Study Design. A prospective randomized clinical study was conducted. Objective. To determine whether the dose and carrier that were successful in rhesus monkeys could induce consistent radiographic spine fusion in humans. of Background Data. Preclinical studies have demonstrated that recombinant human bone morphogenetic protein-2 (rhBMP-2), an osteoinductive bone morphogenetic protein, is successful at generating spine fusion in rabbits and rhesus monkeys. Methods. For this study, 25 patients undergoing lumbar arthrodesis were randomized (1:2:2 ratio) based on the arthrodesis technique: autograft/Texas Scottish Rite Hospital (TSRH) pedicle screw instrumentation (n = 5), rhBMP-2/TSRH (n = 11), and rhBMP-2 only without internal fixation (n = 9). On each side, 20 mg of rhBMP-2 were delivered on a carrier consisting of 60% hydroxyapatite and 40% tricalcium phosphate granules (10 cm 3 /side). The patients had single-level disc degeneration, Grade 1 or less spondylolisthesis, mechanical low back pain with or without leg pain, and at least 6 months failure of non-operative treatment. Results. All 25 patients were available for follow-up evaluation (mean, 17 months; range 12-27 months). The radiographic fusion rate was 40% (2/5) in the autograftl TSRH group and 100% (20/20) with rhBMP-2 group with or without TSRH internal fixation (P = 0.004). A statistically significant improvement in Oswestry score was seen at 6 weeks in the rhBMP-2 only group (-17.6; P = 0.009), and at 3 months in the rhBMP-2/TSRH group (-17.0; P = 0.003), but not until 6 months in the autograft/TSRH group (-17.3; P = 0.041). At the final follow-up assessment, Oswestry improvement was greatest in the rhBMP-2 only group (-28.7, P< 0.001). The SF-36 Pain Index and PCS subscales showed similar changes. Discussion. This pilot study is the first with at least 1 year of follow-up evaluation to demonstrate successful posterolateral spine fusion using a BMP-based bone graft substitute, with radiographs and CT scans as the determinant. Consistently, rhBMP-2 was able to induce bone in the posterolateral lumbar spine when delivered at a dose of 20 mg per side with or without the use of internal fixation. Patients with spondylolisthesis classified higher than Meyerding Grade 1 or with more than 5 mm of translational motion may still require internal fixation. Some patients did smoke during the postoperative period, and all in the rhBMP-2 groups still obtained solid fusions. Conclusions. Consistently, rhBMP-2 with the biphasic calcium phosphate granules induced radiographic posterolateral lumbar spine fusion with or without internal fixation in patients whose spondylolisthesis did not exceed Grade 1. Statistically greater and quicker improvement in patient-derived clinical outcome was measured in the rhBMP-2 groups.

Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial: 2002 Volvo Award in clinical studies.

Calcium phosphate cements as bone drug delivery systems: a review.

TGF-β1 is a ubiquitous growth factor that is implicated in the control of proliferation, migration, differentiation, and survival of many different cell types. It influences such diverse processes as embryogenesis, angiogenesis, inflammation, and wound healing. In skeletal tissue, TGF-β1 plays a major role in development and maintenance, affecting both cartilage and bone metabolism, the latter being the subject of this review. Because it affects both cells of the osteoblast and osteoclast lineage, TGF-β1 is one of the most important factors in the bone environment, helping to retain the balance between the dynamic processes of bone resorption and bone formation. Many seemingly contradictory reports have been published on the exact functioning of TGF-β1 in the bone milieu. This review provides an overall picture of the bone-specific actions of TGF-β1 and reconciles experimental discrepancies that have been reported for this multifunctional cytokine.

Transforming Growth Factor-β1 to the Bone

TGF1 is a ubiquitous growth factor that is implicated in the control of proliferation, migration, differentiation, and survival of many different cell types. It influences such diverse processes as embryogenesis, angiogenesis, inflammation, and wound healing. In skeletal tissue, TGF1 plays a major role in development and maintenance, affecting both cartilage and bone metabolism, the latter being the subject of this review. Because it affects both cells of the osteoblast and osteoclast lineage, TGF1 is one of the most important factors in the bone environment, helping to retain the balance between the dynamic processes of bone resorption and bone formation. Many seemingly contradictory reports have been published on the exact functioning of TGF1 in the bone milieu. This review provides an overall picture of the bone-specific actions of TGF1 and reconciles experimental discrepancies that have been reported for this multifunctional cytokine. (Endocrine Reviews 26: 743–774, 2005)

Transforming Growth Factor- 1 to the Bone

Strategies for Controlled Delivery of Growth Factors and Cells for Bone Regeneration

A substantial interest exists in developing substitute materials and human recombinant bone-inducing factors to enhance bone regeneration both in the craniofacial complex and in other parts of the skeleton A persistent problem has been to find an animal model that allows for the comparison of different osteopromotive materials The purpose of this investigation was 1) to determine whether a 5-mm calvarial defect in adult rats fulfilled the requirements of a critical-size bone defect and 2) to discuss the use of this animal model in assessing bone repair in the craniofacial region Bilateral full-thickness calvarial defects were trephined in the calvarial bone of 56 5- to 6-month-old Wistar rats Except for minor amounts of bone formation limited to the margins of the defect, none of the defects revealed any signs of spontaneous bone regeneration 6 and 12 months after surgery The full-thickness 5-mm calvarial defects thus fulfill the criteria for a critical-size bone defect This animal model allows for an experiment with a paired design, it avoids inclusion of the sagittal suture in the osseous defect, and it thereby minimizes morbidity by reducing the risk of damaging the midsagittal sinus An adequate experimental model has been developed to evaluate the efficiency of osteopromotive materials in the healing of bone defects in the craniomaxillofacial region

Importance of the critical-size bone defect in testing bone-regenerating materials

Several members of the bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-beta) families are molecular regulators of cartilage and bone regeneration, although their actual roles and combined interactions in skeletal repair are poorly understood. The presence of several molecular forms suggests multiple functions in vivo as well as synergistic interactions during both embryonic bone development and regeneration of cartilage and bone in postfetal life. Here we show for the first time that recombinant human transforming growth factor-beta1 (TGF-beta1) induces endochondral bone formation in extraskeletal sites of adult baboons. We also show that TGF-beta1 and recombinant human osteogenic protein-1 (OP-1, bone morphogenetic protein-7) synergize in inducing large ossicles in extraskeletal sites of the primate as early as 15 days after implantation. A single application of OP-1, in conjunction with an insoluble collagenous matrix as carrier (5, 25, and 125 microg/100 mg of carrier matrix) induced bone differentiation in the rectus abdominis of the baboon. This level of tissue induction was raised several-fold by the simultaneous addition of comparatively low doses of TGF-beta1 (0.5, 1.5, and 5 microg), which by itself induces bone formation in the rectus abdominis at doses of 5 microg/100 mg of carrier matrix. Combinations of OP-1 and TGF-beta1 yielded a 2- to 3-fold increase in cross-sectional area of the newly generated ossicles, with markedly elevated key parameters of bone formation, and corticalization of the newly formed bone by day 15, culminating in bone marrow generation by day 30. The tissue generated by the combined application of OP-1 and TGF-beta1 showed distinct morphological differences when compared with OP-1-treated specimens, with large zones of endochondral development and extensive bone marrow formation. At the doses tested, synergy was optimal at a ratio of 1:20 by weight of TGF-beta1 and OP-1, respectively. These results provide evidence for a novel function of TGF-beta1 in the primate and the scientific basis for synergistic molecular therapeutics for the rapid regeneration of cartilage and bone.

Recombinant Transforming Growth Factor-β1 Induces Endochondral Bone in the Baboon and Synergizes with Recombinant Osteogenic Protein-1 (Bone Morphogenetic Protein-7) to Initiate Rapid Bone Formation

Objective: Conventional cephalometry is an inexpensive and well-established method for evaluating patients with dentofacial deformities. However, patients with major deformities, and in particular asymmetric cases are difficult to evaluate by conventional cephalometry. Both two- and three-dimensional computed tomography (CT) have been proposed to alleviate some of these difficulties. Only a few studies using metallic markers have indicated 3-D CT to be a useful diagnostic method, whereas no studies have evaluated the reliability of the anatomic cephalometric points used in 3-D CT. The aim of our study therefore was to compare the reliability of anatomic cephalometric points from conventional cephalograms and 3-D CT. Methods: Nine human dry skulls were CT scanned. In addition standard lateral and frontal cephalograms were obtained. The CT scans were 3-D image reconstructed, and the cephalometric points were recorded as x, y, and z co-ordinates by two investigators. Computerized cephalometrics were...

Comparison of the Reliability of Craniofacial Anatomic Landmarks Based on Cephalometric Radiographs and Three-Dimensional CT Scans

Placement of an endosseous implant in a growing child with ectodermal dysplasia

Objective: To analyze the long-term effect of mandibular bone as donor material in bone grafting of the alveolar process defect in patients with unilateral cleft lip and palate (UCLP), compared with iliac crest cancellous bone. Method: During a 7-year period, 101 UCLP patients were bone grafted, 57 cases with iliac crest cancellous bone and 44 with mandibular symphyseal bone. The long-term results with an observation time of more than 4 years were analyzed with respect to marginal bone level and dental and gingival condition in the grafted area. Complications were recorded. Results: The bone level in the grafted area was satisfactory in both groups. Impaction of cleft-side canines was found in 35% of the patients in both groups. Patients with agenesis of the cleft side lateral incisor had significantly more impacted canines, compared with patients with a cleft-side lateral situated in the lesser maxillary segment, probably due to the fact that the lateral incisors help in guiding the canine down ...

Carles Bosch

Papers

Importance of the critical-size bone defect in testing bone-regenerating materials

Recombinant Transforming Growth Factor-β1 Induces Endochondral Bone in the Baboon and Synergizes with Recombinant Osteogenic Protein-1 (Bone Morphogenetic Protein-7) to Initiate Rapid Bone Formation

Comparison of the Reliability of Craniofacial Anatomic Landmarks Based on Cephalometric Radiographs and Three-Dimensional CT Scans

Placement of an endosseous implant in a growing child with ectodermal dysplasia

Mandibular bone graft material for reconstruction of alveolar cleft defects: long-term results.