No description available.

Titanium has been widely used for dental implants, and in particular, roughened titanium surfaces have provided a means for increasing bone apposition and strengthening the implant-to-bone interface. Finding a way to further increase osseointegration is important because there is a significant clinical benefit to patients if a stable anchor can be established instead of anchoring orthodontic hardware to the molars. In this study, the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the ability of temporary anchorage devices (TADs) to osseointegrate was investigated. The temporary anchorage devices (TADs) used in this study were manufactured from commercially pure titanium and divided into 2 types of treatments: (1) sandblasted and acid-etched (i.e. the control) and (2) sandblasted and acid-etched treated with Medtronic INFUSE® Bone Graft (recombinant human bone morphogenetic protein-2 placed on an absorbable collagen sponge). The implants were placed on the cranial bones of 10 adult male Sprague-Dawley rats. The rats were euthanized by carbon dioxide asphyxiation 6 weeks following surgery for histological examination and biomechanical testing. The results from visual inspection and biomechanical testing showed that the sandblasted and acid-etched TADs treated with rhBMP-2 promoted better osseointegration than TADs that were only sandblasted and acid-etched. Specifically, surface modified TADs treated with rhBMP-2 on bottom showed an increased surface coverage by bone and an increase in the adhesion strength at the TAD-to-bone interface.

No description available.

A irradiação com laser em baixa intensidade (LLLI) e a proteína morfogenética óssea recombinante humana do tipo 2 (rhBMP-2) tem sido utilizadas para estimular a formação óssea. A LLLI estimula a proliferação de células precursoras de osteoblastos e a diferenciação celular e a rhBMP-2 recruta células osteoprogenitoras para a área de cicatrização óssea. Este estudo teve por objetivo avaliar os efeitos da LLLI e da rhBMP-2 sobre o processo de cicatrização óssea em calvária de ratas Wistar. Foram utilizados 42 animais e foram criados defeitos ósseos críticos nos ossos parietais. Os animais foram divididos em seis grupos de tratamento com 7 animais cada: Grupo 1- aplicação única de laser; Grupo 2 - 7 &mu;g de rhBMP- 2 pura; Grupo 3 - aplicação única de laser e 7 &mu;g de rhBMP-2 pura; Grupo 4 - 7 &mu;g de rhBMP-2 associada ao gel de monoleína; Grupo 5 - aplicação única de laser e 7 &mu;g de rhBMP-2 associada ao gel de monoleína e Grupo 6 - defeito ósseo crítico sem qualquer tipo de tratamento (grupo controle). Foi utilizado o laser diodo de arseneto de gálio-alumínio (AsGaAl, comprimento de onda de 780 nm, potência 60mW, área do feixe de 0,04 cm2, tempo de irradiação de 80 segundos, densidade de energia de 120 J/cm2, irradiância de 1,5 W/cm2). Após 15 dias as calvárias foram removidas para análise histomorfométrica. Após análise estatística, verificou-se que o Grupo 3 apresentou a maior quantidade de osso neoformado (37,89%) quando comparado aos outros grupos (p<0,05). As quantidades de osso neoformado nos defeitos ósseos dos Grupos 1 e 4 não foram estatisticamente significantes (24,00% e 24,75%, respectivamente), mas foram significantes quando comparadas aos valores dos outros Grupos (p<0,05). As quantidades de osso neoformado nos defeitos ósseos dos Grupos 2 e 5 não foram estatisticamente significantes (31,42% e 31,96%, respectivamente), mas foram significantes quando comparadas aos valores dos outros Grupos (p<0,05). O Grupo 6 apresentou neoformação óssea (14,10%) e esta foi estatisticamente significante quando comparada aos valores dos outros Grupos (p<0,05). Pode-se concluir que a LLLI administrada durante a cirurgia efetivamente acelerou a cicatrização de defeitos ósseos críticos preenchidos com rhBMP-2 pura, conseguindo melhores resultados quando comparadas com a aplicação isolada da LLLI ou da rhBMP-2. / Low-level laser irradiation (LLLI) and recombinant human bone morphogenetic protein type 2 (rhBMP-2) have been used to stimulate bone formation. LLLI stimulates proliferation of osteoblast precursor cells and cell differentiation and rhBMP-2 recruits osteoprogenitor cells to the bone healing area. This in study evaluated the effects of LLLI and rhBMP-2 on the bone healing process in calvaria of female Wistar rats. Critical bone defects were created in the parietal bone in 42 animals, and the animals were divided into six treatment groups with 7 animals: Group 1 - laser in a single application; Group 2- 7 &mu;g of pure rhBMP-2; Group 3 - laser in a single application and 7 &mu;g of pure rhBMP-2; Group 4 - 7 &mu;g of rhBMP-2 combined with monoolein gel, Group 5 - laser in a single application and 7 &mu;g of rhBMP-2 combined with monoolein gel; and Group 6 - critical bone defect controls. A gallium-aluminumarsenide diode laser was used (GaAlAs; wavelength 780 nm, output power 60mW, beam area 0.04 cm2, irradiation time 80 s, energy density 120 J/cm2, irradiance 1.5 W/cm2). After 15 days, the calvarial tissues were removed for histomorphometric analysis. Group 3 defects showed higher amounts of newly formed bone (37.89%) than the defects of all the other Groups (p<0.05). The amounts of new bone in defects of Groups 1 and 4 were not significantly different from each other (24.00% and 24.75%, respectively), but were significantly different from the amounts in the other Groups (p<0.05). The amounts of new bone in the defects of Groups 2 and 5 were not significantly different from each other (31.42% and 31.96%, respectively), but were significantly different from the amounts in the other Groups (p<0.05). Group 6 defects had 14.10% new bone formation, and this was significantly different from the amounts in the other Groups (p<0.05). It can be concluded that LLLI administered during surgery effectively accelerated healing of critical bone defects filled with pure rhBMP-2, achieving a better result than LLLI alone or the use of rhBMP-2 alone.

La technique des membranes induites par un conformateur en polymethylmethacrylate (PMMA) et greffe d’os spongieux autologue a été décrite par Masquelet pour la régénération des pertes de substance osseuse segmentaire des os longs. Cette technique en deux temps pourrait avantageusement être utilisée pour la reconstruction des pertes de substances osseuses segmentaires mandibulaires en cancérologie en cas d’échec ou de contre-indication des greffes osseuse revascularisées. Le premier objectif de ce travail était d’évaluer les propriétés histologiques et biologiques des membranes induites par un conformateur en PMMA avec radiothérapie, et de les comparer avec celles induites par un conformateur en silicone. Ce matériau plus souple que le PMMA a été choisi comme alternative au PMMA dans le but de faciliter l’ablation du conformateur. Les membranes induites par le PMMA ou le silicone en sous-cutané chez des rats Wistar avaient une structure histologique et des propriétés biologiques comparables mais les résultats étaient plus stables pour les membranes induites par le silicone. Le second objectif de ce travail était de proposer un procédé d’ingénierie tissulaire en alternative à la greffe d’os spongieux autologue. La néoformation osseuse au sein d’une membrane induite par un conformateur en silicone avec greffe de différentes combinaisons de céramique phosphocalcique biphasique macroporeuse (MBCP+™), de moelle osseuse totale, de simvastatine et de rhBMP-2 a été évaluée chez des rats Wistar en sous-cutané puis en site osseux fémoral. Les résultats n’ont pas permis de montrer de néoformation osseuse significative dans les groupes avec simvastatine. Par contre, une néoformation osseuse significative a été montrée dans les groupes avec rhBMP-2, avec ou sans radiothérapie. Un effet substantiel de l’adjonction de moelle osseuse totale a également été retrouvé. / Induced membrane technique with a polymethylmethacrylate (PMMA) spacer and autologous cancellous bone graft has been proposed by doctor Masquelet for segmental long bone reconstruction. This two stage technique could be proposed for segmental mandibular bone reconstruction in oncological situations in case of failure or contraindication of revascularized autologous bone graft. The first objective of this study was to evaluate the histological and biological properties of membranes induced by PMMA with radiotherapy, and to compare them to membranes induced by silicone. This material smoother than PMMA has been chosen to facilitate spacer removal. Membranes induced by both materials in subcutaneous models in rats had similar histological and biological properties, but membranes induced by silicone were less affected by radiotherapy. The second objective of this study was to propose a tissue engineering procedure as an alternative to autologous bone graft. The new bone formation inside silicone induced membranes has been analyzed after implantation of different combinations of macroporous biphasic phosphocalcic ceramic (MBCP+™), total bone marrow, simvastatine and rhBMP-2 in subcutaneous and femoral osseous models in rats. No significant new bone formation has been demonstrated in simvastatin groups. However, a significant new bone formation has been demonstrated in rhBMP-2 groups, with or without radiotherapy. An increased new bone formation has also been demonstrated with total bone marrow.

A irradiação com laser em baixa intensidade (LLLI) e a proteína morfogenética óssea recombinante humana do tipo 2 (rhBMP-2) tem sido utilizadas para estimular a formação óssea. A LLLI estimula a proliferação de células precursoras de osteoblastos e a diferenciação celular e a rhBMP-2 recruta células osteoprogenitoras para a área de cicatrização óssea. Este estudo teve por objetivo avaliar os efeitos da LLLI e da rhBMP-2 sobre o processo de cicatrização óssea em calvária de ratas Wistar. Foram utilizados 42 animais e foram criados defeitos ósseos críticos nos ossos parietais. Os animais foram divididos em seis grupos de tratamento com 7 animais cada: Grupo 1- aplicação única de laser; Grupo 2 - 7 &mu;g de rhBMP- 2 pura; Grupo 3 - aplicação única de laser e 7 &mu;g de rhBMP-2 pura; Grupo 4 - 7 &mu;g de rhBMP-2 associada ao gel de monoleína; Grupo 5 - aplicação única de laser e 7 &mu;g de rhBMP-2 associada ao gel de monoleína e Grupo 6 - defeito ósseo crítico sem qualquer tipo de tratamento (grupo controle). Foi utilizado o laser diodo de arseneto de gálio-alumínio (AsGaAl, comprimento de onda de 780 nm, potência 60mW, área do feixe de 0,04 cm2, tempo de irradiação de 80 segundos, densidade de energia de 120 J/cm2, irradiância de 1,5 W/cm2). Após 15 dias as calvárias foram removidas para análise histomorfométrica. Após análise estatística, verificou-se que o Grupo 3 apresentou a maior quantidade de osso neoformado (37,89%) quando comparado aos outros grupos (p<0,05). As quantidades de osso neoformado nos defeitos ósseos dos Grupos 1 e 4 não foram estatisticamente significantes (24,00% e 24,75%, respectivamente), mas foram significantes quando comparadas aos valores dos outros Grupos (p<0,05). As quantidades de osso neoformado nos defeitos ósseos dos Grupos 2 e 5 não foram estatisticamente significantes (31,42% e 31,96%, respectivamente), mas foram significantes quando comparadas aos valores dos outros Grupos (p<0,05). O Grupo 6 apresentou neoformação óssea (14,10%) e esta foi estatisticamente significante quando comparada aos valores dos outros Grupos (p<0,05). Pode-se concluir que a LLLI administrada durante a cirurgia efetivamente acelerou a cicatrização de defeitos ósseos críticos preenchidos com rhBMP-2 pura, conseguindo melhores resultados quando comparadas com a aplicação isolada da LLLI ou da rhBMP-2. / Low-level laser irradiation (LLLI) and recombinant human bone morphogenetic protein type 2 (rhBMP-2) have been used to stimulate bone formation. LLLI stimulates proliferation of osteoblast precursor cells and cell differentiation and rhBMP-2 recruits osteoprogenitor cells to the bone healing area. This in study evaluated the effects of LLLI and rhBMP-2 on the bone healing process in calvaria of female Wistar rats. Critical bone defects were created in the parietal bone in 42 animals, and the animals were divided into six treatment groups with 7 animals: Group 1 - laser in a single application; Group 2- 7 &mu;g of pure rhBMP-2; Group 3 - laser in a single application and 7 &mu;g of pure rhBMP-2; Group 4 - 7 &mu;g of rhBMP-2 combined with monoolein gel, Group 5 - laser in a single application and 7 &mu;g of rhBMP-2 combined with monoolein gel; and Group 6 - critical bone defect controls. A gallium-aluminumarsenide diode laser was used (GaAlAs; wavelength 780 nm, output power 60mW, beam area 0.04 cm2, irradiation time 80 s, energy density 120 J/cm2, irradiance 1.5 W/cm2). After 15 days, the calvarial tissues were removed for histomorphometric analysis. Group 3 defects showed higher amounts of newly formed bone (37.89%) than the defects of all the other Groups (p<0.05). The amounts of new bone in defects of Groups 1 and 4 were not significantly different from each other (24.00% and 24.75%, respectively), but were significantly different from the amounts in the other Groups (p<0.05). The amounts of new bone in the defects of Groups 2 and 5 were not significantly different from each other (31.42% and 31.96%, respectively), but were significantly different from the amounts in the other Groups (p<0.05). Group 6 defects had 14.10% new bone formation, and this was significantly different from the amounts in the other Groups (p<0.05). It can be concluded that LLLI administered during surgery effectively accelerated healing of critical bone defects filled with pure rhBMP-2, achieving a better result than LLLI alone or the use of rhBMP-2 alone.

Biorelevant in vitro release/dissolution tests are designed to predict the in vivo behavior of a drug and are crucial in understanding its in vivo performance. Currently, there is no standardized compendial in vitro release testing methods or regulatory guidance’s for release/dissolution testing of implants due to their complex physiological locations.Furthermore, existing compendial methods do not capture the local release profile of ‘novel’ parenterals in physiological low fluid volume surrounding areas. Long acting and in situ forming implants with orthobiologic proteins and peptides have increased over the past few decades due to a better understanding of genetic engineering. One of these products, INFUSE® Bone Graft (Medtronics, MN, USA), is an implant which helps in bone regeneration at the trauma site and is comprised of a) an absorbable collagen sponge (ACS) and b) recombinant human bone morphogenetic protein-2 (rhBMP-2). INFUSE® Bone Graft is an FDA approved product for acute, open shaft tibial fractures, lumbar spinal fusions and sinus or ridge augmentations in the jaws. The evaluation of implant products such as INFUSE® Bone Graft requires a good understanding of local and systemic release in vivo in order to ensure safe, effective, and predictable product performance. The primary goal of this study is to develop a predictive ‘biorelevant’ release model, which factors in clinically relevant physiological parameters suitable for studying and effectively predicting extended release of implants, using INFUSE Bone Graft® as our model implant. A novel biorelevant in vitro model was designed and tested. The model was observed to be discriminatory between two different carrier formulations of rhBMP-2 using a model independent approach - similarity factor (f2). Additionally, a high throughput assay to quantify rhBMP-2 release using high performance liquid chromatography with UV/VIS detection was also developed and validated. Successful completion of this study facilitated an in vitro release study design that incorporated the complex biorelevant parameters of implant dosage forms, the model will offer crucial insights into biological performance, and aid in developing methods to characterize release of other similar dosage forms.

Non-union bone fractures are a standing problem for clinical treatments. It has been found that the exogenous growth factor recombinant human bone morphogenetic protein-2 (rhBMP-2) induces bone healing in potential non-union fractures. However, the currently used clinical dose of rhBMP-2 is high and causes side-effects. Mechanical loading is known to enhance the induced effects of rhBMP-2 in bone healing, which may lead to a reduced required dose. Yet, the exact underlying mechanism is unknown. To further investigate the combined role of mechanical loading and rhBMP-2 in the early phase of fracture healing a 2D computational model was developed. The model uses a lattice-based approach where biological rule-based events are combined with finite element analysis to simulate both untreated bone healing progression and when subjected to mechanical loading and rhBMP-2. Two healing cases were investigated:  normal fracture healing in a small bone defect (1 mm gap) and non-union fracture healing in a large bone defect (5 mm gap). By varying the magnitude and timing of applied load as well as the rhBMP-2 dose, a combination that would reduce the currently used rhBMP-2 dose and still enable healing in a large bone defect was searched. The model could simulate fracture healing in a large bone defect when subjected to rhBMP-2, independently of the applied load. Also the expected non-union result in a large bone defect without applied rhBMP-2 was obtained. The model could not capture normal fracture healing in a small bone defect as well as bone remodelling. It was found that a 50 % reduced rhBMP-2 dose could not induce healing in a large bone defect when applied separately but when applied together with load. Additionally, this combination of stimulation gave similar results compared to other combinations using higher rhBMP-2 doses. To conclude, even though the model was able to replicate some of the healing events seen experimentally, it is in need of modifications to correct current deficiencies. Still, after some further development and validation, the model has the potential to be used in future studies of fracture healing when influenced by mechanical loading and rhBMP-2. The found possibility for a reduced dosage of rhBMP-2 when applied together with load has to be further investigated before any conclusions can be drawn.

Over the past 5 years, the use of titanium implants as temporary anchorage devices (TADs) has become an important tool in clinical orthodontic practices. The use of TADs have provided orthodontists a way of moving teeth against fixed objects rather than against the surrounding teeth, which tend to counteract desired motion. At present, viable attachment of TADs involves direct insertion through gingival tissue and piercing of the bone. Surface modifications such as sandblasted and acid-etched treatment or bone morphogenetic protein surface treatment, however, can be applied to the TADs to promote enhanced osseointegration, thereby allowing the TADs to serve as stable anchors while avoiding bone puncture. In this study, a comparison was made between sandblasted/acid-etched TADs and sandblasted/acid-etched/recombinant human bone morphogenetic protein-2 (rhBMP-2) treated TADs to determine whether rhBMP-2 promotes enhanced osseointegration. A total of 10 rats (4 controls and 6 treated with rhBMP-2) were used in the study, with 1 TAD placed on the skull of each rat. At the end of 6 weeks, the animals were euthanized by carbon dioxide asphyxiation, and bone blocks, each containing a TAD, were prepared for histological examination and biomechanical characterization. The results of this study showed that TADs treated with rhBMP-2 had greater bone formation at the bone-implant interface and an increase in total implant stability.

Recombinant human bone morphogenic proteins (rhBMPs) are extensively studied and employed clinically for treatment of various bone defects. Current clinical delivery vehicles suffer wasteful burst releases that mandate supra-physiological dosing driving concerns over safety and cost. It was therefore investigated whether a unique drug delivery vehicle sequestered within a composite scaffold could lower the burst release of rhBMP-2. PLGA-calcium phosphate tri-phasic composite scaffolds delivered model protein BSA with burst release of ~13% and sustained kinetics of 0.5-1.5% BSA/day up to 45 days. rhBMP-2 was delivered with zero burst release however at much lower levels, totaling 0.09% to 0.9 % release over 10 days, but had up to 6.3-fold greater bioactivity than fresh rhBMP-2 (p<0.05). In conclusion, the three-phase composite scaffold can deliver bioactive proteins with a reduced burst release and sustained secondary kinetics.