PMC:4137170 / 23062-31108 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4137170","sourcedb":"PMC","sourceid":"4137170","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4137170","text":"Discussion\nIn general, during the dental implant fixation, there should be enough quantity and good quality of an alveolar bone to cover the entire implant for long-term success [20, 21]. However, the number of patients with an alveolar bone that are not suitable for dental implant fixation have increased due to the growing number of elderly people in the population and the need for re-surgery. Thus, the present study was conducted to improve bone formation at a site that has bone defect or insufficient bone quality, and to evaluate dental implant osseointegration using hyaluronic acid, which is soluble and injectable, and a mixture of rhBMP-2 and β-TCP microsphere, which has well-established osteoconductivity and binds well with rhBMP-2.\nThe hyaluronic acid that was used for this study underwent hydroexpansivity by binding with water molecules [22], and it could be expand thoroughly on the defect area by contact with blood or tissue fluid when it was injected into the bone defect. Moreover, unlike slow degrading hydroxyapatite, the ability of the fast degrading TCP results in the release of calcium ions. Therefore, TCP is known for its osteoinductive ability to trigger the signaling pathway through protein kinase C pathways and promote the gene expression of BMPs [23–25].\nOne role of rhBMP-2 is to promote differentiation of monocytes or mesenchymal stem cells into chondrocytes by promoting their recruitment or proliferation, and then inducing new bone formation through osteoblastic differentiation [26]. Therefore, the number of mesenchymal stem cells in the host is important. From this aspect, the rabbit tibia diaphyseal implantation model used in this study has the advantage of being able to create a similar environment without causing a bone defect because there is no directly contacted osseous tissue around an implant in the marrow space except for the tibial cortical bone. Since the proximal metaphyseal area of the tibia has thin cortical bone and large portion of cancellous bone, a dental implant can be fixed by cancellous bone around near cortex and marrow space although it is not fixed to the far cortex. So, in the present study, the dental implant was not placed in the metaphysis; rather, it was fixed to the near cortex of the diaphysis without contacting the far cortex after countersinking. Thus, it is more difficult to generate newly formed bone when inserting an implant into the tibial diaphysis than when making a bone defect in the mandible or maxilla and then inserting a dental implant. For this reason, this model has the advantage of being able to reduce experimental errors because it is favorable for evaluating the experimental results and the stability of the implant can be well-maintained by the cortical bone.\nOne limit of this model is that it is unable to provide an environment that is similar to a bone defect site insertion environment. The powder gel-BMP-2 that was implanted into the tibial diaphyseal intramedullary space could not be contained within the defect area and intramedullary blood was infiltrated into BMP-2, which may affect the bone formation [14]. Even though the porous β-TCP microsphere-hyaluronic acid powder gel composite shows osteoconductivity of β-TCP, the rate of osseointegration and new bone formation in this group was similar to the control group. This is possibly because new bone formation did not easily occur in the animal model used in this study. Therefore, in the present study, the new bone formation using the powder gel-BMP-2 composite was significantly high, indicating that the powder gel performed effectively as a carrier of rhBMP-2.\nA fairly long time is required for in vivo bone formation, which means that rhBMP-2 needs to be released continuously [27]. The results of the present study showed that a collagen carrier gave an initial burst of released rhBMP-2 in a period of 1 day, whereas the hyaluronic acid-based powder gel released rhBMP-2 continuously for up to 7 days. A previous report on bone healing revealed that the sustained release of growth factor is more favorable than a burst release [28].\nThe micro-CT and histomorphometric results showed that the newly formed bone fraction was significantly higher in the BMP-2 group, when compared to the levels in the implant group and the hydrogel group.\nThese results indicate that the composite was efficacious as a carrier of rhBMP-2 and bone was formed in an adjacent area where rhBMP-2 was directly and in where no host bone exists. The bone quantity and quality in the BMP-2 group were significantly improved when compared to the results from the implant group, as the BMP-2 group showed significantly higher parameters of micro-CT for bone quantity, such as percent bone volume, trabecular thickness, and trabecular number in the newly formed bone, and significantly lower parameters for bone quality, such as trabecular separation and trabecular pattern factor. These results imply that the rhBMP-2 loaded powder gel composite strengthened osseointegration through new bone formation around the dental implant in the rabbit tibia model. In comparison, the hydrogel group showed even lower new bone formation than the implant group (although the difference was not statistically significant), indicating that the porous β-TCP microspheres acted as a barrier between the implant and the tissue surrounding the implant because the hyaluronic acid powder gel only shows osteoconductivity [29–31]. This phenomenon is evident in the histology results. The fact that fibrous tissue formation was observed between the implant and the bone means that, when only β-TCP microspheres and hyaluronic acid powder gel are implanted, the combination may negatively affect the osseointegration of an implant. In contrast, if β-TCP microspheres and hyaluronic acid powder gel are mixed with rhBMP-2 and injected, they are expected to strengthen the osseointegration of the dental implant by promoting significant formation of new bone through their action as carriers of rhBMP-2, even in an environment where a bone defect exists or bone quality is poor.\nThe rhBMP-2 release experiment showed that the degree of osteoinductivity is difficult to ascertain because less than 20 % of the total rhBMP-2 in the composite was released after seven days. While both of the components in the composite used in this study could act as carriers of rhBMP-2, the β-TCP microspheres are considered to have combined more strongly with rhBMP-2. Because the rhBMP-2 release was relatively small in this study, when compared to rhBMP-2 release kinetics using a hyaluronic acid-based hydrogel which were previously reported [32, 33]. Moreover, the authors have observed that the rhBMP-2 release pattern of the β-TCP microsphere in the present data seemed similar to the pattern in our previous unpublished data. Thus, this indicates that β-TCP binds more strongly with rhBMP-2 and β-TCP is the rate limiting step of the rhBMP-2 kinetic release.\nGelatin release kinetics has indicated that the initial burst of rhBMP-2 is achieved by diffusion [34, 35]. However, in a situation where sustained release primarily occurs, enzymatic degradation is the more important mechanism [35]. As shown in the present study, the porous β-TCP microsphere and hyaluronic acid powder gel composite may not release sufficient amounts of rhBMP-2 in situations where sustained release occurs due to the strong binding of rhBM-2. In fact, the ratio and particle size of the β-TCP microsphere are important in determining the degradation rate [36]. Moreover, the β-TCP used in this study had a particle size ranging from 45 to 75 μm and it was less degraded than a nano-sized β-TCP. Therefore, in order to achieve the maximum efficacy of rhBMP-2, the composite properties must be improved.\nHowever, the powder has been determined to be a long-term delivery carrier while collagen is used as a short-term delivery carrier of rhBMP-2, and the powder would be expected to improve the bone healing rate at the same dose [37].","divisions":[{"label":"title","span":{"begin":0,"end":10}},{"label":"p","span":{"begin":11,"end":748}},{"label":"p","span":{"begin":749,"end":1293}},{"label":"p","span":{"begin":1294,"end":2777}},{"label":"p","span":{"begin":2778,"end":3650}},{"label":"p","span":{"begin":3651,"end":4127}},{"label":"p","span":{"begin":4128,"end":4331}},{"label":"p","span":{"begin":4332,"end":6121}},{"label":"p","span":{"begin":6122,"end":6992}},{"label":"p","span":{"begin":6993,"end":7814}}],"tracks":[{"project":"2_test","denotations":[{"id":"24928668-21123283-61779600","span":{"begin":858,"end":860},"obj":"21123283"},{"id":"24928668-20643969-61779601","span":{"begin":1286,"end":1288},"obj":"20643969"},{"id":"24928668-22285104-61779601","span":{"begin":1286,"end":1288},"obj":"22285104"},{"id":"24928668-9528003-61779602","span":{"begin":1525,"end":1527},"obj":"9528003"},{"id":"24928668-23990717-61779603","span":{"begin":3770,"end":3772},"obj":"23990717"},{"id":"24928668-22902517-61779604","span":{"begin":4123,"end":4125},"obj":"22902517"},{"id":"24928668-16690121-61779605","span":{"begin":5470,"end":5472},"obj":"16690121"},{"id":"24928668-24035888-61779605","span":{"begin":5470,"end":5472},"obj":"24035888"},{"id":"24928668-22687758-61779606","span":{"begin":6673,"end":6675},"obj":"22687758"},{"id":"24928668-24167632-61779607","span":{"begin":6677,"end":6679},"obj":"24167632"},{"id":"24928668-10837630-61779608","span":{"begin":7092,"end":7094},"obj":"10837630"},{"id":"24928668-23977328-61779609","span":{"begin":7096,"end":7098},"obj":"23977328"},{"id":"24928668-23977328-61779610","span":{"begin":7222,"end":7224},"obj":"23977328"},{"id":"24928668-23226019-61779611","span":{"begin":7569,"end":7571},"obj":"23226019"},{"id":"24928668-19886733-61779612","span":{"begin":8042,"end":8044},"obj":"19886733"}],"attributes":[{"subj":"24928668-21123283-61779600","pred":"source","obj":"2_test"},{"subj":"24928668-20643969-61779601","pred":"source","obj":"2_test"},{"subj":"24928668-22285104-61779601","pred":"source","obj":"2_test"},{"subj":"24928668-9528003-61779602","pred":"source","obj":"2_test"},{"subj":"24928668-23990717-61779603","pred":"source","obj":"2_test"},{"subj":"24928668-22902517-61779604","pred":"source","obj":"2_test"},{"subj":"24928668-16690121-61779605","pred":"source","obj":"2_test"},{"subj":"24928668-24035888-61779605","pred":"source","obj":"2_test"},{"subj":"24928668-22687758-61779606","pred":"source","obj":"2_test"},{"subj":"24928668-24167632-61779607","pred":"source","obj":"2_test"},{"subj":"24928668-10837630-61779608","pred":"source","obj":"2_test"},{"subj":"24928668-23977328-61779609","pred":"source","obj":"2_test"},{"subj":"24928668-23977328-61779610","pred":"source","obj":"2_test"},{"subj":"24928668-23226019-61779611","pred":"source","obj":"2_test"},{"subj":"24928668-19886733-61779612","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93bdec","default":true}]}]}}