PRECLINICAL and CLINICAL STUDIES on and LEONARDO – Oral surgery

Leonardo – for bone grafting 4. Biocompatibility evaluation (A) 12 PROLIFERATION AND GROWTH OF BONE Preclinical studies on Leonardo granules 4.1 Biocompatibility tests following NF EN ISO 10993-1 standard 11 CRYSTALLIZATION OF MATRIX Biocompatibility evaluation has been conducted following the table 10 GENERATION OF MATRIX of the NF EN ISO 10993-1 standard. Since bioactive glass is a 1. General informations on bioactive glasses very low, but can vary with pH. Tricalcium phosphate ß (ß-TCP) is 100 9 DIFFERENTATION OF STEM CELLS well-known material which has been clinically used for more than much more soluble than HA and degrades rapidly in vivo. Bioactive Bioactive glasses are classified as ceramic , and more 20 years, biocompatibility tests which have been conducted aim precisely as bioactive ceramic materials, just like hydroxyapatite glass 45S5 can be considerate as perfectly absorbable since it com- 8 ATTACHMENT OF STEM CELLS 20 at evaluating the toxicity of manufacturing residues. [1] pletely dissolves in order to form carbonated hydroxyapatite. Its and other calcium phosphate ceramics . Bioactive glasses are 7 ACTION OF MACROPHAGES mainly composed of silicon dioxide (SiO ), sodium oxide (Na O), degradation rate depends on its composition. 10 2 2 Here is the list of the tests which have been conducted and the calcium oxide (CaO) and phosphorous pentoxide (P O ). L. L. Hench 6 ADSORPTION OF BIOLOGICAL MOIETIES IN HCA LAYER 2 5 2 providers involved in the study: was the inventor of bioactive glass 45S5 in 1971, called Bioglass® LOG TIME (HOURS) 5 CRYSTALLIZATION OF HYDROXYL CARBONATE APATITE (HCA) 2. Description of mechanism of bioactivity (composed, in weigh, of 45 % SiO2, 24.5 % Na2O, 24.5 % CaO and

1 ADSORPTION OF AMORPHOUS Ca+PO +CO 6 % P O ). Since then, different types of bioactive glasses or glass- A cascade of physical and chemical reactions occurs at the periph- 4 4 3 BIOCOMPOTIBILITY TESTS PERFORMED

2 5 SURFACE REACTION STAGES ery of bioactive glasses in contact with body fluids. A hydrolytic ceramic materials (glasses incorporating hydroxyapatite crystals 3 POLYCONDENSATION OF SiOH + SiOH Si-O-Si PROLIFERATION AND GROWTH OF BONE and/or wollastonite), with different properties, have been devel- degradation of bioactive glass happens[2], followed by numerous and oped[1]. complex reactions. Figure 1 below summarizes the cascade of the 1&2 FORMATION OF SiOH BONDS IRRITATION (ISO 10993-10) 11 reactions occurring at the surface of bioactive glass during the BIOACTIVE GLASS DELAYED-TYPE HYPERSENSITIVITY (ISO 10993-10) Bioactive glasses are effective materials for bone grafting or pros- formation of a solid grip with the bone. thesis coating. They have been used in different types of surgeries: Figure 1: Sequence of interfacial reactions involved in forming a bond between ACUTE SYSTEMIC TOXICITY (ISO 10993-11) The five first reactions take place in the periphery of bioactive glass bone and a bioactive glass. L. L. Hench[1] orthopedic surgery, oral surgery, cranio-facial surgery and spinal AMES TEST (ISO 10993-3) surgery. These materials are known for their excellent biocompat- and do not depend on the presence of tissue. This reactions has been ibility. In contact with body fluids, they are able to create a solid studied and could take place in distilled water or buffer solution 3. Osteostimulation PYROGENICITY (USP 31) like TRIS or SBF[3,4]. These reactions make up a layer of crystallized Recent in vitro studies have been led to the understanding of the grip at the interface /host tissues. These biomaterials do not CYTOTOXICITY (ISO 10993-5) promote any fibrous encapsulation at the interface implant/tissue; carbon hydroxyapatite at the top of material. The implant fastens mechanism of action of bioactive glass[5,6]. They show that ionic the connection between the implant and the bone tissues is thus down with the tissue for the step 6 to 11 like as growth of bone. products such as silicon and calcium have an influence on the stem cells differentiation and on the growth of bone. Besides, the bone direct. The surface of bioactive glasses serves as a support for bone The set of biocompatibility tests performed show that bioactive mineralization happens thanks to phosphor transit. The dissolution regrowth. The degree of bioactivity depends on the composition of glass 45S5 products: bioactive glasses, in particular on the proportion of silica (SiO ), products of bioactive glass 45S5 develop an extracellular environ- 2 are not cytotoxic [2] ment that is capable of supporting osteoblast phenotype expression sodium oxide (Na2O), phosphorus pentoxide and calcium oxide (CaO) . and extracellular matrix deposition and mineralization in vitro[6]. do not induce irritation do not induce delayed-type hypersensitivity Absorbable biomaterials are known for their ability to gradual- 5 I. D. Xynos et al. Bioglass 45S5 Stimulates Osteoblast Turnover and Enhances Bone do not induce acute systemic toxicity ly degrade while being replaced by the natural host bone tissue. Formation In Vitro: Implications and Applications for Bone Tissue Engineering. are neither toxic nor mutagen Hydroxyapatite is hardly soluble and its in vivo degradation rate is 3 L. L. Hench, G. P. Latorre. Reaction kinetics of bioactive ceramics. PartIV: Calcif Tissue Int (2000) 67:321 effect of glass and solution composition. Bioceramics (1992) 5: p. 67-74 6 Olga Tsigkou et al. Differentiation of fetal osteoblasts and formation of mineralized are not pyrogen 1 L. L. Hench. The Story of Bioglass. J. Mater. Sci: Mater Med (2006) 17: p. 967-978 4 A. E. Clark, C. G. Pantano, L. L. Hench. Auger spectroscopy analysis of bioglass bone nodules by 45S5 Bioglass conditioned medium in the absence of osteogenic 2 L. L. Hench. Bioceramics. J. Am. Ceram. Soc. (1998) 81: p. 1705-28 corrosion films. J. Am. Ceram. Soc. (1976) 59: p. 37-39 supplements. Biomaterials 30 (2009) 3542–3550

| 2 3 | 4.2 Implantation of different bone grafting materials on rabbits: global evaluation of NORAKER products Clinical Data An implantation study has been conducted on rabbits in order to evaluate the biological response of tissues to different bone graft- ing materials, including bioactive glass 45S5. This study has been 1. Literature review conducted in adaptation to the ISO 10993-6 norm. Bioactive glass A literature review including products similar to Leonardo has been 45S5 product is compared to a ß-TCP control material. Granules are realised using PubMed database. implanted in 5 animals for each time, in the area of the femoral epiphysis (either distal or proximal). Observation times are 4, 12 The following products, composed of bioactive glass 45S5, are and 24 weeks. Figure 3: Figure 4: marketed: PerioGlas® (oral surgery), NovaBone® (orthopaedic sur- Histological section in the Histological section in the gery) and NovaBone-C/M® (Skull-maxillo-facial surgery) marketed implantation area of implantation area of bioactive glass 45S5 Bioactive glass 45S5 by NovaBone (developped by US biomaterials) and Biogran® (de- at 12 weeks (section by at 24 weeks (section by velopped by Orthovita). One can also find bioactive glass 53S4 or microtome/Giemsa) microtome/Giemsa) S53P4 (Vivoxid, Finlande) with a different composition to 45S5: 53 % of SiO2, 23 % of Na2O, 20 % of CaO and 4 % de P2O5. Another After 24 weeks, materials have the following biological characteristics: surface of the material, 4/ degradation of the material (with differ- product contains 60 % of SiO2 who is called 60S. A mix of bioac- ent rates), and replacement by mature bone. Materials are in particle form and damage. tive glass and wollastonite called Cerabone A/W is also available No reactions to foreign body are visible. on the market. Addition of wollastonite to the ceramic gives better The picture shows a normal marrow without any sign of residual Materials are totally inserted to the bone. mechanical properties. This product is used for hip and spine surgery. ossification. Some Bioactive glass 45S5 residues can be observed, under granuled shapes (BG) in very isolated trabeculae. Bioactive glass 45S5 and ß-TCP materials can be considered as bio- BIOAKTIVE GLASS 45S5: Figure 2: active implants which contribute bone remodeling. At first, they Histological section in the PERIOGLAS (NOVABONE) After 12 weeks, Bioactive glass 45S5 granules quickly resorbed are colonized by monocyte cells, then by a soft conjonctive tissue. implantation area of NOVABONE (NOVABONE) bioactive glass 45S5 whereas control material (ß-TCP) had a slowier degradation. Osteoblasts then differentiate at their surface and are responsible PRODUCTS BIOGRAN (ORTHOVITA/BIOMET 3i) at 4 weeks (section by for the synthesis of immature bone matrix. Finally, the immature EQUIVALENT microtome/Giemsa) Outside the cortical area, the picture shows a heap of bioactive matrix is remodelled, repaced by mature bone. During this final stage, TO LEONARDO BIOACTICE GLASS S53P4: Bioactive glass 45S5 granules (material) are of particle shapes. We glass 45S5 particulates. They are included in a soft conjonctive tis- implants are damaged with variable-speed. 12 weeks the material (MIX OF Ca, Na, Si, P) BONALIVE (VIVOXID) can see numerous monocyte cells in the existing soft connective sue which is denser at the interface with particulates. In the medul- implantation, bioactive glass 45S5 was more damaged than the BIOACTIVE GLASS AW: tissue, between the ossified areas, only at the surface of the parti- lar implantation area, some trabeculae remain. They seam to result ß-TCP control materialß-TCP. After 24 weeks, both materials were CERABONE (AAP) cles (dark blue). from the presence of the particulates. damaged and totally integrated to the bone. No foreign body was visible in the implantation sites. After 4 weeks, at histological observation, both materials (bioactive vigilance has been conducted on bioactive glass glass 45S5 and control) have a bioactive appearance. They went products available in the market. One alert has been had as a conse- through different successive stages: 1/ invasion by monocyte cells, quence a hospitalization of patient despite the relationship between 2/ by a soft connective tissue, 3/ osteoblasts differentiation at the inflammation and Perioglas use was established.

| 4 5 | 2. Publications on bioactive glass Title Authors Journal Indication Patients Follow-up Conclusion Only the clinical studies with more than 12 patients have been selected. They can be found in the table below, named [EC1] to [EC18]. Bioabsorbable membrane Mengel J Periodontol Bioactive glass 16 patients: Clinical and radiological No signifi cant difference between the and bioactive glass in the et al. 77 (10), 1781 in the treatment 22 intrabony defects prospective 5-year study two groups. Both regenerative materi- treatment of intrabony (2006) of intrabony peri- treated with the Resolut als gave good results in the treatment Title Authors Journal Indication Patients Follow-up Conclusion defects in patients with odontal defects XT membrane and 20 tre- of intrabony periodontal defects. generalized aggressive ated with Perioglas 45S5 periodontitis: results of a bioactive glass Repair of orbital fl oor Aitasalo J oral maxillo- Orbital fl oor 36 patients Clinical and radio- Bioactive glass implants were well-to- 5-year clinical and radio- fractures with bioactive et al. facial surg fractures from 1995 to 1999 locical follow-up of 28 lerated. No foreign body reaction and logical study [EC5] glass implants [EC1] 2001, vol Use of bioactive patients at one-year no infl ammation. New bone formation Clinical evaluation of an Sculean J Periodontol Treatment of 28 patients: Clinical study at 1 No signifi cant improvements of the 59:12, page glass S53P4 around the implants. enamel matrix protein et al. 73 (4), 401 deep intrabony 14 in each group years with evaluation of investigated clinical parameters after 1 1390 implants derivative combined with (2002) defects Perioglas + Emdogain probing depth, clinical year. Both therapies led to signifi cant a bioactive glass for the or Perioglas alone attachment level and improvements of the investigated Using 45S5 Bioglass Stanley Int J Oral Use of bioactive 168 implants Clinical follow up Good results. Only 7.7 % of the treatment of intrabony gingival recession clinical parameters, and the combina- cones as endosseous ridge et al. Maxillofac glass 45S5 cones in 20 recalled patients at fi ve-years implants required recontouring. High periodontal defects in tion of enamel matrix derivative and maintenance implants Implants 12 after removal of rate of bioactive glass cone retention humans [EC6] bioactive glass does not seem to addi- to prevent alveolar (1), 95 (1997) tooth roots to (85.7 % ) after 5 years. The authors tionally improve the clinical outcome ridge resorption: a 5-year delay the resorp- recommend their placement into fresh of the therapy. evaluation [EC2] tion of alveolar sockets to maintain the alveolar ridge. Clinical evaluation of Lovelace J Periodontol Treatment of hu- 15 patients: Clinical follow-up at 6 No statistical difference was found ridges. bioactive glass in the et al. 69 (9), 1027 man periodontal 30 osseous defects months with evaluation when comparing bioactive glass to DF- Effects of pretreatment Park J Periodontol Clinical effects 38 intrabony Evaluation of preoperati- Use of a bone substitute in a fl ap ope- treatment of periodontal (1998) osseous defects treated: 15 with Perioglas of probing depth, clinical DBA. The study suggests that bioactive clinical parameters on et al. 72 (6), 730 of bioactive glass defects from 38 patients ve and postoperative pro- ration resulted in signifi cantly greater osseous defects in human and 15 with DFDBA attachment level and glass is capable of producing results in bioactive glass implantati- (2001) 45S5 implanta- bing depth (PD), clinical improvements in CAL and BPD over [EC7] (demineralised freeze- gingival recession the short term similar to DFDBA. on in intrabony periodon- tion in intrabony attachment level (CAL), fl ap operation alone and seemed to dried bone allograft) tal defects [EC3] periodontal bone probing depth (BPD) have positive effects in postoperative Bioactive glass S53P4 in Peltola Head Neck Osteoplastic 42 patients Clinical and radiological Accurate obliteration of sinuses was defects. and gingival recession at PD, CAL, BPD in those cases with more frontal sinus obliterati- et al. 28 (9), 834 frontal sinus Use of bioactive glass prospective after 1, 6 and achieved in 39 patients. Uneventful 6 months after surgery severe preoperative CAL and BPD. on: a long-term clinical (2006) operations on S53P4 (granules from 12 months recovery and clinical outcome were Clinical comparison of Yukna J Periodontol Treatment 27 pairs of mandibulaire Follow up during 6 Equal clinical results with bioactive experience [EC8] patients suffering 0.5 to 1 mm) seen in 92 % of the patients. Bioactive bioactive glass bone repla- et al. 72 (2), 125 problems of man- molars in 27 patients months: clinical attach- glass bone replacement graft material from chronic glass S53P4 appears to be a reliable cement graft material and (2001) dibulaire Class II (27 molars with Perioglas ment level, bone probing and e-PTFE barriers in mandibular frontal sinusitis frontal sinus obliteration material. expanded polytetrafl uo- furcations (granules from 0.09 to depth and gingival molar Class II furcations. Bioactive Bioactive glass granules as Turunen Clin Oral Bilateral sinus 17 patients 62 weeks of Clinical Similar results between two groups. roethylene barrier mem- 0.71 mm) and 27 molars recession glass required no additional material a bone adjunctive material et al. Implants Res fl oor augmentati- Use of bioactive glass follow-up. Biopsies for Bioactive glass granules can be used brane in treating human with ePTFE membrane) removal procedures. in maxillary sinus fl oor 15 (2), 135 on procedure S53P4 (granule from 0.8 histological analyses together with autologous bone chips mandibular molar class II augmentation [EC9] (2004) to 1 mm) mixed with were studied. for sinus augmentation procedure, furcations [EC4] autologous bone or bone thus decreasing the amount of bone alone. needed.

| 6 7 | Title Authors Journal Indication Patients Follow-up Conclusion Title Authors Journal Indication Patients Follow-up Conclusion

Maxillary sinus fl oor Cordioli Clin Oral Maxillary sinus 12 patients: Radiography and histo- Biogran with autologous bone graft Particulate bioglass as a Zamet J Clin Peri- Treatment of 20 patients: Follow-up was the Bioactive glass is as effective as an augmentation using et al. Implants Res augmentation unilateral or bilateral logical studies (CT) bet- combination used in one-stage sinus grafting material in the et al. odontol 24 , periodontal intra- 44 sites (22 sites with carried out weekly and at adjunct to conventional surgery in the bioactive glass granules 12 (3), 270 with simulta- sinus augmentation with ween 9 and 12 months. augmentation yields suffi cient quality treatment of periodontal 410 (1997) bony defects Perioglas and 22 fl as 3, 6, 9 months and 1year treatment of intrabony defects. and autogenous bone with (2001) neous implant grafting of 27 implants Biopsies for histological and volume of mineralized tissue for intrabony defects [EC14] surgery) post-surgery. Recording simultaneous implant placement analyses were taken predictable simultaneous implant of probing pocket depth, placement [EC10] biogran 70–80 % placement in patients with 3–5 mm probing attachment level (orthovita) + of bone height prior to grafting. and gingival recession. 20–30% autolo- 26 implants were stable 12 months Radiography evaluation. gous bone post loading. A bioactive glass particu- Anderegg J Periodontol Treatment of 15 patients Follow-up at 3 and 6 The study revealed the benefi ts of reconstruction of orbital Kinnunen J Cranioma- Repair of orbital 28 patients: Clinical and radiography Bioactive glass implants are well-tole- late in the treatment of et al. 70 (4), 384 molar furcation received surgical therapy months and evaluation bioactive glass in the treatment of fl oor fractures using et al. xillofac Surg fl oor defects after 14 with bioactive glass follow-up between 2 and rated and seem to be a promising re- molar furcation invasions (1999) invasion defects using bioactive glass of probing depth probing Class II furcation defects. study proves bioactive glass [EC11] 28 (4), 229 trauma. S53P4 et 14 with 5 years pair material for orbital fl oor fractures [EC15] compared to open fl ap attachment level and that the use of bioactive glass as a (2000) autologous bone as well as use of autologous bone debridement alone in bleeding bone grafting material is safe and human mandibular molar gives good results that are similar to Four-year results of a Sculean J Clin Perio- Regenerative pe- 25 patients: Following therapy at 1 Results indicate that the clinical furcation defects the use of autologous bone. prospective-controlled et al. dontol 34 (6), riodontal surgery 12 using enamel matrix and 4 years. Evaluation improvements obtained with both clinical study evaluating 507 (2007) at intra-bony de- protein and bioactive of clinical attachment regenerative modalities can be Comparison of Bioactive Froum J Periodontol Repair response 16 patients: Clinical Follow-up at 6, 9 Bioactive glass showed signifi cant healing of intrabony de- fects with either glass, 13 treated with level, probing depth and maintained over a period of 4 years. glass synthetic bone graft et al. 69 (6), 698 of bioactive glass 32 bone defects with and 12 months, evalua- improvements in clinical parameters fects following treatment a combination of enamel matrix protein gingival recession particles and open debri- (1998) synthetic bone Périoglas and 27 with fl ap tion of probing depth, compared to open fl ap debridement. with an enamel matrix an enamel matrix alone dement in the treatment graft particles surgery probing attachment level protein derivative alone or protein derivative of human periodontal and open debri- and gingival recession combined with a bioactive and bioactive defects. A clinical study dement in the glass [EC12] glass or with [EC16] treatment of hu- protein alone man periodontal osseous defects Alveolar ridge reconstruc- Yilmaz J Clin Perio- Filling of the 16 patients, 3 groups: Clinical and radiography After 12 months, no dehiscences tion and/or preservation et al. dontol 25 (10), alveolar ridge bioactive glass 45S5 studies until 12 months were detected and the differences in Histological observations Tadjoedin Clin Oral Bone augmen- 10 patients: Histomorphometrical All bioactive glass particles had di- using root form bioglass 832 (1998) after extraction cones, artifi cial sockets, height between the groups remained on biopsies harvested et al. Implants Res tation capacity bilateral grafting using methods at 4, 6 et 16 sappeared by resorption at 16 months cones [EC13] in order to avoid fresh extraction sockets signifi cant. Results indicate that this following sinus fl oor 11 (4), 334 of bioactive a mixture of autogenous months from bone after grafting and had been replaced deformities of the procedure is effi cient in reconstructing elevation using a bioactive (2000) glass particles in bone particles and biopsiesv by bone tissue: mixture of autogenous residual alveolar alveolar ridges deformed as a result of glass material of narrow human sinus fl oor bioactive glass 45S5 or bone and bioactive glass particles ridge in the extraction. size range [EC17] elevations bone particles. seems a promising alternative to maxillary anterior autogenous bone only. region. Clinical evaluation of Demir et J Clin Perio- Filling intrabony 29 patients: Clinical evaluation of Both PRP and bioactive glass combina- platelet-rich plasma and al. dontol 34 (8), defects 15 patients treated with probing depth, probing tion and bioactive glass alone are bioactive glass in the 709 (2007) bioactive glass+ PRP attachment level and effective in the treatment of intra- treatment of intra-bony (platelet rich plasma) and gingival recession at 9 bony defects. Using PRP with bioactive defects [EC18] 14 treated with bioactive months glass has no additional benefi ts. glass only

| 8 9 | 3. Evaluation of the clinical data ted silicon oxide is eliminated after 19 days. Another study [EC15] showed that bone grafting with bioactive glass is the best: the pro- Evaluation of clinical publications on bioactive glass is based on concerning human-beings follow-up has been studying the rate of bing depth was better and attachment level too. the literature review already published. The previous table sums up silicon in the blood. 25 patients had graft surgery using bioactive scientific studies where bioactive glass is used in oral clinical sur- glass or autologous bone after tumors resection. Blood analyses have geries. This paragraph is devised in two parts: been realised at different times until 36 months. Results showed 3.3 Literature review conclusion ■ Preclinical and clinical studies on bioactive glass resorption that there is no significant difference in the patients’ blood silicon ■ Clinical studies in oral surgery. concentration between the group treated with bioactive glass only Clinical data showed that the use of bioactive glass for bone graf- and the group treated with autologous bone. Besides, the quantity ting in oral surgery gives good results, similarly to autologous bone. of implanted bioactive glass, which depends on the volume of the The majority of these published studies are randomised and compa- 3.1 Bioactive glass resorption defect to fill, has no influence on the silicon concentration in blood. rative studies with a little number of patients. A clinical study with more patients could improve the scientific evidence of effectiveness Bioactive glass particles are composed of an amorphous mixture Moreover, studies have proved that silicon is involved in bone remo- of bioactive glass. of calcium, silicon, phosphate and sodium. The resorption by ionic delling. Indeed, Reffitt [d] has showed that addition of orthosilicic dissolution improves the contact surface of the material, allowing a acid in osteoblast cell culture stimulated type I collagen synthesis This great number of studies proves that the use of bioactive glass better blood circulation and increasing the cells anchoring. and osteoblastic differentiation. We can think that silicon released as a bone grafting material is safe and gives good results that are by bioctive glass could have a positive effect on bone remodelling. similar to the use of autologous bone. Different in vivo studies assessed bioactive glass resorption. A his- tomorphometrical study[7] conducted on rabbits showed the disso- This evaluation of clinical studies is completed with the clinical lution capacities of three different types of bioactive glasses. The 3.2 Clinical studies in oral surgery follow-up of Bioactive glass 45S5 product. authors observed that 45S5 bioactive glass had the most important kinetics of bone fixation and the faster resorption rate. Oonishi’s There are numerous clinical studies related to the use of bioactive study[8] showed that the he major part of bioactive glass particles glass in oral surgery, with a follow-up at different levels: clinical is absorbed between 8 to 12 months after implantation in femoral parameters, radiographs, biopsies. The main clinical studies in previ- condyles of rabbits. Particles could not be identified at further times ous table deal with the treatment of periodontal defects. of observation. Diagnostic of periodontal diseases is made on clinical signs such as Ducheyne[9] evaluated the elimination of bioactive glass resorption redness, oedema or inflammation. Periodontal clinical examination products and showed that silicon oxide elimination was included has to evaluate presence and quantity of bacterium blotch, bloo- into the acceptable limits for the tested animals. The approximate ding, probe depth, probe attachment level and mobility. Three diffe- time of silicon oxide elimination is 2.4 mg/day and 100 % of implan- rent surgical techniques have been identified: flap surgery, guided tissue regeneration technique, and bone grafting treatment.

7 Vogel, M., et al., In vivo comparison of bioactive glass particles in rabbits. Biomaterials, 2001. 22(4): p. 357–62. Three comparative and randomized studies compare two first 8 Oonishi, H., et al., Particulate bioglass compared with hydroxyapatite as a bone graft techniques to bone grafting using bioactive glass. Zamet [EC14] substitute. Clin Orthop Relat Res, 1997(334): p. 316–25. showed that bone grafting with bioactive glass is better than flap 9 Lai, W., et al., Excretion of resorption products from bioactive glass implanted in rabbit muscle. J Biomed Mater Res A, 2005. 75(2): p. 398–407 surgery from bone remodelling aspect. Froum [EC16] and Park [EC3]

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