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Reconstruction of #7 Facial Cleft With Distraction-Assisted In Situ Osteogenesis (DISO): Role of Recombinant Human Bone Morphogenetic Protein-2 With Helistat-Activated Collagen Implant
Abstract
A case involving concomitant presentation of a #7 lateral facial cleft with a complete cleft of the ipsilateral lip, alveolus, and palate is presented. The mandibular defect was Pruzansky III with a foreshortened body, absent ramus and absent masseter. Taking advantage of developmental field theory, reconstruction of the osseous defect was undertaken using the autogenous periosteum as a source of mesenchymal stem cells. Expansion of the periosteum was followed by implantation of Helistat (Integra Life Sciences, Plainsboro, NJ) collagen sponge saturated with recombinant human bone morphogenetic protein-2. Stimulation of this distraction-induced envelope by rhBMP-2 resulted in abundant production of bicortical membranous bone in situ within 12 weeks. The neoramus was subsequently suspended from the cranial base, and a temporalis muscle transfer was used to provide motor control of the jaw. Synthesis of bone in this manner is termed DISO (distraction-assisted in situ osteogenesis). The biologic rationale and clinical implications of DISO are discussed.
... An open-label, non-randomised clinical trial involving 20 patients with alveolar atrophy, chronic periodontitis, periapical lesions and peri-implantitis showed that the use of a material containing vascular endothelial growth factor (VEGF) plasmid was effective in 100 % of patients. A long- (Fiorellini et al., 2005;Howell et al., 1997), -sinus floor elevation ( Boyne et al., 2005( Boyne et al., , 1997 Off-label: -alveolar cleft reconstruction (Alonso et al., 2010;Canan et al., 2012;Carstens et al., 2005;Chin et al., 2005;Dickinson et al., 2008;Herford et al., 2007a); -mandibular bone defect ( Carter et al., 2008) 'Novosis' (Bongros/ BMP-2) (CGBio Co., Korea) ...
The restoration of bone defects resulting from tooth loss, periodontal disease, severe trauma, tumour resection and congenital malformations is a crucial task in dentistry and maxillofacial surgery. Growth factor- and gene-activated bone graft substitutes can be used instead of traditional materials to solve these problems. New materials will overcome the low efficacy and difficulties associated with the use of traditional bone substitutes in complex situations. One of the most well-studied active components for bone graft substitutes is bone morphogenetic protein-2 (BMP-2), which has strong osteoinductive properties. The aim of this review was to examine the use of BMP-2 protein and gene therapy for bone regeneration in the oral and maxillofacial region and to discuss its future use.
... Eight human studies met the inclusion criteria and were included in this review (Table 2). Five studies were retrospective [12,[18][19][20][21], one was case report [22], and one study was case series [23]. Menezes et al. [24] was the only randomized clinical trial. ...
Purpose
This study aimed to analyze the effect of injecting chemical factors compared to conventional distraction osteogenesis (DO) treatment on the bone formation of the distracted area of the maxillofacial region in human and animal studies.
Method
Electronic search was done in PubMed, Scopus, Embase, and Cochrane database for studies published until September 2021. The studies’ risk of bias (ROB) was assessed using the Cochrane Collaborations and NIH quality assessment tools. Meta-analyses were performed to assess the difference in the amount of bone formation and maximal load tolerance.
Results
Among a total of 58 included studies, eight studies analyzed the bone formation rate of the distracted area in human models and others in animal models. Results of the human studies showed acceptable outcomes in the case of using bone morphogenic protein-2 (BMP-2), autologous bone-platelet gel, and calcium sulfate. However, using platelet reach plasma does not increase the rate of bone formation significantly. Quantitative analyses showed that both BMP-2 (SMD = 26.57; 95% CI = 18.86 to 34.28) and neuron growth factor (NGF) (SMD = 16.19; 95% CI = 9.64 to 22.75) increase the amount of bone formation. Besides, NGF increased the amount of load tolerance significantly (SMD = 30.03; 95% CI = 19.91 to 40.16). Additionally, BMP-2 has no significant impact on the post-treatment maxillary length (SMD = 9.19; 95% CI = − 2.35 to 20.73).
Conclusion
Limited number of human studies with low quality used chemical factors to enhance osteogenesis and showed acceptable results. However, more studies with higher quality are required.
... However, the lack of bioactivity, biomechanical weaknes, and susceptibility to infection are still detrimental to the use of most of them; [3] and even for bone morphogenetic proteins, recently suggested as an effective alternative [4][5][6][7], significant restraints concerning high costs and severe adverse events have emerged [8][9][10][11]. ...
Background:
To reduce morbidity to cleft patients, new approaches have been developed and here, we report for the first time the use of deciduous dental pulp stem cells (DDPSC) associated with a hydroxyapatite-collagen sponge (Bio-Oss Collagen® 250 mg, Geistlich) for closing alveolar defects during secondary dental eruption, further comparing these results to historical controls.
Methods:
Six patients, aged 8 to 12, were selected. Autologous DDPSC were isolated from each patient, then associated with the biomaterial and this bone tissue engineered set was used to fill the alveolar defect. Computed tomography was performed to assess both preoperative and 6- and 12-month postoperative outcomes. Overall morbidity was recorded. Historical controls consisted of sixteen patients previously selected and randomly assigned to group one (rhBMP-2) or group two (iliac crest bone graft).
Results:
DDPSC could be isolated and characterized as mesenchymal stem cells. Progressive alveolar bone union has occurred in all patients. Similarly to group two 75.4%, SD ± 4.0, p > 0.999, but statistically different from group one (59.6%, SD ± 9.9, p > 0.999, but statistically different from group one (59.6%, SD ± 9.9.
Conclusion:
For this selected group of patients, DDPSC therapy resulted in satisfactory bone healing with excellent feasibility and safety, which adds significantly to the prospect of stem cell use in clinical settings. Clinical Question/Level of Evidence. Therapeutic, II. This trial is registered with https://clinicaltrials.gov/ct2/show/NCT01932164?term=NCT01932164&rank=1.
... [28][29][30] Clinical use of rh-BMP-2 approved its efficacy in bone augmentation in the presence of barrier membrane 31 and without barrier membrane. 32,33 Interestingly, in this study, histologic sections showed new bone formation within the CMs. This finding can be explained by the known effects of collagen, as it is hemostatic, stimulates platelet attachment, and increases fibrin linkage. ...
The complex of bones that makes up the maxilla, alveolus, and hard palate is enclosed within a periosteal envelope containing mesenchymal stem cells (MSCs) in the cambium layer. This stem cell organ is responsible for growth of all the membranous bone fields of the face. Conventional methods of cleft lip repair sever the arcade of vessels from the infraorbital artery that supplies the anterior (buccolingual) alveolar mucoperiosteum. Six months later, at palatoplasty, lingual incisions along the border of the hard palate and alveolus permanently isolate the lingual mucoperiosteum from its palatal source of blood. The osteogenic alveolar mucoperiosteum thus suffers sequential vascular isolation from its angiosomes. This tissue converted from a richly supplied boundary zone between the two angiosomes into an ischemic zone for survival is dependent on osseous backflow. Cleft-sided growth disturbance is considered from this perspective. Subperiosteal techniques that preserve the blood supply to the alveolar neuroangiosomes are considered in a sequential plan of cleft management. The learning objectives of this chapter are to understand the following concepts:
Developmental field reassignment cheiloplasty (DFR), based on neurovascular angiosomes, transfers stem cells into a new location for anatomically appropriate bone synthesis.
Alveolar extension palatoplasty (AEP) is the surgical application of DFR for clefts of the primary and secondary palate.
This chapter traces out the neuromeric origins of the four germ layers of the embryo. In order of appearance, these are: endoderm, mesoderm, ectoderm (what remains of the epiblast), and a special zone of the neuroectoderm, the neural crest. We shall see how these layers, once formed, morph into the five pharyngeal arches from which the structures of the head and neck are constructed. Within these arches, developmental fields arise, each based on a specific neurovascular supply which relates them to the neuromeric system of the CNS. We shall then use the pedestrian model of facial clefting to observe how these fields are assembled into recognizable structures and further more into their final configuration by the end of the embryonic period. The principal learning objectives here are: (1) to understand the relationship between the germ layers and their respective points of origin along the embryonic axis, (2) to apply the model to the development of facial clefts.
Bioengineering of bone represents a rapidly evolving frontier of craniofacial reconstruction. The combination of powerful morphogens, scaffolds, templates, and mesenchymal cells capable of assuming an osteogenic fate can produce a biomaterial which can induce its own blood supply and thereby escape the constraints of vascularized bone flaps. This chapter describes selected aspects of this field from a perspective derived from early work with recombinant human bone morphogenetic protein-2 and connecting forward to autologous adipose-derived mesenchymal cells. This discussion is designed to serve as a springboard for further innovation by readers with an interest in stem cell biology and tissue engineering. The learning objective is to unleash your own imagination.
In the current era, data plays a vital role as data is everything nowadays. But availability of data in very large quantity it has become tedious to retrieve the data in minimum time span. Various tools and
techniques are developed by various experts in this field. Query optimization is one of the important features in the data retrieval. Very basic concepts in the DBMS are indexed key and non indexed
keys. The performance of the query is also depends on these keys. The greatest advantage of this indexed coverage is that it will dramatically boost database efficiency because it includes all fields
needed by request and the best results are always obtained by filtering or joining parameters in the index main fields and inserting the fields specified in the SELECT list into the INCLUDE portion of the
coverage table. The covering index helps one to handle non-key columns at a non-clustered index leaf node so that, without looking through the basis list, the optimizer deletes the columns from the
index itself. Including for non-key tables provides SQL Server with the non-clustered index.
Recombinant human bone morphogenetic protein-2 (rhBMP-2) is one of the most commonly used osteogenic agents in the craniofacial skeleton. This study reviews the safety and efficacy of rhBMP-2 as applied to craniofacial reconstruction and assesses the level of scientific evidence currently available.
Methods:
An extensive literature search was conducted. Randomized controlled trials (RCTs), case series and reports in the English language as well as Food and Drug Administration reports were reviewed. Studies were graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence Scale. Data heterogeneity precluded quantitative analysis.
Results:
Seventeen RCTs (Levels of evidence: Ib-IIb) were identified evaluating the use of rhBMP-2 in maxillary sinus, alveolar ridge, alveolar cleft, or cranial defect reconstruction (sample size: 7-160; age: 8-75 years). Study designs varied in rigor, with follow-up ranging 3-36 months, and outcome assessment relying on clinical exam, radiology, and/or histology. There was wide variation in rhBMP-2 concentrations, carriers, and controls. Most studies evaluating rhBMP-2 for cranial defect closure, mandibular reconstruction, or distraction osteogenesis consisted of retrospective cohorts and case reports. The evidence fails to support RhBMP-2 use in maxillary sinus wall augmentation, calvarial reconstruction, mandibular reconstruction, or distraction osteogenesis. RhBMP-2 may be effective in alveolar reconstruction in adults, but is associated with increased postoperative edema.
Conclusions:
A risk-benefit ratio favoring rhBMP-2 over alternative substitutes remains to be demonstrated for most applications in plastic and reconstructive surgery. Long-term data on craniofacial growth is lacking, and using rhBMP-2 in patients younger than 18 years remains off-label.
Alveolar bone grafting was first introduced to Brazil by the Bauru Cleft Team in 1993, brought from Oslo, Norway (Abyholm et al. 1981a). Since that time, the use of autologous bone grafting harvested from the iliac crest using Boyne’s technique has become the gold standard for the rehabilitation of the vast majority of cleft patients worldwide (Boyne and Sands 1972). Secondary alveolar bone grafting is ideally performed at 8–10 years of age, when dental development is finishing and the canine is partially formed, with a root of at least 2/3 of final size, ready to erupt into the maxilla. Preoperatively, the use of transverse maxillary expansion and orthodontics for dental alignment facilitates greatly the alveolar bone grafting procedure (Abyholm et al. 1981a, b).
Chapters provides overview of pathways of development and reviews of dysmorphic syndromes for which the causative gene has been identified. For each disorder, an analysis of the role of the gene in the relevant developmental pathway is provided, along with the mechanism by which mutations in the gene cause the developmental pathology. Emphasis is placed the developmental roles of genes in the causation of hereditary conditions affecting appearance and function.
Background: Bone morphogenic proteins (BMPs) are known to promote osteogenesis, and clinical trials are currently underway to evaluate the ability of certain BMPs to promote fracture-healing and spinal fusion. The optimal BMPs to be used in different clinical applications have not been elucidated, and a comprehensive evaluation of the relative osteogenic activity of different BMPs is lacking. Methods: To identify the BMPs that may possess the most osteoincluctive activity, we analyzed the osteogenic activity of BMPs in mesenchymal progenitor and osteoblastic cells. Recombinant adenoviruses expressing fourteen human BMPs (BMP-2 to BMP-15) were constructed to infect pluripotent mesenchymal progenitor C3H10T1/2 cells, preosteoblastic C2C12 cells, and osteoblastic TE-85 cells. Osteogenic activity was determined by measuring the induction of alkaline phosphatase, osteocalcin, and matrix mineralization upon BMP stimulation. Results: BMP-2, 6, and 9 significantly induced alkaline phosphatase activity in pluripotential C3H10T1/2 cells, while BMP-2, 4, 6, 7, and 9 significantly induced alkaline phosphatase activity in preosteolblastic C2C12 cells. In TE-85 osteoblastic cells, most BMPs (except BMP-3 and 12) were able to induce alkaline phosphatase activity. The results of alkaline phosphatase histochemical staining assays were consistent with those of alkaline phosphatase colorimetric assays. Furthermore, BMP-2, 6, and 9 (as well as BMP-4 and, to a lesser extent, BMP-7) significantly induced osteocalcin expression in C3H10T1/2 cells. In C2C12 cells, osteocalcin expression was strongly induced by BMP-2, 4, 6, 7, and 9. Mineralized nodules were readily detected in C3H10T1/2 cells infected with BMP-2, 6, and 9 (and, to a lesser extent, those infected with BMP-4 and 7). Conclusions: A comprehensive analysis of the osteogenic activity of fourteen types of BMPs in osteolblastic progenitor cells was conducted. Our results suggest an osteogenic hierarchical model in which BMP-2, 6, and 9 may play an important role in inducing osteoblast differentiation of mesenchymal stem cells. In contrast, most BMPs are able to stimulate osteogenesis in mature osteoblasts. Clinical Relevance: These findings have implications for the development of effective formulas for bone-healing and spinal fusion. The efficacy of osteogenesis may depend not only on the type of BMP or the combination of BMPs that is used but also on the cell types that are present.
Background: Commonly occurring extensive osseous defects in the oral and maxillofacial area are seen following complete or partial resection of the mandible and other facial bones in oncologic surgery or following traumatic injury. Autogenous osseous grafts have been used to restore these defects. Additionally, bone graft substitute materials and autogenous osseous grafts are applied to congenital defects such as cleft palate, facial clefts, and facial asymmetry. We have simulated these types of defects in appropriately aged Macaca fascicularis and Macaca mulatta monkeys to study the efficacy of using bone morphogenetic protein (BMP) as an osseous inductor. The objective of these studies was to obtain information on the feasibility of employing bone inductors to regenerate large continuity critical-sized maxillofacial defects without using bone grafts. Methods and Results: In one study, involving eight animals, the body of the mandible was removed, simulating hemi-mandibulectomy defects following traumatic bone loss or oncologic surgery. Recombinant human (rh) BMP-2 (Genetics Institute, Cambridge, Massachusetts) in a collagen carrier (Colla-Tec Inc., Plainsboro, New Jersey) then was placed in the hemi-mandibulectomy defect with use of titanium orthopaedic mesh fixation (Sofamor Danek-Medtronic, Memphis, Tennessee). Entire bone regeneration of the defect was observed 5 and 6 months postoperatively. In another group of subhuman primates, the restored area was functionally stimulated at the 5-month post-BMP implantation level by placement of intraoral titanium implants. The animals were allowed to function for 8 months with these titanium implants. Microscopic results showed increased density, bone volume, and thickness of the trabecular bone pattern. The bone cortex in the restored defect also increased in thickness compared with the nonsurgical areas. To evaluate the effect of rhBMP-2 in aging individuals, a group of six Macaca animals over 20 years of age received the same type of mandibular resection followed by BMP grafting with functional stimulation by mastication on root form implants placed at 5 months after BMP implantation. The entire mandible regenerated as in the younger group of animals; therefore, age did not appear to be a factor in the reparative process. Thus, the number of stem cells supposedly reduced with increasing age did not appear to affect the overall result of BMP-induced bone regeneration. Additionally, in applying the inductor material to younger monkeys (1-11/2 years of age), the rhBMP-2 was placed in simulated bilateral cleft palate defects. On one side, the rhBMP-2 was placed with use of the collagen sponge carrier. The autogenous graft most frequently used at present for regeneration of the osseous defects of maxillary clefts is iliac crest particulate cancellous bone. As a control graft on the contralateral side, therefore, autogenous particulate bone and marrow was placed. At the end of 3 months, the cleft side receiving the BMP-2 showed complete osseous restoration of the simulated cleft. The autogenously grafted side exhibited bone repair but incomplete regeneration of the bone defect at the early (3-months postoperative) stage of healing. Conclusions and Clinical Relevance: The results of these three subhuman primate defect studies-(a) mandibular resection defects in middle-aged Macaca fascicularis animals, (b) mandibular resection defects in Macaca fascicularis animals over 20 years of age, and (c) simulated bilateral clefts in Macaca mulatta animals 11/2 years of age (comparable with a 5-year-old child)-were very encouraging. Histomorphometric analysis in all of these investigations indicated that the use of rhBMP-2 in bone repair without the use of bone grafting materials will offer a new method of osseous reconstruction in clinical facial bone defects.
Field theory provides a rational basis for birth defects terminology. During blastogenesis in higher metazoa, pattern formation in the primary field leads to the establishment of upstream expression domains of growth and transcription factors, which, in various permutations and at specific sites and times, lay down the pattern of progenitor fields. Further spatially coordinated, temporally synchronized, and epimorphically hierarchical morphogenetic events, mostly during organogenesis, lead to the attainment of final form in the secondary, epimorphic fields. Because of shared molecular determinants, spatial contiguity, and close timing of morphogenetic events during blastogenesis, most malformations arising during blastogenesis are polytopic, i.e., involving two or more progenitor fields, e.g., acrorenal, cardiomelic, gastromelic, or splenomelic anomalies. Defects of organogenesis tend to be monotopic malformations, e.g., cleft palate or postaxial polydactyly. We suggest that what were called "associations" (e.g., VATER, schisis) be designated primary polytopic developmental field defects, or simply polytopic field defects, and that the term "association" be reserved for the original definition of a statistical combination of anomalies (mostly of organogenesis) [Spranger et al. (1982): J Pediatr 100:160-165]. If genetically caused or predisposed, all structures involved in a polytopic or monotopic malformation are genetically abnormal, whereas the parts secondarily affected as a consequence of a malformation sequence (e.g., spina bifida) are genetically normal. Polytopic field anomalies, per se, must be distinguished from pleiotropy, although such anomalies may constitute a part of pleiotropy (e.g., in trisomy 18). Because they are downstream from pattern-forming events in the primary field, multiple anomalies of organogenesis more likely represent syndromal pleiotropy.
Three mesenchymal tissues participate in the formation of orofacial tissues; these are the neural crest, paraxial mesoderm, and lateral mesoderm. Interactions both among these populations and between them and surrounding epithelial tissues are an essential feature of facial development. Perturbation of these interactions may result in craniofacial malformations and dysmorphologies. This review outlines the origins and early morphogenetic movements of each of the three mesenchymal populations, then describes experiments which reveal some of the interactions that control their development. Spatial organization within cephalic mesenchyme is manifest initially in connective tissue precursors. In the facial region these are derived from the neural crest; in contrast, much of the neurocranium is derived from paraxial mesoderm. Most crest populations become spatially programmed prior to their emergence from the neuroepithelium, presumably during the primary induction of the neural plate. As they migrate to form the branchial arches, the crest populations bring spatial information to these peripheral regions. Connective tissue-forming populations within cephalic paraxial mesoderm display a similar inherent spatial programming, but it is not known when or how they acquire this information.
Based on personal observations a new classification of facial, cranio-facial and latero-facial clefts is proposed. The orbit is used as the primary structure of reference. Fifteen locations for clefts can be differentiated. Their course through soft tissues and bone is described in detail and illustrated with typical cases. Combinations of several types of clefts and associated malformations are discussed. The new classification offers the following advantages: it eliminates the old confusing terminology (based on personal experience and case descriptions in the literature it seems to be complete); it facilitates recording of malformations (communication between observers becomes easier); it increases the appreciation for the scope and the tridimensional structure of cranio-facial deformities; and, finally, the better understanding of these rare malformations will lead to more careful investigations, and to more adequate planning of treatment. More complications in corrective surgery will be avoided and the results achieved will improve.
Craniofacial mesenchyme is heterogeneous with respect to origins (e.g., paraxial mesoderm, lateral mesoderm, prechordal mesoderm, neural crest, placodes) and fates. The many disparate cell migratory behaviors exhibited by these mesenchymal populations have only recently been revealed, necessitating a reappraisal of how these different populations come together to form specific tissues and organs. The objectives of this review are to characterize the diverse migratory behaviors of craniofacial mesenchymal subpopulations, to define the interactions necessary for their assembly into tissues, and to discuss these data in the context of recent discoveries concerning the molecular basis of craniofacial development. The application of antibodies that recognize features unique to migrating neural crest cells has verified the results of previous transplantation experiments in birds and shown the migratory pathways in murine embryos to be similar. Within paraxial or prechordal mesoderm arise myoblasts that are precursors of craniofacial voluntary muscles. These cells migrate, usually en masse, to the sites where overt muscle differentiation occurs. Whereas the initial alignment of primary myotubes presages the fiber orientation seen in the adult, the time at which individual myotubes appear relative to the formation of discrete, individual muscle bundles and attachments with connective tissues varies with each muscle. The pattern of primary myotube alignment is determined by local connective tissue-forming mesenchyme and is independent of the source of myoblasts. Also found within paraxial and lateral mesodermal tissues are endothelial precursors (angioblasts). Some of these aggregate in situ, forming vesicles that coalesce with ingrowing endothelial cords. Others are highly invasive, moving in all directions and infiltrating tissues such as the neural crest, which lacks endogenous angioblasts. The patterns of initial blood vessel formation in the head are also determined by local connective tissue-forming mesenchyme and are independent of the origin of endothelial cells. Neural crest cells, which constitute the predominant connective tissue-forming mesenchyme in the facial, oral, and branchial regions of the head, acquire a regional identity while still part of the neural epithelium, and carry this with them as they move into the mandibular, hyoid, and branchial arches. Some of these regionally unique propensities correspond spatially to genetic and cellular patterns unique to rhombomeres, although the links between gene expression and crest population phenotypes are not yet known. In contrast, the inherent spatial programming of those crest cells that populate the maxillary and frontonasal regions is altered by their proximity to the prosencephalon.