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PubMed2002

The effect of recombinant human bone morphogenetic protein-4 on the osteoblastic differentiation of mouse calvarial cells affected by Porphyromonas gingivalis.

BACKGROUND: A number of studies have shown effective bone regeneration induced by bone morphogenetic proteins (BMPs), but it is not clear whether the presence of periodontopathic bacteria has any significant modulation effect on the bone regeneration ability of BMPs. The present study examined whether pretreatment of mouse calvarial cells with Porphyromonas gingivalis extracts can make a difference in their osteoblastic differentiation exerted by recombinant human bone morphogenetic protein-4 (rhBMP-4). METHODS: Primary mouse calvarial osteoblastic (MCO) cells were cultured until they reached confluence. At confluence, cells were untreated or pretreated with 1 microgram/ml of sonicated P gingivalis extracts (SPEs) for 2 days. After washing, the cells were further incubated in the presence of rhBMP-4 (0 to 100 ng/ml) for 3 days. At the end of the treatment, the cells were harvested and lysed for measurement of the alkaline phosphatase (ALP) activity. Total RNA was extracted, and reverse transcription-polymerase chain reaction (RT-PCR) analysis for expression of ALP mRNA was conducted. The amount of prostaglandin E2 (PGE2) secreted into the culture supernatant was determined using an enzyme immunoassay. RESULTS: The stimulatory effect of rhBMP-4 on ALP activity was observed in both untreated MCO cells and in cells pretreated with 1 microgram/ml of SPEs in a dose-dependent manner. The ALP activities were significantly reduced in the cells pretreated with SPEs at all concentrations of rhBMP-4 used in the study when compared to untreated cells. Similar results were obtained in the RT-PCR analysis for ALP mRNA. Cells pretreated with SPEs released significantly larger amounts of PGE2 than untreated cells, but the treatment with 100 ng/ml of rhBMP-4 had no significant effect on the amount of PGE2 released. These results suggest that the stimulatory effect of rhBMP-4 on osteoblastic differentiation might be significantly reduced by P gingivalis, possibly through the endogenous PGE2 pathway, but rhBMP-4 still has a stimulatory effect on osteoblastic differentiation of mouse calvarial cells affected by P gingivalis. CONCLUSION: Our results suggest that supplemental BMPs would be beneficial for improved treatment of osseous defects, although their biologic effect might be significantly reduced by periodontopathic bacteria.

Alkaline Phosphatase↗
PubMed1994

Advances in the use of guided tissue regeneration for localized ridge augmentation in combination with dental implants.

Osseointegrated dental implants placed into adequate bone enjoy a high success rate. However, placing implants into resorbed alveolar ridges can result in fixtures that are not optimally positioned or must be placed in insufficient bone, thus reducing their rate of success. Recently, techniques for bone regeneration developed for use around teeth have been applied to implant dentistry. Guided Tissue Regeneration (GTR), also called Guided Bone Regeneration (GBR), uses thin membranes which act as barriers to soft tissue ingrowth. This approach for regenerating bone around implants is described in detail in this paper. Initial approaches and modifications are covered as are specific details of current techniques.

Alveolar Bone Loss↗
PubMed1994

Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy.

Bone formation in the embryo, and during adult fracture repair and remodeling, involves the progeny of a small number of cells called mesenchymal stem cells (MSCs). These cells continuously replicate themselves, while a portion become committed to mesenchymal cell lineages such as bone, cartilage, tendon, ligament, and muscle. The differentiation of these cells, within each lineage, is a complex multistep pathway involving discrete cellular transitions much like that which occurs during hematopoiesis. Progression from one stage to the next depends on the presence of specific bioactive factors, nutrients, and other environmental cues whose exquisitely controlled contributions orchestrate the entire differentiation phenomenon. An understanding of the cellular and molecular events of osteogenic differentiation of MSCs provides the foundation for the emergence of a new therapeutic technology for cell therapy. The isolation and in vitro mitotic expansion of autologous human MSCs will support the development of novel protocols for the treatment of many clinically challenging conditions. For example, local bone defects can be repaired through site-directed delivery of MSCs in an appropriate carrier vehicle. Generalized conditions, such as osteoporosis, may be treatable by systemic administration of culture-expanded autologous MSCs or through biopharmaceutical regimens based on the discovery of critical regulatory molecules in the differentiation process. With this in mind, we can begin to explore therapeutic options that have never before been available.

Animals↗
PubMed2005

The role and effectiveness of bone marrow in osseous regeneration.

Autologous bone marrow serves as the richest and most readily available repository of progenitor cells capable of differentiating into mature bone forming cells. Numerous studies have demonstrated that bone marrow alone or cell suspensions of marrow usually diluted in culture medium affect de novo bone formation when implanted in soft tissue sites. Consequently, when bone marrow is used to enrich orthopaedic grafting matrices such as xenograft, demineralized bone matrix, or ceramic materials it almost invariably produces faster and more consistent defect healing compared to bone marrow or the carrier matrix alone and, in some cases, equivalent healing to autograft. This article evaluates the clinical effectiveness of these grafting materials for various orthopaedic applications such as healing long bone defects and enhancing spinal fusion procedures, and hypothesizes that enrichment with bone marrow is integral to timely and satisfactory graft incorporation. Methods such as centrifugation, culture expansion and selective cell retention that concentrate and deliver marrow-derived osteoprogenitor cells to the graft site as a means of mimicking more closely the consistent bone forming potential of autologous bone graft are also discussed.

Animals↗
PubMed2005

Effects of chitosan nonwoven membrane on periodontal healing of surgically created one-wall intrabony defects in beagle dogs.

The purpose of this study was to investigate the periodontal regenerative effects of a chitosan nonwoven membrane applied to surgically created preclinical one-wall intrabony defects in beagle dogs. One-wall intrabony defects (4 x 4 x 4 mm) were surgically created bilaterally in the mandibular second and fourth premolars of six beagle dogs. The surgical control group received a flap operation only. The resorbable-membrane (RM) group was treated with resorbable membrane. The chitosan-nonwoven-membrane (CNWM) group was treated with chitosan nonwoven membrane. The amount of junctional epithelium migration and the amount of connective tissue adhesion did not show any statistically significant differences among the groups. However, the amount of suprabony cementum regeneration, intrabony cementum regeneration, and alveolar bone regeneration showed significant differences (p < 0.05) between CNWM site group and control group. The results demonstrate the regenerative effects of the chitosan nonwoven membrane in one-wall intrabony defects of beagle dogs. The chitosan nonwoven membrane has the potential to support the cementum and bone regeneration, possibly by providing the conditions needed for guided tissue regeneration in the one-wall intrabony periodontal defects of beagle dogs.

Animals↗
PubMed2000

A biodegradable polymer scaffold for delivery of osteotropic factors.

Despite discoveries and developments in osteotropic factors, therapies exploiting these macromolecules have been limited due to a lack of suitable delivery vehicles and three dimensional (3D) scaffolds that promote bone regeneration. To address this limitation, an emulsion freeze-drying process was developed to fabricate biodegradable scaffolds with controlled microarchitecture, and the ability to incorporate and deliver bioactive macromolecules for bone regeneration. The effect of median pore size and protein loading on protein release kinetics was investigated using scaffolds with different protein loading and median pore sizes ranging from 7 to 70 microm. Graphs of protein release from scaffolds showed an initial burst followed by a slower sustained release. Release kinetics were characterized using an unsteady-state, diffusion-controlled model with an effective diffusivity that took tortuosity (tau) and partition coefficient for protein adsorption (Kp) onto the scaffold walls into account. Tortuosity and partition coefficient significantly reduced the protein diffusivity by a factor of 41 +/- 43 and 105 +/- 51 for 60 and 30-microm median pore-sized scaffolds, respectively. The activity of the protein released from these scaffolds was demonstrated by delivering rhBMP 2 and [A-4] (an amelogenin derived polypeptide) proteins from the scaffold and regenerating bone in a rat ectopic bone induction assay [Whang et al. J Biomed Mater Res 1998;42:491-9, Veis et al. J Bone Mineral Res, Submitted].

Biocompatible Materials↗
PubMed2005

Periodontal repair in dogs: guided tissue regeneration enhances bone formation in sites implanted with a coral-derived calcium carbonate biomaterial.

BACKGROUND: Previous studies suggest that a bioresorbable calcium carbonate coral implant (CI) supports space provision and bone formation for guided tissue regeneration (GTR). However, it could not be discerned whether observed effects were because of GTR or whether the CI possessed osteoconductive properties enhancing bone formation. The objective of this study was to evaluate bone formation associated with the CI biomaterial in the presence and absence of provisions for GTR. METHODS: Routine, critical size, 6 mm, supra-alveolar periodontal defects were created in 12 young adult Beagle dogs. Five animals received the CI alone (Biocoral 1000). Seven animals received the CI/GTR combination using an expanded polytetrafluoroethylene barrier (GORE-TEX Regenerative Material). The animals were euthanized at 4 weeks postsurgery and tissue blocks of the experimental sites were collected and processed for histometric analysis. RESULTS: Clinical healing was uneventful. The histopathologic and histometric analysis revealed significantly increased bone formation (height and area) in sites receiving the CI/GTR combination compared with CI alone (2.3+/-0.6 versus 1.2+/-0.9 mm; and 3.1+/-0.8 versus 1.2+/-1.1 mm2; p<0.05). The CI biomaterial appeared to be mostly unassociated with new bone formation; the CI particles were observed sequestered in newly formed bone, fibrovascular marrow, and in the supra-alveolar connective tissue. Cementum formation was limited and observed in few sites for both treatment protocols. CONCLUSION: While GTR promoted new bone formation, the CI contributed limited, if any, osteoconductive effects.

Absorbable Implants↗
PubMed2004

Mepe is expressed during skeletal development and regeneration.

a bone metabolism regulator that is expressed by osteocytes in normal adult bone. Here, we used an immunohistochemical approach to study whether Mepe has a role in murine long bone development and regeneration. Our data showed that Mepe protein was produced by osteoblasts and osteocytes during skeletogenesis, as early as 2 days postnatal. During the healing of non-stabilized tibial fractures, which occurs through endochondral ossification, Mepe expression was first detected in fibroblast-like cells within the callus by 6 days postfracture. By 10 and 14 days postfracture (the hard callus phase of repair), Mepe was expressed within late hypertrophic chondrocytes and osteocytes in the regenerating tissues. Mepe became externalized in osteocyte lacunae during this period. By 28 days postfracture (the remodeling phase of repair), Mepe continued to be robustly expressed in osteocytes of the regenerating bone. We compared the Mepe expression profile with that of alkaline phosphatase, a marker of bone mineralization. We found that both Mepe and alkaline phosphatase increased during the hard callus phase of repair. In the remodeling phase of repair, Mepe expression levels remained high while alkaline phosphatase activity decreased. We also examined Mepe expression during cortical bone defect healing, which occurs through intramembranous ossification. Mepe immunostaining was found within fibroblast-like cells, osteoblasts, and osteocytes in the regenerating bone, through 5 to 21 days postsurgery. Thus, Mepe appears to play a role in both long bone regeneration and the latter stages of skeletogenesis.

Alkaline Phosphatase↗
PubMed1998

[Autogenous bone cell transplantation].

In this study the outcome of autologous bone cell transplantation in artificial femur defects was tested within an animal study in sheep. The bone cells were harvested by a small ilium biopsy and cultivated in an individual medium with 10% autogenous serum and 90% X-Vivo 10. After two weeks 4 millions of the cultured bone cells were transplanted in artificial femur defects with bone gelatin as carrier. The remaining cells were characterized by various tests (Alkaline phosphatase, osteocalcin, collagen type I, calcification). This procedure was tested in 24 adult male sheep. The side of transplantation was randomized by plan. The corresponding femur side represents the control side. After 10 days, 4, 8 and 12 weeks animals were killed and the femura were taken for the following evaluation: histology, radiology, bone density and mechanical testing. The results show that the autologous bone transplantation leads to a significant higher bone regeneration in the bone defects. After ten days there was a lower migration of inflammation cells. After 4 weeks we find a significant increase of new bone formation on the transplanted side in the histological examination. After 8 weeks this significant difference was found even in the bone density. This difference increased in the 12 weeks group further on. The autogenous bone cell transplantation in the described way seems to be an potent method in the treatment of bone defects.

Animals↗
PubMedDate not supplied

[Porous hydroxylapatite ceramics with homologous osteoblasts from cell cultures for bone replacement].

In an animal model using 24 inbred Lewis rats the effect of the simultaneous implantation of in vitro cultivated osteoblasts and a porous hydroxyl apatite ceramic material on bone regenerations was studied. Bone tissue was harvested from 2 inbred rats and a cell line of osteoblasts was established. The osteoblasts were multiplied in cell cultures and after 3 passages inserted along with granular HA into monocortical femur defects in 24 rats of the same inbred line. After various times of observation the femurs were examined radiographically and bone growth was assessed histologically. No significant increase in bone growth rate was observed, although earlier studies in the same model showed a marked qualitative effect of reimplanted in vitro cultured osteoblasts on new bone formation. Considering that pre-incubation largely reduces the toxic effect of HA ceramics, the results of this study indicate that the activity of the implanted osteoblasts in the defect is prevented by the simultaneous implantation of replacement material and cells.

Animals↗
PubMed2006

Commercially available demineralized bone matrix compositions to regenerate calvarial critical-sized bone defects.

BACKGROUND: Demineralized bone matrix products are often used by surgeons to regenerate bone. Several different types of carriers have been combined with demineralized bone matrix to improve clinical handling and surgical outcome. The aim of the study was to quantitate bone regeneration in standard-sized calvarial defects (a critical-sized defect) in response to commercially available demineralized bone matrix formulations. METHODS: The commercial demineralized bone matrix formulations were tested as received in 8-mm-diameter calvarial critical-sized defects in an athymic rat model. The demineralized bone matrix treatment groups included the following: (1) Allomatrix; (2) demineralized bone matrix plus sodium hyaluronate (DBX); (3) DBX with poly(DL-lactide) mesh; 4) Dynagraft; (5) Grafton; (6) Regenafil; and (7) human demineralized bone matrix without a carrier. An eighth treatment was a poly(DL-lactide) mesh. At designated times of 2, 4, and 8 weeks, the critical-sized defects were recovered and processed for undecalcified histology and histomorphometry. Histomorphometric data were subjected to an analysis of variance and Fisher's protected least significant difference multiple comparison test. Significance was established at p <or= 0.05. RESULTS: Allomatrix, Dynagraft, Regenafil, and poly(DL-lactide) mesh alone had less bone formation than DBX, Grafton, DBX plus mesh, and demineralized bone matrix. CONCLUSIONS: DBX, DBX plus mesh, demineralized bone matrix, and Grafton produced more bone formation than Allomatrix, Dynagraft, mesh alone, and Regenafil.

Animals↗
PubMed2003

[Animal model study of guided bone tissue regeneration around implant by titanium membrane].

OBJECTIVE: To evaluate the titanium membrane-guided bone tissue regeneration around implant and HA granules. METHODS: Three adult cross-bred dogs were used. In the animal's mandible, man-made bone damaged regions (diameter 6.5 mm, depth 4 mm) being concentric with the implant holes were prepared. The implants were planted into the holes and were rendered to separate the damaged regions into two parts with two titanium sheets. One part was filled with HA granules while the other with nothing. Histological evaluation was done at 4, 8 and 12 weeks of implantation. RESULTS: The bone around the implants grew obviously at 4 weeks; the bone grew more and the structure of the bone was similar to that of the normal bone at 12 weeks. CONCLUSION: As a new type of GTR materials, titanium membrane can keep the existence of spaces underneath. HA granules can give guiding effects to bone tissue regeneration.

Animals↗
PubMed2006

Local signals in stem cell-based bone marrow regeneration.

The cellular basis of bone marrow (BM) tissue development and regeneration is mediated through hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Local interplays between hematopoietic cells and BM stromal cells (BMSCs) determine the reconstitution of hematopoiesis after myelosuppression. Here we review the BM local signals in control of BM regeneration after insults. Hematopoietic growth factors (HGFs) and cytokines produced by BMSCs are primary factors in regulation of BM hematopoiesis. Morphogens which are critical to early embryo development in multiple species have been added to the family of HSCs regulators, including families of Wnt proteins, Notch ligands, BMPs, and Hedgehogs. Global gene expression analysis of HSCs and BMSCs has begun to reveal signature groups of genes for both cell types. More importantly, analysis of global gene expression coupled with biochemical and biological studies of local signals during BM regeneration have strongly suggested that HGFs and cytokines may not be the primary local regulators for BM recovery, rather chemokines (SDF-1, FGF-4) and angiogenic growth factors (VEGF-A, Ang-1) play instructive roles in BM reconstitution after myelosuppression. A new direction of management of BM toxicity is emerging from the identification of BM regenerative regulators.

Bone Marrow Cells↗
PubMed2004

Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats.

Prostaglandin E(2) (PGE(2)) is essential for fracture healing. Systemic administration of EP4 ligands such as PGE(2) and other synthetic EP4 agonists appears to transduce anabolic signals by binding to receptor EP4. Therefore, the present study was designed to test whether administration of EP4 agonist accelerates the healing of drill-hole injury in the femoral diaphysis. After surgery, a total of 128 Wistar rats, at the age of 12 weeks, were assigned to basal control (n = 8), and three groups with respective doses of 0 (vehicle control), 10 (low-dose), and 30 (high-dose) microg/kg body weight of the agent were subcutaneously injected twice a day. Femoral specimens were obtained at 0, 5, 7, 14, 21, and 28 days. In EP4 agonist-treated groups, the total bone volume of the regenerating bone in the defect did not significantly differ, but the regenerated cortical bone volume measured by histomorphometry and cortical bone mineral content (Ct. BMC) by pQCT dose-dependently increased at 14 and 21 days compared to the control. In the high-dose group, the value of osteoclast surface significantly increased compared with that in the control at 14 days. Expression levels of osteocalcin and TRAP mRNAs in the injured tissue increased at 14 days. Expression levels of EP4, BMP-2, and RANKL mRNAs increased at 7 days in the high-dose group. The bone mineral values of the lumbar bone at 28 days, measured by DXA, did not differ in the three groups. These data indicated that systemic administration of EP4 agonist ONO-4819.CD accelerated cortical bone healing after drill-hole injury by upregulating the local turnover of the regenerating bone.

Animals↗
PubMed2005

Noggin improves bone healing elicited by muscle stem cells expressing inducible BMP4.

The aim of this study was to test the hypothesis that a specific antagonist may enhance the efficacy of its corresponding growth factor in a regulated tissue engineering strategy. Our prior research has led to the development of a retroviral vector that enables optimal regulated bone morphogenetic protein 4 (BMP4) expression in vitro and regulated bone formation in vivo with transduced muscle stem cells. However, when implanted in critical-sized calvarial defects, these cells led to residual bone formation without induction or bone overgrowth with induction, even at reduced cell doses. We thus co-implanted the aforementioned cells with stem cells engineered to express Noggin, a specific BMP antagonist. This approach, while preserving our ability to regulate bone regeneration closely, prevented both the basal level bone regeneration and the bone overgrowth and, more importantly, led to the regeneration of bone that more closely resembled normal bone. We believe that this regulatable tissue engineering strategy, enhanced by utilizing a specific antagonist, constitutes a new paradigm for tissue engineering and regenerative medicine.

Adenoviridae↗
PubMed2001

Intraindividual comparative animal study of alpha- and beta-tricalcium phosphate degradation in conjunction with simultaneous insertion of dental implants.

An intraindividual comparative study of proximal tibial marrow defects in nine adult Goettinger miniature pigs (GMPs) was undertaken. The left side of the defect was filled with granular beta-tricalcium phosphate (TCP) ceramic ad modum Cerasorb, and the right side was filled with granular alpha-TCP ceramic ad modum Biobase alpha pore. Simultaneously, dental screw implants were inserted in each ceramic and fixed within the orthotopically replanted corticalis lids. Control defects were made in two other animals. The survival period ranged from 4 to 86 weeks (control study, 16 and 20 weeks). The reorganization and degree of bone regeneration, dynamics of ceramic degradation, and remodeling characteristics of the bone regenerate referring to osseo-integration of the dental implants were examined histomorphologically in nondecalcified specimens. The results reveal that both ceramic types were osteoconductive exclusively. Centripetally oriented angiogene bone regeneration occurred at the margins of the circular defects. Ceramic degradation was performed hydrolytically and within cells. Furthermore, it was demonstrated that decomposition of the intratrabecularly integrated ceramic residues underlies a dynamic process of degradation. Within 86 weeks, nearly 80% to 90% of the larger alpha-TCP granules, and nearly 90% to 95% of the beta-TCP granules were degraded. At this time, especially for the alpha-TCP modification, ceramic microparticles were found in the marrow, either unbound or within polynuclear macrophages. The predictable degradation of both ceramic types provides an early functional adaptation of bone regenerates and facilitates a biofunctional, anisotropic orientation of the neotrabeculae without delay. It is concluded that because of the initially pronounced accumulation of macrophages, dental implants should not be inserted simultaneously with ceramic, but after further progress of ceramic degradation (5 to 6 months after TCP implantation).

Absorbable Implants↗
PubMed2000

Efficacy of high-density versus semipermeable PTFE membranes in an elderly experimental model.

OBJECTIVE: The clinical effectiveness of expanded polytetrafluoroethylene (PTFE) membranes for guided bone regeneration has been reported in the literature on several occasions. However, one major drawback of this material is the need for a second surgical operation for removal of the membrane. In addition, most studies involving guided bone regeneration in animal models have used young animals or animals of unspecified age, but in some clinical situations guided bone regeneration may be indicated in elderly jaw bones. The objectives of this investigation were (1) to evaluate the effectiveness of a newly introduced high-density PTFE membrane (TefGen-FD)-a material that does not require second-stage surgery for its removal-for enhancement of bone ingrowth in elderly rabbits' calvaria and (2) to compare the findings with those obtained with the commonly used semipermeable expanded PTFE membrane (Gore-Tex). STUDY DESIGN: Eighteen elderly rabbits (each more than 30 months old) served as the experimental animals in this study. Two non-self-healing, full-thickness defects were created in each rabbit calvarium. One of the 2 defects was fully covered with macroprous expanded PTFE membrane (Gore-Tex); the other defect was covered with microporous PTFE membrane (TefGen-FD). Specimens were obtained at 4, 8, and 16 weeks and examined by means of light microscopy. RESULTS: Clinically, the high-density TefGen membrane was much easier to detach from the underlying bone than was the semipermeable Gore-Tex membrane, which showed strict adherence to bone surface on removal. Microscopically, the Gore-Tex membrane lamellae were infiltrated by fibro-osseous tissue at the membrane's lower surface. A relatively greater speed and quantity of bone regeneration were observed in the defective cavities covered with Gore-Tex membrane than in those covered with TefGen membrane. CONCLUSIONS: It appears that the semipermeable Gore-Tex membrane is more effective than the high-density TefGen-FD membrane with respect to guided bone regeneration in elderly bone. These findings have relevance for the clinical situation of using guided bone regeneration in conjunction with implant placement and ridge augmentation procedures in atrophic elderly jaws.

Age Factors↗
PubMed1994

Force required for bone segment transport in the treatment of large bone defects using medullary nail fixation.

In distraction osteogenesis, different factors influence quality and quantity of bone formation. These factors are rigidity of fixation, frequency, and velocity of transport; and integrity of periosteum, endosteum, and intramedullary vascularization. Little data are available on forces related to distraction osteogenesis and limb lengthening, and no data on forces related to bone segment transport. This experiment investigates the correlation of the bone regeneration process with transport forces. Bone segment transport over an intramedullary nail provides an excellent model for measurement of external forces during distraction osteogenesis because soft-tissue and muscle resistance is reduced as compared with limb lengthening. In an animal experiment (sheep), tibial shaft defects of 20 mm and 45 mm were treated. External transport forces were measured daily during bilateral wire transport of a bone segment over an intramedullary nail. Forces increased during transport. Overall transport forces for large defects were slightly higher than those for small defects, reaching 350 N by the end of transport. For large defects, transport forces leveled off during bone transport and rose again at the end. Correspondingly, for large defects, stress relaxation within the tissues increased during the third and the sixth week of transport. This plateau may be interpreted as a reduction of internal forces within the repair tissues at the distraction site, implying a spreading of the healing phases during the bone regeneration process or geometrically different shapes of the regenerate.

Animals↗