Use Of BMPs Research Articles

Bringing gene therapy to regenerative medicine

Bringing gene therapy to regenerative medicine

Bioinspired gelatin/bioceramic composites loaded with bone morphogenetic protein-2 (BMP-2) promote osteoporotic bone repair

There are currently several commercialized products approved by the Food and Drug Administration and the European Medicines Agency based on the use of recombinant human BMP-2 for the treatment of non-unions long fractures and spinal fusion. However, the adverse effects recorded with the use of BMPs suggest the need for drug delivery carriers that allow reducing the required doses and improve their cost-effectiveness. Herein, we have developed a new osteoconductive scaffold that reduces the required doses of BMP-2 for promoting bone regeneration in an osteoporotic defect model. The composite is, in brief, a gelatin-based 3D scaffold reinforced with either calcium sulfate or hydroxyapatite as an inorganic osteoconductive biomaterial. To this end, the organic/inorganic composite systems showed high hydration capacity and good in vitro degradability. The incorporation of 7.5% (m/v) ceramic compounds resulted in scaffolds with stiffer Young modulus (179 and 75 kPa for CaSO4_7 and HA_7, respectively) than bare gelatin hydrogels (48 kPa). Studies with human bone-marrow derived mesenchymal stem cells (hBM-MSCs) revealed that the 3D scaffolds promote cell adhesion and proliferation along with osteogenic differentiation capabilities. Specifically, downregulation of stemness (Nanog, Oct4) genes and upregulation of osteogenic markers (ALP, Col1a1, Fmod) by two fold were observed over 10 days under basal culture conditions. Promisingly, the sustained in vitro release of BMP-2 observed from the porous reinforced scaffolds allowed us to address the critical-sized osteoporotic mice calvarial defects with a relatively low growth factor doses (600 ng BMP-2/scaffold) compared to conventional doses at 2–15 micrograms. Overall, this study demonstrates the promising potential of osteoconductive gelatin/calcium bioceramics composites as osteogenic growth factors delivery carriers for bone-regeneration via ultra-low growth factor doses.

The application of bone morphogenetic proteins in medicine, dentistry, sport and rehabilitation: A review of literature

Bone tissue is a mineralized structure with a complicated metabolism and due to its mechanical functions its structure must be adapted to the bone function. The BMP protein group stimulates the formation of bone and cartilage and influences numerous non-osteogenic processes. As a result of their osteogenic effect, BMP proteins are used in numerous areas of medicine, including dentistry and orthopaedics, as well as sport and rehabilitation. The publications used in this paper were sourced from the PubMed and the Google Scholar databases. The index entries used to search the databases included BMP, bone morphogenetic proteins, medicine, dentistry and sport. BMP proteins have a wide range of applications, particularly in dentistry and sports medicine. The study demonstrates that autogenous material is the best for bone regeneration as a result of using resources of BMP proteins and bone-forming cells. Undeniably, the condition of the patient's body undergoing treatment with BMP is not without significance. According to the authors of the article, all applications and treatment options with the use of BMPs are yet to be known. Perhaps further development of medicine will make their discovery possible.

O uso de proteínas morfogenéticas ósseas (BMP) e pseudoartroses, uma revisão de literatura

Bone morphogenetic proteins (BMP) are multi‐functional growth factors to promote bone healing with the proposal of less morbidity compared to the usual methods of bone graft harvest. Pseudoarthrosis occur when the fusion attempt fails, a solid fusion is not achieved, or there is motion across the segment leading to it, and it can be clinically symptomatic as pain, deformity, neurocompression, or hardware failure. BMPs are used at spinal fusion as a tool for the treatment of degenerative, traumatic, neoplastic and infectious conditions of the spine. This review shows that the use of BMPS is effective and secure when compared with iliac crest bone graft (ICGB); however, depending of the location of usage (cervical spine, lumbar spine or sacrum) and the medical status of the patient (presence of comorbidities, tobacco usage), it is more likely to exhibit complications. Therefore, the use of these proteins must be an informed decision of patient and physician preferences.

Application of BMP-2 for bone graft in Dentistry

Introduction: The global increase life expectancy and the resulting tooth loss has required searching for new rehabilitation alternatives in Dentistry. Biomaterials can be defined as any material that acts replacing a lost bone defect and its function. In Dentistry, many studies have aimed to improve bone regeneration through the use of BMPs for bone replacement. Objective: To review the literature on the use and clinical viability of human morphogenetic protein for the jaws reconstruction. Material and methods: The following databases were searched: Pubmed, Bireme, Lilacs, and Scielo and 30 articles published between 1965 and 2013 were found using the following descriptors: “dental implants”, “maxillary sinus”, and “biocompatible materials”. Results: Several studies demonstrate the biological advantages of rhBMP-2 on bone regeneration of the jaws. In recent years, morphogenetic protein has presented a large clinical use. Conclusion: Despite being a high-cost biomaterial, rhBMP-2 is a viable and very effective alternative for reconstruction of defects of the face.

The use of bone morphogenetic proteins (BMP) and pseudarthrosis, a literature review

Bone morphogenetic proteins (BMP) are multi-functional growth factors to promote bone healing with the proposal of less morbidity compared to the usual methods of bone graft harvest. Pseudoarthrosis occur when the fusion attempt fails, a solid fusion is not achieved, or there is motion across the segment leading to it, and it can be clinically symptomatic as pain, deformity, neurocompression, or hardware failure. BMPs are used at spinal fusion as a tool for the treatment of degenerative, traumatic, neoplastic and infectious conditions of the spine. This review shows that the use of BMPS is effective and secure when compared with iliac crest bone graft (ICGB); however, depending of the location of usage (cervical spine, lumbar spine or sacrum) and the medical status of the patient (presence of comorbidities, tobacco usage), it is more likely to exhibit complications. Therefore, the use of these proteins must be an informed decision of patient and physician preferences.

Application of BMP-2 for bone graft in Dentistry

The global increase life expectancy and the resulting tooth loss has required searching for new rehabilitation alternatives in Dentistry. Biomaterials can be defined as any material that acts replacing a lost bone defect and its function. In Dentistry, many studies have aimed to improve bone regeneration through the use of BMPs for bone replacement. Objective: To review the literature on the use and clinical viability of human morphogenetic protein for the jaws reconstruction. Material and methods: The following databases were searched: Pubmed, Bireme, Lilacs, and Scielo and 30 articles published between 1965 and 2013 were found using the following descriptors: “dental implants”, “maxillary sinus”, and “biocompatible materials”. Results: Several studies demonstrate the biological advantages of rhBMP-2 on bone regeneration of the jaws. In recent years, morphogenetic protein has presented a large clinical use. Conclusion: Despite being a high-cost biomaterial, rhBMP-2 is a viable and very effective alternative for reconstruction of defects of the face.

The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.

Membrane nanowaves in single and collective cell migration.

We report the characterization of three-dimensional membrane waves for migrating single and collective cells and describe their propagation using wide-field optical profiling technique with nanometer resolution. We reveal the existence of small and large membrane waves the amplitudes of which are in the range of ∼3–7 nm to ∼16–25 nm respectively, through the cell. For migrating single-cells, the amplitude of these waves is about 30 nm near the cell edge. Two or more different directions of propagation of the membrane nanowaves inside the same cell can be observed. After increasing the migration velocity by BMP-2 treatment, only one wave direction of propagation exists with an increase in the average amplitude (more than 80 nm near the cell edge). Furthermore for collective-cell migration, these membrane nanowaves are attenuated on the leader cells and poor transmission of these nanowaves to follower cells was observed. After BMP-2 treatment, the membrane nanowaves are transmitted from the leader cell to several rows of follower cells. Surprisingly, the vast majority of the observed membrane nanowaves is shared between the adjacent cells. These results give a new view on how single and collective-cells modulate their motility. This work has significant implications for the therapeutic use of BMPs for the regeneration of skin tissue.

Initial Experience With rhBMP‐2 Delivered in a Compressive Resistant Matrix for Mandibular Reconstruction in 5 Dogs

To document cumulative initial experience and long-term follow-up of the use of rhBMP-2/CRM for reconstruction of large mandibular defects (≥5 cm) in dogs. Retrospective case series. Dogs (n = 5). Medical records (October 1999-April 2011) of dogs that had mandibular reconstruction for defects/resections of ≥5 cm using rhBMP-2/CRM were reviewed. Signalment, preoperative assessment/rationale for mandibular reconstruction, surgical methods, postoperative assessment of the reconstruction (evaluation of occlusion), and complications were recorded. A definitive histologic diagnosis was obtained in dogs that had mandibular resection for mass removal. Long-term complications were determined. A minimum time frame of 2-year in-hospital follow-up was required for case inclusion. Mandibular reconstruction was successfully performed in all dogs' defects where gaps of 5-9 cm were bridged. Surgical reconstruction rapidly restored cosmetic appearance and function. All dogs healed with new bone formation across the gap. New bone formation was present within the defects as early as 2 weeks after surgery based on palpation, and new bone formation bridging the gap was documented radiographically by 16 weeks. Minor complications occurred in all dogs in the early postoperative period, and included early firm swelling and gingival dehiscence in 1 dog; late plate exposure in 3 dogs; and exuberant/cystic bone formation in 2 dogs (related to concentration/formulation of rhBMP-2/CRM). Two dogs had minor long-term complications of late plate exposure and a non-vital canine tooth; the plates and the affected canine tooth were removed. Long-term in-hospital follow-up was 5.3 years (range, 2-12.5 years); further long-term telephone follow-up was 6.3 years (range, 2-12.5 years). All owners were pleased with the outcome and would repeat the surgery again under similar circumstances. The efficacy and success of this mandibular reconstruction technique, using rhBMP-2/CRM with plate fixation, was demonstrated with bridging of large mandibular defects regardless of the underlying cause, and with excellent cosmetic and functional results. Complications were common, but considered minor and easily treated. The complications encountered revealed the importance of tailoring the use of BMPs and fixation methods to this specific anatomic location and indication.

Surgical treatment of spondylodiscitis. An update.

Spondylodiscitis refers to an infection affecting the intervertebral disk, the vertebral body or the posterior arch of the vertebra being aetiologically, pyogenic, granulomatous (tuberculosis, brucellosis, or fungal infection) or parasitic. Spondylodiscitis diagnosis is based on clinical symptoms, a combination of erythrocyte sedimentation rate with C-reactive protein (CRP) tests and, less useful, leukocytosis. Blood culture is also a very cost-effective method of identifying organisms. Plain radiographs are useful, however changes may take several months to appear. Radionuclide tests are currently less used; nevertheless, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) shows encouraging results particularly when magnetic resonance images (MRI) are unconvincing in the distinction between degenerative changes and infection. MRI with gadolinium enhancement is the choice for image diagnosis. Medical management is usually the basis for treatment, alone or in combination with surgery. Surgical approach, either by endoscopy or open, is indicated for biopsy when clinical evolution is unsatisfactory and no micro-organism has been isolated, and also whenever a root, spinal cord or dural compression is seen on MRI; spinal instability or severe deformity are also clear indications for surgical treatment. Less invasive surgery either CT-scan guided or, particularly, by endoscopy has good results. However open surgery is still the standard. The anterior approach allows for anterior disc and bone debridement. The posterior approach is indicated when posterior elements are involved or in the presence of an epidural abscess. Although good results have been claimed, the use of instrumentation in the presence of an infected focus is controversial, as the use of cages or BMPs are.

Use of BMPs and bisphosphonates to improve bone fracture healing

In orthopaedics, focus is often placed on increasing bone formation by an anabolic drug like the recombinant human bone morphogenetic protein (rhBMP). However, premature or excessive bone resorption, due to stress-shielding, instability or infection/inflammation can lead to poor, delayed, or absent bone union. Anti-catabolic drugs such as bisphosphonates have therefore been explored to improve bone repair. This short review discusses the current literature underlying the anabolic-catabolic paradigm for bone repair with a focus on BMP and bisphosphonate combination approaches.

Preliminary studies on the use of BMPs in Orthognatic surgery

The amount of postoperative bone esorption after genioplasty was studied n 16 patients. The subjects of this study ere 5 patients who underwent genioplasty lone, and 11 who underwent genioplasty ombined with other techniques for corecting skeletal Class II and Class III eformity. Large advancement genioplasties were erformed on 16 patients by horizontal steotomy of the inferior border of the andible, with preservation of a muscuoperiosteal pedicle to the advanced genial egment. Preoperative, immediate postoprative, and long-term follow-up lateral ephalometric radiographs were retrospecively analyzed to evaluate the osseous hanges of the chin. We examined the corelation between bone resorption and the egree of advancement, the height of the enial segment, and the distance from the xisting bone to the genial segment. The esults showed a correlation between bone esorption and the distance from existing one to the genial segment. We can thereore expect the supply of blood between xisting bone and the genial segment to ave an influence on bone resorption. Conflict of interest: None declared.

Are Endogenous BMPs Necessary for Bone Healing during Distraction Osteogenesis?

Previous reports suggest the application of exogenous BMPs can accelerate bone formation during distraction osteogenesis (DO). However, there are drawbacks associated with the use of exogenous BMPs. A possible alternative to the use of exogenous BMPs is to upregulate the expression of endogenous BMPs. Since DO results in spontaneously generated de novo bone formation in a uniform radiographic, histological, and biomechanical temporal sequence, a genetically engineered model lacking endogenous BMP2 should have measurable deficits in bone formation at different time points. We performed DO on BMP2(fl/+) and BMP2(fl/+ cre) mice using a miniature Ilizarov fixator. Distracted samples were collected at various time points and analyzed using real time-quantitative PCR, lCT, radiology, immunohistochemistry, histology, and biomechanical testing. Immunohistochemical studies of 34-day heterozygous samples showed reduced expression of BMP2, BMP7, BMPR1a, ACTR1, and ACTR2b. lCT analysis of 51-day heterozygous samples revealed a decrease in trabecular number and increase in trabecular separation. Biomechanical testing of 51-day heterozygous samples revealed decreased stiffness and increased ultimate displacement. Radiological analysis showed the heterozygotes contained a decreased bone fill score at 17, 34, and 51 days. These data suggest endogenous BMPs are important for bone healing and manipulating endogenous BMPs may help accelerate bone consolidation during DO.

The effect of the association of NIR laser therapy BMPs, and guided bone regeneration on tibial fractures treated with wire osteosynthesis: Raman spectroscopy study

Bone fractures are lesions of different etiology; may be associated or not to bone losses; and have different options for treatment, such as the use of biomaterials, guided bone regeneration, techniques considered effective on improving bone repair. Laser therapy has also been shown to improve bone healing on several models. The association of these three techniques has been well documented by our group using different models. This study aimed to assess, through Raman spectroscopy, the incorporation of calcium hydroxyapatite (CHA ∼ 958 cm −1) on the repair of complete tibial fractures in rabbits treated with wire osteosynthesis (WO); treated or not with laser therapy; and associated or not with the use of BMPs and/or Guided Bone Regeneration. Complete tibial fractures were created in 12 animals that were divided into four groups: WO; WO + BMPs; WO + laser therapy; and WO + BMPs + laser therapy. Irradiation started immediately after surgery; was repeated at every other day during 2 weeks; and was carried out with λ 790 nm laser light (4 J/cm 2 per point, 40 mW, φ ∼ 0.5 cm 2, 16 J per session). Animal death occurred after 30 days. Raman spectroscopy was performed at both the surface and the depth of the fracture site. Statistical analysis showed significant difference on the concentrations of CHA between surface and depth. The analysis in each of the areas showed at the depth of the fracture significant differences between all treatment groups ( p < 0.0001). Significant differences were also seen between WO + BMPs + laser therapy and WO ( p < 0.001) and WO + laser therapy ( p < 0.001). At the surface, significant difference was seen only between the treatment groups and the non-fractured subjects ( p = 0.0001). However, no significant difference was seen between the treatment groups ( p = 0.14). It is concluded that the use of NIR laser therapy associated to BMPs and GBR was effective in improving bone healing on the fractured bones as a result of the increasing deposition of CHA measured by Raman spectroscopy.

Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion

Since the identification of the osteogenic protein-1 (OP-1) gene, also called bone morphogenetic protein-7 (BMP-7), almost 20 years ago, OP-1 has become one of the most characteristic members of the BMP family. The biological activity of recombinant human OP-1 has been defined using a variety of animal models. These studies have demonstrated that local implantation of OP-1 in combination with a collagen matrix results in the repair of critical size defects in long bones and in craniofacial bones and the formation of bony fusion masses in spinal fusions. Clinical trials investigating long bone applications have provided supportive evidence for the use of OP-1 in the treatment of open tibial fractures, distal tibial fractures, tibial nonunions, scaphoid nonunions and atrophic long bone nonunions. Clinical studies investigating spinal fusion applications have provided supportive evidence for the use of OP-1 in posterolateral lumbar models and compromised patients as an adjunct or as a replacement for autograft. Both long bone repair and spinal fusion studies have demonstrated the efficacy and safety of OP-1 by clinical outcomes and radiographic measures. Future clinical investigations will be needed to better define variables, such as dose, scaffold and route of administration. Clearly the use of BMPs in orthopaedics is still in its formative stage, but the data suggest an exciting and promising future for the development of new therapeutic applications.

Optimized use of a biodegradable polymer as a carrier material for the local delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2)

To improve the efficacy of a block copolymer of poly- d, l-lactic acid with randomly inserted p-dioxanone and polyethylene glycol (PLA-DX-PEG) as a drug delivery system for recombinant human bone morphogenetic proteins (rhBMPs), we examined the relationship between the volume of PLA-DX-PEG, the dose of rhBMP-2 and osteoinduction in a mouse model of ectopic bone formation. In a series of studies, we compared the size and bone mineral content (BMC) of ectopically induced bone by PLA-DX-PEG and collagen sponges carrying different quantities of rhBMP (0, 1, 2, 5, 10, 20 μg). An additional experiment was designed to investigate how a range of PLA-DX-PEG polymer volumes (15, 30, 60, 90 mg) with a fixed rhBMP concentration (0.01 wt%), altered the size and BMC of the induced ossicle. The influence of polymer volume was also examined in a further experiment wherein a fixed amount of rhBMP was placed in a range of PLA-DX-PEG copolymer volumes to give different concentrations of the protein per implant (0.02–0.0017 wt%). The results indicate that the bone yields were linearly dependent on the dose of rhBMP and also were proportional to the polymer volume above the minimal concentration of rhBMP-2 (0.0017 wt% in this series). The optimal concentration of rhBMP-2 in PLA-DX-PEG was 0.003 wt% in mice. The data provide important insights into the fabrication of implants that provide efficacious delivery of rhBMP-2 using the lowest possible dose of this expensive osteoinductive protein. This information will be of value for the clinical use of BMPs.

Testing the Empirical Relationship between Best Management Practice Adoption and Farm Profitability

Several “best management practices” (BMPs) aimed at reducing movement of nutrients, pesticides, and sediment into surface water resources have been developed and promoted by Extension and other agencies over the past several years. This study utilizes actual farm-level economic and BMP adoption data to rigorously analyze the relationship between BMP use and farm profitability. Results indicate that adoption of nutrient BMPs has a significant positive effect on net farm income (NFI) for wheat and corn, while herbicide BMP adoption, particularly use of BMPs related to the application of atrazine on corn, has a small (but statistically significant) negative impact on income. Adoption of soil conservation BMPs is not shown to have a statistically significant impact on farm income.

Watershed‐scale effects of urbanization on sediment export: Assessment and policy

Built components of watersheds are associated with impervious surfaces that alter hydrology, disrupt ecosystems, and affect water quality. This study focuses on the impervious factor as a tool for assessment and policy design to address water quality impacts. The empirical model uses a combination of watershed simulation and statistical regression modeling to study sediment loading at various stages of urbanization. The policy design is based on private behavior in a watershed setting to develop appropriate economic approaches. The incentives through taxes, subsidies, and cost sharing are based on water quality impacts. It was observed that nonlinearity in response functions resulted in transition effects that are continuous. This is due to gradual shifts in landscape characteristics as a result of urbanization. On a regional basis, impervious factor had a varying effect on water quality and depend on the state of urbanization and spatial characteristics. Economic policies based on a metric like impervious cover can be used to mitigate the negative effects of urbanization in watersheds through use of appropriate BMPs, urban forestry methods, and spatial targeting. While linear rules in policy are easier to implement, nonlinear rules were more effective in representing the changes in marginal social cost of impervious factor, especially initial and late stages of urbanization. There exists excellent scope in using this targeted policy to address specific problems associated with complex urban systems.

A pilot safety and efficacy study of osteoinductive protein–1 (recombinant human bone morphogenetic protein–7) in posterolateral lumbar fusion as a replacement for iliac crest autograft

Tushar Ch. Patel, MD, Hopkinton, MA, USA; John A. McCulloch, MD, FRCSC, Akron, OH, USA; Alexander R. Vaccaro, MD, Philadelphia, PA, USA; Eeric Truumees, MD, Royal Oak, MI, USA; Jeffrey S. Fischgrund, MD, Harry N. Herkowitz, MD, Southfield, MI, USA; Todd J. Albert, MD, Alan Hilibrand, MD, Philadelphia, PA, USA; Frank M. Phillips, MD, F. Todd Wetzel, MD, Chicago, IL, USAIntroduction: Posterolateral intertransverse lumbar fusion is a commonly performed procedure for stabilization of the degenerated lumbar spine. A typical clinical scenario for which such fusions are used is the stabilization of a degenerative spondylolisthesis after decompression. In a recent large series reported in the literature, this type of fusion was noted to have a pseudarthrosis rate of up to 45% [1].Materials and methods: A pilot study was designed to evaluate the safety and efficacy of osteoinductive protein-1 (OP-1, also known as recombinant human bone morphogenetic protein–7 [BMP-7]) in lumbar posterolateral fusion. Thirty-six patients with the diagnosis of symptomatic spinal stenosis and single-level degenerative spondylolisthesis in the lower lumbar spine (L3–S1) were enrolled. The patients were randomized to either the OP-1 group or the control group. The OP-1 group received 3.5 mg of OP-1 per side in a putty carrier. The control group received iliac crest autograft alone. Outcomes were measured clinically using the Oswestry score and radiographically using dynamic radiographs evaluated independently by two blinded radiologists using digital calipers.Results: At 6 months, the OP-1 group had a 32% higher success rate than the autograft group. Patients were deemed a success with both radiographic (bridging bone and spinal stability on flexion/extension films) and clinical (greater than 20% improvement in Oswestery score) success. No adverse events related to the use of OP-1 were noted.Discussion: Despite the nonstatistical number of patients enrolled in this pilot study, these preliminary results suggest that OP-1 appears to be a safe and effective replacement for iliac crest autograft in human posterolateral lumbar fusion. The OP-1 group had a higher radiographic fusion rate than the autograft group. This correlated well with the greater clinical success experienced by the OP-1 group, as measured by improvement in the Oswestry score. None of the previously reported device-related complications related to the use of BMPs in animal studies, such as exuberant bone growth with subsequent neural impingement, ectopic ossification or spinal stenosis, were seen in the treatment group.Conclusion: OP-1 appears to be a safe and effective replacement for iliac crest autograft in human posterolateral lumbar fusion. The dose, 3.5 mg per side, and the carrier, biodegradable putty, appear to provide a safe and effective means of delivering the bone morphogenetic protein OP-1 to the human lumbar spine.