensional scaffold because the fibrous collagen structure of original tissues remains [30]. Since DBM is easily diluted and does not provide a mechanical packing effect for a bone defect lesion, its single use is limited, and DBM is manufactured with a variety of transmitters, including glycerol, hyaluronic acid, and calcium sulfate. Osteoinductivity of DBM is dependent on the levels of BMP-2 and BMP-7 as main growth factors. Various osteoinductivity potentials of individual DBM products are attributable to differences in DBM extraction and processing and a reduced amount of BMP in the process of sterilization and storage [31]. Although a product undergoes the same process, difference depending on the bone quality of allogeneic bone donor as a material are noted [32]. DBM has some expectations in terms of clinical use and efficacy, but research that supports its single use as a bone substitute is limited [33]. Accordingly, it is effective to add allogeneic cancellous bone or autogenous bone marrow. The most successful grafts may be composites of DBM and autogenous bone graft when used with stable fixation. DBM also has a potential risk of transmitted viral infection because it is an allogenic material. Currently, there is relevant research with a small number of randomized controlled trials. Therefore, to establish DBM as a reliable method for regular clinical use, it is necessary to produce long-term follow-up results and data.


The most ideal bone substitute should include the ability of providing a scaffold for osteoconductivity and growth factors for osteoinductivity and should be structurally similar to real bone. The scaffold for ideal osteoconductivity should exhibit osseointegration and a 3D structure suitable for growing cells and blood vessels. In addition, it should have good biocompatibility, biodegradation, and biomechanics similar to surrounding bone tissues. Numerous bone substitutes that satisfy these conditions are commercially available in orthopedics.


Ceramic bone substitutes are typical calcium-based synthetic bone substitutes that are already approved in terms of stability and effect. Given the problems with autogenous bone and allogeneic bone, osteoconductive ceramic with biodegradation draws considerable attention these days. For synthesized graft to exert its biological effects, several conditions are required: compatibility with surrounding tissues, chemical stability in body fluid, biomechanical and physical compatibility, durability in sterilization process, reasonable price, and consistency of reliable quality [34]. Today, various types of ceramic products are composed of calcium phosphate, including hydroxyapatite (HA) and tricalciumphosphate (TCP), or (calcium sulfate), or their compounds [34, 35].


There are a few studies with a small number of randomized controlled trials only. The US Food and Drug Administration approved the use of BMP-2 for open tibial shaft fracture as a selective clinical indication [65] and the use of BMP-7 for iliac nonunion and traumatic bone defect [66]. BMP is used as an adjuvant for the spinal lumbar. When BMP-2 was used together with an allograft, its fusion rate was similar to that of autogenous bone graft [67]. These BMPs account for only 0.1% of total bone proteins and are mainly found in cortical bone. Since BMPs exist in the extracellular matrix, it is impossible to obtain BMPs until the bone matrix is demineralized [28, 68]. Accordingly, to obtain several grams (g) of BMPs, several kilograms (kg) of bones are needed. In addition, regardless of high-quality purity, they can include impurities, potentially causing unexpected reactions and results.


With the development of molecular cloning technology, these problems were solved by the creation of a large amount of recombinant human BMPs (rhBMP), which do not trigger immune reactions [69]. In the rhBMP- or bovine BMP-based animal test, these substances exhibited considerably good results. According to the research in which partially purified bovine BMPs were used for canine thoracic vertebrae fusion, the use of BMPs and autogenous bone together had the highest success rate (71%) [70]. In the thoracic vertebrae fusion of canine posterolateral transverse processes with the use of rhBMP-2, it was possible to achieve faster fusion [68]. Using an excess amount of BMPs physiologically can trigger osteolysis [71]. Depending on patients and body regions, the requirement of BMPs varies. Regarding the side effect of BMPs in the cervical vertebrae, contraindications are reported [72]. Therefore, tissue engineering approaches for long-term control and local transmission of these growth factors are a promising research area. Tissue engineering related to bone grafts have been conducted to provide all the fundamental properties of an ideal bone graft; however, it has proven difficult to achieve vascularisation in grafts which are large enough for use in clinical applications [55, 73]. 153554b96e