SUPORT CURS – MASTERAT SUBSTITUENTI OSOSI
Dr. SIRBU PAUL
PROF. DR. PAUL BOTEZ
Bone defects of different etiology – trauma, osteoporosis, tumors or metabolic diseases – represent an important medical issue with socio-economical involvement, due mainly to the lack of spontaneous healing or to the treatment problems and long lasting healing.
Approximately 10% of the bone surgery requires bone grafts or bone substitutes usage ((Katsuko 2004)). Autografts are still considered the golden standard in treatment of bone defects, even if the literature reports difficulties in graft harvesting and graft availability. The allograft usage involves the infection risk (viral or bacterial) and high costs, while it requires a bone bank with all facilities.
For over a century, scientists are trying to discover or synthesize inorganic products that could be used as bone substitutes; these products must provide long lasting bone biocompatibility and must provide bone healing abilities. These bone substitutes must solve the autograft and allograft disadvantages.
The last decade literature is plenty of works regarding bone substitutes applications in vivo and in vitro; the researchers are looking for the crystallographic, physical and chemical and biomechanical properties of the bone substitutes and also for the biological behavior during implantation in the living tissues. (Ribeiro 2006, Gisep 2004, Verne 2002).
The promising results of these studies have issued a classification for the bone substitutes as follows: phospohocalcic compounds (hydroxiapatite and calcium triphosphate), bone ceramics and various growth factors (bone morphogenetic proteins). The usage of these bone substitutes for bone healing is based on inducing bone apposition (e.g. osteoinductive products as hydroxiapatite or calcium triphosphate) or bone neoformation from the precursor mesenchimal cells. (e.g. osteoinductive products as bone morphogenetic proteins) (Yamamoto 2006, Hidaka 2006, El-Ghannam 2005, Grauer J.N. 2005.).
Nowadays, there are described or synthesized many bone substitutes with different osteointegrative properties; the multitude of products has imposed the generation and usage of the experimental models and the evaluation methods required for an accurate comparison.
In most cases, in vivo studies for these compounds requires the usage of an epiphyseal (trabecular) or diaphyseal bone defect, in which the bone healing process is investigated in detail, by radiological, histological, morphometric and biomechanical means. (Schmidhammer 2006, Misch 2006, Akca 2006, Li 2006.).
The evaluation and research of bone substitutes in bone defect treatment is a complex process whose goal is the clinical usage. The last step represents a decisive and a maximum interest subject for the practitioner and the patient.
References
1 Akca K, Cehreli MC., Biomechanical consequences of progressive marginal bone loss around oral implants: a finite element stress analysis. Med Biol Eng Comput. 2006 Jul;44(7):527-535. Epub 2006 Jun 10. PMID: 16937188
2 El-Ghannam A., Bone reconstruction: from bioceramics to tissue engineering. Expert Rev Med Devices. 2005 Jan;2(1):87-101. Review. PMID: 16293032
3 Gisep A, Kugler S, Wahl D, Rahn B., Mechanical characterisation of a bone defect model filled with ceramic cements. J Mater Sci Mater Med. 2004 Oct;15(10):1065-71. PMID: 15516866
4 Grauer JN, Beiner JM, Kwon B, Vaccaro AR., The evolution of allograft bone for spinal applications. Orthopedics. 2005 Jun;28(6):573-7; quiz 578-9. Review. PMID: 16138470
5 Hidaka C, Cunningham ME, Rodeo SA, Maher SA, Zhu W., Modern biologics used in orthopaedic surgery. Curr Opin Rheumatol. 2006 Jan;18(1):74-9. Review. PMID: 16344622
6 Katsuko S. Furukawa, Shunsuke Miyauchi, Daisuke Suzuki, Yoshikazu Umezu, Tsuneo Shinjo, Takashi Ushida, Miki Eguchi, Tetsuya Tateishi, Bone tissue engineering based on bead–cell sheets composed of calcium phosphate beads and bone marrow cells, Materials Science and Engineering C 24 (2004) 437–440
7 Li ZH, Liao W, Liu SQ, Zhang YF, Wang CY, Zhao Q., The study of tissue-engineering bone for repair of segmental bone defects, Zhonghua Zheng Xing Wai Ke Za Zhi. 2006 Jan;22(1):55-9. PMID: 16573169
8 Misch KA, Yi ES, Sarment DP., Accuracy of cone beam computed tomography for periodontal defect measurements. J Periodontol. 2006 Jul;77(7):1261-6. PMID: 16805691
9 Ribeiro C.C., Barrias C.C., Barbosa M.A., Preparation and characterisation of calcium-phosphate porous microspheres with a uniform size for biomedical applications. J Mater Sci Mater Med. 2006 May; 17 (5): 455-63. PMID: 16688586.
10. Schmidhammer R, Zandieh S, Mittermayr R, Pelinka LE, Leixnering M, Hopf R, Kroepfl A, Redl H., Assessment of bone union/nonunion in an experimental model using microcomputed technology. J Trauma. 2006 Jul;61(1):199-205.
PMID: 16832271
11. Verne E, Bosetti M, Brovarone CV, Moisescu C, Lupo F, Spriano S, Cannas M., Fluoroapatite glass-ceramic coatings on alumina: structural, mechanical and biological characterisation. Biomaterials. 2002 Aug;23(16):3395-403. PMID: 12099282
12. Yamamoto M, Takahashi Y, Tabata Y., Enhanced bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel. Tissue Eng. 2006 May;12(5):1305-11.
PMID: 16771643
The importance of bone substitutes
Autografts, allografts and bone synthetic substitutes plays an important role in orthopaedic and reconstructive surgery while the understanding of their biological effects is required for directed applications.
Bone grafting materials are those implants that promotes bone healing by one of the following actions: osteogenesis, osteoinduction and osteoconduction.
Osteoconductive materials became more important, especially in bone pathology while they are used as bone substitutes. These substances have a composition similar to the bone mineral matrix and are biocompatible. Their main function is of bone tissue support, allowing bone apposition on their surface; thus, they are used mainly for treating the bone defects. More recently, they are used as a vehicle for osteoinductive substances, augmenting bone formation.
While initially, only coral hydroxiapatite, calcium phosphate (Plaster-of-Paris) and then bioactive glasses (bioviotroceramics) were used as bone substitutes, nowadays we are using osteoconductive ceramic materials and phosphocalcic cements.
From the ceramic materials used in medical applications, we mention here the calcium triphosphate (β-TCP), hydroxyapatite (HA) (Feifel 1995, Mihăilă 2005, Ohura 1999) and calcium biphosphate (or biphasic calcium phosphate or BCP or β-TCP-HA).
Phosphocalcic cements (CPC) consist in one or more calcium phosphates (CaP) soluble in aqueous solutions. Many experimental and clinical studies have used phosphocalcic cements (Constantz 1998, Frankenburg 1998, Mihăilă 2005).
The proposed subject underlines the practical application by a histologic, histo-morphometric and biomechanical investigation between organic bone substitutes (e.g. phosphorilated cellulose) and import phosphocalcic compounds, whose prices are still prohibitive, even if they are biocompatible and osteoinductive. This study will represent also the first step for the homologation process for the Romanian products.
To reach this goal, we will use fundamental research methods, as in vivo research on animal model followed by a histologic evaluation on calcified and decalcified bone and electronic methods for biomechanical histomorphometric evaluation.
Up to now, the phosphocalcic cements were successfully used in maxillofacial surgery, in radius lower extremity fractures or calcaneal fractures, trochanteric fractures, tibial plate fractures, and also as filler for the osteoporosis in vertebrae bone. Another application is represented by osteosynthesis augmentation by sponge screws or pedicular screws in spine surgery.
In this domain, our proposed subject shows an important practical application, by providing useful information in practical orthopaedics for phosphocalcic cement usage in order to improve screws osteosynthesis for osteoporotic bones
The goal of this study is based on fundamental research methods in the biomechanical field, as torsion and bending tests.
The usage of the bone morphogenetic proteins (BMP), alone or associated with osteoconductive materials is a very actual subject regarding the bone healing subject. Our proposed subject is important because it proposes to find an optimal combination between the osteoconductive and osteoinductive material in order to promote bone healing.
Bibliografie selectivă
1. Constantz BR, Barr BM, Ison IC, Fulmer MT, Baker J, McKinney L, Goodman SB, Gunasekaren S, Delaney DC, Ross J, Poser RD. Histological, chemical, and crystallographic analysis of four calcium phosphate cements in different rabbit osseous sites. J Biomed Mater Res. 1998 Winter;43(4):451-61. PMID: 9855204
2. Feifel H, Gerner A, Schmidt KH, Wimmer F, Schmitz HJ. Die Beeinflussung der Knochenregeneration in phykogener Hydroxylapatitkeramik durch einen osteoinduktiven Proteinkomplex. Dtsch Z Mund Kiefer GesichtsChir 19, 25-27 (1995).
3. Frankenburg EP, Goldstein SA, Bauer TW, Harris SA, Poser RD. Biomechanical and histological evaluation of a calcium phosphate cement. J Bone Joint Surg Am. 1998 Aug;80(8):1112-24. PMID: 9730120
4. Mihăilă RI, Thurnher M, Kropik K, Moser Doris, Redl H, Tratamentul cu Algipore® al defectelor osoase segmentare
diafizare la iepure, Revista de Ortopedie şi Traumatologie (Bucureşti), 2005, vol. 15, nr. 3-4, p. 279-284
5. Ohura K, Hamanishi C, Tanaka S, Matsuda N. Healing of segmental bone defects in rats induced by a beta-TCP
MCPM cement combined with rhBMP-2. J Biomed Mater Res 1999 Feb;44(2):168-75. PMID: 10397918 Popescu Negreanu T. Utilizarea biovitroceramicilor şi materialelor compozit pe bază de biovitroceramicăşi colagen în ortopedie, Revista de Ortopedie şi Traumatologie (Bucureşti), 2001, vol. 11, nr. 1-2, 3-13
ACTUAL KNOWLEDE STAGE IN THE AREA RELATED TO THE SUBJECT PROPOSED
Autografts, allografts and synthetic bone substitutes are playing an important role in reconstructive bone surgery and the understanding of their biological effects is requireed for their coorect usage. Muschler and Lane are proposing the name of bone graft propun denumirea de material de grefare for any implant that promotes the bone healing by one or more of the following activities: osteogenesis, osteinduction and osteoconduction.
1. International research goals
1.1. The first research goal is represented by the discovery and usage of bone subtitutes with osteoconductive and osteoinductive properties
In 1965 Urist reported that the demineralized bone matrix (DBM) induces bone formation when implanted in the loose extraskeletal tissues; then he isolated from the demineralized bone matrix a protein called bone morphogenetic protein (BMP) (fig.1).
Fig 1. Molecular structure of the human BMP2. Protein Databank www.rcsb.org
growth factor supergamily called TGF-β (transforming growth factors). The most used BMP-s are BMP-2 (Yang 2006, Patel 2006, Sciadini 2000, Singh 2006) and BMP-7 or the osteogenic protein (OP-1) (Tsiridis 2006). An important study in the BMP study is represented by the vehicle through which these proteins are adminstered locaaly. First, a powder demineralized bone matrix was used. The mainly contains a type I collagenand represented the golden standard for the comparison with later synthetised materials (Maeda 2004, Kim 2002). Many other biocompatible materials were evaluated as BMP carriers:
-Extracellular matrix components: various collaen types, fibrin, fibronectin, hialuronic acid, glycosaminoglycans
-Ceramic materials: hydroxiapatitis, calcium triphosphate -Synthetic polymers: polylactic and polyglycolic acid -Bone grafts: autogenous and allogenous
1.2. The second research direction is represented by the discovery, synthesis and usage of the osteoconductive bone subtitutes.
Osteoconductive materials gain an increased importance in the biomaterial field, especially for bone pathology while serving as bone substitutes. These substances has a composition similar to the bone mineralized matrix and are also biocompatible. Their main function is of bone support, allowing aposition of the new bone on their surface for this reason they are used especially in the treatment of bone defects. Recently, they were used as vehicle for the osteoinductive substances, augmenting the bone forming.
1.2.1. Ceramic materials (phosphocalcic products)
In the past 80 years the calcium phosphates were intensively investigated and used in bone repair. The most important property of the phosphocalcic compunds (Bohner 2000) is the water solubility, so as a compound is more resorbable as it is water soluble (e.g. β-TCP) when a compound is less soluble in water and in the bone matrix, it will be less or hard to be resorbed (e.g. HA). The most used compounds in the medical field are represented by the calcium triphosphates (β-TCP), hydroxiapatitis (HA) (Mihăilă 2006, Ohura 1996) and calcium biphosphate (BCP or β-TCP-HA).
1.2.2. Phosphocalcic cements (CPC)
They were discovered by Brown and Chow in the '80. CPC are composed by one or more calcium phosphates (CaP) that are solved and precipitated in an aqueous solution. During precipitation, the calcium phosphate crystals are growing and interweaving so as they confer mechanical rigidity to the newly formed cement. Many experimental and clinical studies have used the phosphocalcic cements (Constantz 1998, Frankenburg 1998, Mihăilă 2006). By difference to the polymetilmetacrilate (PMMA), that is formed by a polymerization reaction, the phosphocalcic cements are formed by a less exothermal reaction while the cement volume remains almost constant during formation Regardless their type, the phosphocalcic cements shows two big disadvantages by comparison with porous phosphocalcic ceramics:
-They are fragile materials, and can be used alone (in low mechanical stress regions) either
combined with osteosynthesis materials (in loading regions, with high mechanical stress)
-The pore dimension is around 1 micron that makes the bone growth difficult inside the pores
while degradation is proceeding step by step. (outside-in).
2. National research
In Romania, Dr. Popescu-Negreanu and the research group led by Prof. Dr. D. Antonescu in UMF ‘C. Davila Bucharest have realized a biovitroceramic, commercially called PAW1, homologated in 1994 and used in many national clinics (Antonescu 1997). Bioactivity tests were performed by PAW1 implantation, as granules or adzed pieces in the rabbit tibia or the dog femur. Microscopy studies at the bone implant interface showed a good osteoconductivity and osseointegration for PAW1. Experimental results were confirmed by the good clinical results of the PAW 1 in treatment of the tibial plate fractures, plumbing of the bone defects after benign tumor resection or cyphosis treatment by anterior arthrodesis. PAW1 showed good results in revision osteosynthesis after hip prostesis and was also combined with antibiotics to treat osteitis with various localizations: humerus, femur, tibia.
The disadvantages of the auto-, allo- and xenografts used in bone substitution favorized the development of synthetic bone substitutes. Between these substitutes, the bi- or triphasic phosphocalcic ceramics plays themain roles. The efficiency of the bone substitutes characterized by the bone material interaction s bound to the main physical properties and especially to the material macroporosity (Botez 2002).(Fig.2)
Fig. 2 Material macroporosity and radiologic result of the material application in the spine
For limited indications on small and medium bone defects, if there is a good contact of the receptor bone and a stable mechanic assembly, the phosphocalcic based and macroporous bone substitut, with or without embedded antibiotic, represents a viable alternative to auto and allografts.(Botez 2002)