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Repair of Alveolar Clefts with Recombinant Human Bone Morphogenetic Protein (rhBMP-2) in Patients with Clefts
Abstract
This article demonstrates the feasibility of using recombinant human bone morphogenetic protein (rhBMP-2) as a substitute for autogenous iliac crest bone for repair of congenital facial clefts in humans. In this series, 50 cleft sites were repaired in 43 patients using rhBMP-2 without the use of autogenous graft tissue. Successful osseous union was achieved in 49 of the 50 sites. In one patient, the graft failed to consolidate. Severe clefts were managed by combining distraction osteogenesis and rhBMP-2. Eliminating the need to harvest autogenous iliac crest bone resulted in substantial decrease in morbidity. The constructed alveolus performed clinically as normal bone and responded to natural tooth eruption and orthodontic movement. Histology of the tissue constructed showed normal, vital bone. Although additional investigation is warranted to determine the optimum protocol for the use of this material in alveolar cleft repair, the technique should be considered as a viable treatment option in cases in which avoiding iliac crest harvesting is desirable.
... Studies have shown that recombinant human bone morphogenetic protein-2 (rhBMP-2) exhibits chemoattraction towards osteoprogenitor and stem cells, which serve as a bone-forming agent [5,6]. Platelet-rich plasma (PRP) is recognized for its abundance of growth factors and cell adhesion molecules, including fibrin, fibronectin, and vitronectin [6,7]. ...
... Studies have shown that recombinant human bone morphogenetic protein-2 (rhBMP-2) exhibits chemoattraction towards osteoprogenitor and stem cells, which serve as a bone-forming agent [5,6]. Platelet-rich plasma (PRP) is recognized for its abundance of growth factors and cell adhesion molecules, including fibrin, fibronectin, and vitronectin [6,7]. The interaction of these components exemplifies the tissue engineering triangle, highlighting the constructive collaboration between biological cues, scaffolds, and cellular elements in regenerative processes. ...
... Various advantages of this technique have been reported in the literature, including the absence of donor site complications, reduced operating time, and shorter hospitalization periods [2,4,5]. The first study on alveolar bone reconstruction using rhBMP-2 was conducted by Chin et al., who reported successful osseous union in 49 maxillary sites, supporting the use of rhBMP-2 for alveolar bone reconstruction [6]. Since then, several studies explored using absorbable collagen sponges (ACS), hyaluronan-based hydrogel, or demineralized bone matrix (DBM) scaffolds for rhBMP-2. ...
Background: Alveolar bone reconstruction with recombinant protein has several advantages, including less surgical timing, and reduced infection. This systematic review aims to assess the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) as a treatment modality for children with cleft lip and palate compared to the conventional iliac crest bone grafting approach. Methods: For current systematic review and meta-analysis, five electronic databases, namely, MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Web of Science, and ScienceDirect, were searched. The primary outcome measured in this review was bone volume and height after alveolar bone reconstruction surgery. The Risk of Bias Tool 2 assessed the risk of bias for randomized control trials and the Risk of Bias tool for non-randomized trials of interventions for non-randomized studies. By evaluating pooled meta-analysis, the mean difference was calculated. GRADE uncertainty of evidence was performed to assess the certainty of the results. Results: Of 230 identified studies, 6 randomized and 2 non-randomized studies were included in the current review. The average bone volume was higher among the rhBMP-2 group at 61.11% ± 24.6% than the iliac crest group at 59.12% ± 18.59%. The calculated mean bone height was higher in the iliac crest group at 78.65% ± 14.38% than in the rhBMP-2 group at 67.5% ± 5.45%. The risk of bias reported in the studies was low to moderate. The result of the meta-analysis supported using rhBMP-2 in alveolar bone reconstruction; however, no significant association was found (mean difference: −1.24; confidence interval: −4.14 to 1.67). Conclusions: The calculated meta-analysis reported no significant difference, and the quality of evidence measured was also moderate. Hence, more clinical trials are required to support using rhBMP-2 as an alternative to traditional techniques for treating cleft lip and palate.
... Cleft lip and palate are congenital deformities of high prevalence in humans [1,2] (1:650 live births) [3], presenting craniofacial malformation due to changes in embryonic development between the 4ª and 10ª week of gestation [1]. They have a multifactorial etiology, resulting from the interaction between genetic and environmental factors. ...
... Autogenous bone con be obtained from the iliac crest to reconstruct the maxilla anatomy as bone grafting [3]. However, it can bring as a result morbidity to the donor site [2,5], pain [2,6] and sensory disturbances in the long term [7]. With the advancement of tissue engineering and its applications in health [3], the grafting procedure, used for the bone defects repair, replaced the autogenous bone by bone morphogenetic proteins (BMP) [3,6,8]. ...
... Autogenous bone con be obtained from the iliac crest to reconstruct the maxilla anatomy as bone grafting [3]. However, it can bring as a result morbidity to the donor site [2,5], pain [2,6] and sensory disturbances in the long term [7]. With the advancement of tissue engineering and its applications in health [3], the grafting procedure, used for the bone defects repair, replaced the autogenous bone by bone morphogenetic proteins (BMP) [3,6,8]. ...
... A total of 21 studies utilized growth factors for alveolar cleft bone regeneration (Tables 2 and 3). In details, recombinant human bone morphogenic protein-2 (rhBMP-2) [25][26][27][28][29][30][31][32][33][34][35][36][37][38], rhBMP-7 [39], platelet-rich plasma (PRP) [40], platelet-rich fibrin (PRF) [41][42][43], autologous blood [44] and plasma rich growth factor [45] were the utilized growth factors. Total of eight studies were RCTs [30,32,33,36,40,41,44,45], eight studies were retrospectives [25,27,28,31,34,35,37,38], three studies were prospectives [26,29,39] and two studies were case reports [42,43]. ...
... In details, recombinant human bone morphogenic protein-2 (rhBMP-2) [25][26][27][28][29][30][31][32][33][34][35][36][37][38], rhBMP-7 [39], platelet-rich plasma (PRP) [40], platelet-rich fibrin (PRF) [41][42][43], autologous blood [44] and plasma rich growth factor [45] were the utilized growth factors. Total of eight studies were RCTs [30,32,33,36,40,41,44,45], eight studies were retrospectives [25,27,28,31,34,35,37,38], three studies were prospectives [26,29,39] and two studies were case reports [42,43]. Collagen sponge [25,26,32,33,[35][36][37][38], tricalcium phosphate (TCP) [27], decellularize bone matrix (DBM) [28,29,31], allogenic bone [25] and hydrogel [30] were used as carriers in rhBMP-2 studies. ...
... Total of eight studies were RCTs [30,32,33,36,40,41,44,45], eight studies were retrospectives [25,27,28,31,34,35,37,38], three studies were prospectives [26,29,39] and two studies were case reports [42,43]. Collagen sponge [25,26,32,33,[35][36][37][38], tricalcium phosphate (TCP) [27], decellularize bone matrix (DBM) [28,29,31], allogenic bone [25] and hydrogel [30] were used as carriers in rhBMP-2 studies. Balaji et al. [34] did not specify the utilized carrier. ...
Objective
Objective: To analyze the efficacy and complications of regenerative medicine compared to autogenous bone graft for alveolar cleft reconstruction.
Method
Method: Electronic search was done in PubMed, Scopus, Embase and Cochrane database for studies published until May 2021. No limitations were considered for the type of the included studies. The risk of bias (ROB) of the studies was assessed using the Cochrane Collaborations and NIH quality assessment tool. Meta-analyses were performed to assess the difference in the amount of bone formation and rate of complications. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used for analyzing the level of the evidence.
Results
Results: Among a total of 42 included studies, 21 studies used growth factors, 16 studies delivered cells, and five studies used biomaterials for bone regeneration of the alveolar cleft. Results showed no significant difference in the amount of bone formation between bone morphogenic protein-2 and iliac graft treated patients after six months (P=0.44) and 12 months (P=0.17) follow-up. Besides, higher swelling (OR=9.46,P<0.01) and less infection (OR=0.19,P=0.01) observed in BMP treated patients. Using stem cells can reduce the post-treatment pain (OR=0.04,P=0.01) but it has no significant impact on other complications (P>0.05). Using tissue engineering methods reduced the operation time (SD=1.06,P<0.01). GRADE assessment showed that results regarding the amount of bone formation volume after six and 12 months have low level of evidence.
Conclusion
Conclusion: Tissue engineering methods can provide a comparable amount of bone formation as of the autogenous graft and reduce some of the complications, operation time and hospitalization duration.
... Alveolar bone grafting is a well-established procedure and a crucial step in the treatment of children with cleft lip and palate. [1][2][3][4][5] This procedure, which also involves the closure of any fistulas when present in order to obtain a watertight compartment, successfully establishes bone continuity in the alveolus, stabilizes the maxillary arch, and allows for the eventual eruption of permanent teeth in the cleft. 1,[5][6][7] While historically there have been different options for the timing of this procedure (either a primary bone graft in infancy or a secondary bone graft during mixed dentition), today the vast majority of cases are performed as a secondary bone graft. ...
... The historical standard of care in alveolar bone grafts (ABG) has been to use anterior iliac crest bone as the donor graft due to its large supply of cortico-cancellous bone and well-documented success rate of 60% to 80% [2][3][4]7,8 However, one significant drawback to autologous bone grafts from the iliac crest is the associated donor-site morbidity, with complications including increased risk for postoperative pain, infection, sensory disturbances, ambulatory difficulties, and the very rare pelvic fracture. [1][2][3][4]9,10 While other sources of autologous bone including mandibular and calvarial bones have been described in the literature, studies have demonstrated inferior outcomes with the calvarial bone when compared to the iliac crest bone. ...
... The historical standard of care in alveolar bone grafts (ABG) has been to use anterior iliac crest bone as the donor graft due to its large supply of cortico-cancellous bone and well-documented success rate of 60% to 80% [2][3][4]7,8 However, one significant drawback to autologous bone grafts from the iliac crest is the associated donor-site morbidity, with complications including increased risk for postoperative pain, infection, sensory disturbances, ambulatory difficulties, and the very rare pelvic fracture. [1][2][3][4]9,10 While other sources of autologous bone including mandibular and calvarial bones have been described in the literature, studies have demonstrated inferior outcomes with the calvarial bone when compared to the iliac crest bone. 9 Mandibular grafts have demonstrated similar outcomes to the iliac crest, but the limited amount of bone obtained from this donor site precludes its use in larger alveolar clefts. ...
Objectives
To gather information about current practices and assess the opinions, preferences, and clinical knowledge of surgeons who perform alveolar bone grafts. In addition, surgical training differences in correlation to techniques and outcomes are evaluated.
Methods
A survey with both multiple choice and narrative answers regarding surgeons’ practices for alveolar bone grafting was designed and sent via email to members of the American Cleft Palate/Craniofacial Association (ACPA) identified as general craniofacial or oral maxillofacial surgeons. Responses were collected via an anonymous online survey tool.
Participants
Members (336) of ACPA identified as craniofacial or oral-maxillofacial surgeons were contacted, and 62 responses were recorded.
Results
The majority of survey respondents were oral-maxillofacial surgeons in practice for more than 15 years. 98.4% of respondents had used iliac crest and at least one additional source for grafting, while only 52.7% had performed grafting using recombinant bone morphogenetic protein (RhBMP). 82% used cone beam CT as their evaluation of choice for graft assessment and the majority (62.9%) waited more than 8 weeks postoperatively to image. Chi-square analysis demonstrated significantly longer time in practice for practitioners without craniofacial fellowship training.
Conclusions
The results of this study demonstrate that there remains significant variation in alveolar bone grafting practices among surgeons. While some consensus exists, new innovations and technologies will require continued evaluation of surgical practices and outcomes. Long-term follow-up studies are needed especially with regard to the use of RhBMP in alveolar clefts.
... Application of these materials effectively shortens the operation time and precludes the need for cutting the autologous bone, thus reducing the pain and complications. However, the non-deformability and non-biodegradability of these synthetic tissue-engineered bone scaffolds hinder the tooth eruption and orthodontic treatment (Feinberg et al., 1989;Chin et al., 2005). Especially during the bone healing period, the scaffolds tend to shift when exposed to stress (Letic-Gavrilovic et al., 2003). ...
... This help reduce the occurrence of pain and complications by precluding the need for cutting the body bone. However, most tissue-engineered scaffolds have exhibited non-absorbability and non-deformability, which hinder tooth eruption and bone movement required for orthodontic treatment (Feinberg et al., 1989;Chin et al., 2005). Moreover, they are prone to shift when stressed during healing (Letic-Gavrilovic et al., 2003), failing to provide appropriate matrix for tooth movement and reconstruction of the dental arch. ...
The advances in the field of tissue engineering and regenerative medicine have opened new vistas for the repair of alveolar clefts. However, the currently available biomaterials used for the repair of alveolar clefts have poor mechanical properties and biocompatibility, which hinders the treatment outcomes. Here, we aimed to develop 3D printed biomimetic scaffolds that fuses β-tricalcium phosphate (β-TCP) and bone marrow mesenchymal stem cells (BMSCs) for improving the repair of alveolar clefts. The methacrylate gelatin (GelMA) was mixed with β-TCP for the preparation of GelMA/β-TCP hybrid scaffolds via 3D printing platform and chemically cross-linking with UV light. The physicochemical properties of the hydrogel scaffolds were characterized. Moreover, the survival state, proliferation ability, morphological characteristics, and osteogenic induction of BMSCs were examined. The prepared hybrid scaffolds showed good biocompatibility and mechanical properties. BMSCs attached well to the scaffolds and proliferated, survived, differentiated, and stimulated osteogenesis for the reconstruction of alveolar clefts. We expect that use of the prepared hybrid hydrogel scaffold can improve the outcomes of alveolar cleft repair in clinic and expand the application of hybrid hydrogel in tissue engineering repair.
... There is also a FDA approved product for alveolar ridge augmentation, including in alveolar clefts, INFUSE bone graft, that consists of a collagen sponge soaked with recombinant human BMP-2 62 . ...
... Bone marrow MSC were used in 3 patients to treat large bone defects, from the tibia, ulna and humerus 74 . The INFUSE bone graft, used for alveolar clefts repair, can also be used for open tibial shaft fractures 62 . A similar product, OP-1 Implant, consisting of recombinant human BMP-2 with a bovine collagen carrier, was FDA approved for long bones non-union refractory lesions 9,75 . ...
The field of tissue engineering applies principles of engineering and life sciences for the development of functional biologic substitutes. The increasing need of tissue for challenging reconstructive surgeries places plastic surgeons involvement as vital in the research and development of engineered constructs and subsequent use. This narrative review aims to summarize tissue engineering principles, to update on its current uses and breakthroughs, to approach its current limitations and possible future directions for this exciting new field of medicine. This revision addressed tissue engineering utilisation in skin lesions, craniocervical defects, musculoskeletal defects, peripheral nerves lesions, vascular tissue defects and adipose tissue uses. Research in tissue engineering is increasing exponentially, however, and although there are already several engineered constructs available, its widespread clinical application is still a hope. More long-term studies that answer outstanding issues are needed in order for that to become reality.
... Recombinant human bone morphogenetic protein-2 (rhBMP-2) is 1 of the growth factors used in the stimulation, proliferation, chemotaxis, and differentiation of osteoprogenitor cells. [12][13][14][15][16] It can be delivered to the bone wound site using absorbable collagen sponges alone or within a scaffold that acts as an extracellular matrix. 16 The outcomes of grafting procedures using rhBMP-2 have also been relatively controversial. ...
... rhBMP-2 has been demonstrated as a growth factor that could provide stimulation, proliferation, chemotaxis, and differentiation of osteoprogenitor cells. [12][13][14][15][16] The use of an osteoconductive scaffold that can act as a compression-resistant agent to prevent collapse of the surrounding tissue has been advocated for optimization of rhBMP-2 delivery. 11,25 bTCP scaffolds have been shown to serve as a substrate for tissue-resident or transplanted mesenchymal stem cells, evidenced by their current use in a variety of bone void fillers clinically. ...
Purpose
To compare the volumetric changes in successfully treated clefts with secondary alveolar grafting using recombinant human bone morphogenic protein-2 delivered in ß-tricalcium phosphate scaffold versus autogenous grafts obtained from the iliac crest and the mandibular symphysis.
Materials and Methods
A retrospective cohort study comprising cone-beam computed tomography scans of 25 subjects with unilateral or bilateral clefts was implemented. Seven subjects received iliac crest bone graft, nine subjects received mandibular symphyseal bone graft, and nine subjects received rhBMP-2/ßTP bone substitute. Volumetric rendering software was used to calculate the amount of new bone formation and residual bone defect in the cleft area. Data were analyzed using Wilcoxon and Kruskal-Wallis tests and Pearson’s correlation coefficient.
Results
Mean percent new bone formation for iliac crest, symphysis and rhBMP-2/ßTP were 85.47, 80.56, and 81.22 %, respectively (p-value = 0.0854). Initial cleft volume had a weak positive correlation with the percentage of new bone formation (r=0.18), but the post-surgical residual cleft volume had a strong negative correlation (r=0.71).
Conclusion
Rh-BMP-2 delivered in ßTP scaffold in alveolar cleft patients can be a viable alternative for autogenous iliac crest and symphysis grafts, eliminating donor site morbidity.
... Tissue engineering entails the application of progenitor cells and/or growth factors delivered to the treatment site on an acellular scaffold. It is well known that bone tissue engineering is partially regulated by the host local microenvironment, including the presence of signaling molecules and host immune cells [5][6][7]. Bone Morphogenetic Proteins (BMPs) are potential osteoinductive growth factors that play a critical role in bone regeneration and repair [8]. It is well known that exogenous administration of recombinant human (rh) BMP-2 can initiate a healing cascade that mediates bone regeneration through the TGF-/BMP signaling pathway [8]. ...
... Owing to their substantial osteogenic properties, the US Food and Drug Administration (FDA) had approved rhBMP-2 and rhBMP-7 for clinical use [9,10]. However, application of exogenous growth factors also has a number of drawbacks, including serious adverse effects which are occasionally fatal; moreover, recombinant growth factors have reduced biological activity, requiring high concentrations to be used in vivo and therefore are associated with high costs [5,[11][12][13]. These shortcomings have driven the quest for the development of alternative strategies. ...
Antibody-mediated osseous regeneration (AMOR) has been introduced by our research group as a tissue engineering approach to capture of endogenous growth factors through the application of specific monoclonal antibodies (mAbs) immobilized on a scaffold. Specifically, anti-Bone Morphogenetic Protein- (BMP-) 2 mAbs have been demonstrated to be efficacious in mediating bone repair in a number of bone defects. The present study sought to investigate the application of AMOR for repair of mandibular continuity defect in nonhuman primates. Critical-sized mandibular continuity defects were created in Macaca fascicularis locally implanted with absorbable collagen sponges (ACS) functionalized with chimeric anti-BMP-2 mAb or isotype control mAb. 2D and 3D analysis of cone beam computed tomography (CBCT) imaging demonstrated increased bone density and volume observed within mandibular continuity defects implanted with collagen scaffolds functionalized with anti-BMP-2 mAb, compared with isotype-matched control mAb. Both CBCT imaging and histologic examination demonstrated de novo bone formation that was in direct apposition to the margins of the resected bone. It is hypothesized that bone injury may be necessary for AMOR. This is evidenced by de novo bone formation adjacent to resected bone margins, which may be the source of endogenous BMPs captured by anti-BMP-2 mAb, in turn mediating bone repair.
... 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.
... On the other hand, as the advantages of rhBMP-2, which can reduce the operation time and hospitalization period and the absence of complications related to the donor site, have emerged, rhBMP-2 has begun to be considered as an alternative for the reconstruction of the alveolar cleft. A study that applied rhBMP-2 to repair the alveolar cleft for the first time was conducted by Chin et al. [42] in 2005. Their case series reported successful osseous unions in 49 sites where rhBMP-2/ACS was applied to 50 sites out of 43 patients, suggesting that rhBMP-2 could be a treatment option to avoid iliac bone harvesting. ...
Recombinant human bone morphogenetic protein-2 (rhBMP-2) has shown potential in maxillofacial surgery owing to its osteoinductive properties. However, concerns about its safety and high cost have limited its widespread use. This review presents the status of rhBMP-2 use in maxillofacial surgery, focusing on its clinical application, efficacy, safety, and limitations. Studies have demonstrated rhBMP-2’s potential to reduce donor site morbidity and increase bone height in sinus and ridge augmentation; however, it may not outperform autogenous bone grafts. In medication-related osteonecrosis of the jaw treatment, rhBMP-2 has been applied adjunctively with promising results, although its long-term safety requires further investigation. However, in maxillofacial trauma, its application is limited to the restoration of large defects. Safety concerns include postoperative edema and the theoretical risk of carcinogenesis. Although postoperative edema is manageable, the link between rhBMP-2 and cancer remains unclear. The limitations include the lack of an ideal carrier, the high cost of rhBMP-2, and the absence of an optimal dosing regimen. In conclusion, rhBMP-2 is a promising graft material for maxillofacial surgery. However, it has not yet become the gold standard owing to safety and cost concerns. Further research is required to establish long-term safety, optimize dosing, and develop better carriers.
... [50] Commercially available products recommended a concentration within the milligram per millilitre range (1.05-1.5 mg·ml -1 ), but this value represents approximately 200'000 times the estimated physiologic concentration of natural BMP-2 found in bone. [87] Moreover, other drawbacks related to BMPs include short half-life, protein instability, control over release rate, and high production costs, which makes routine application not possible yet. [41] From this point of view, small bioactive molecules may represent a valid alternative to growth factors, because they have relatively simple structures, are easy to prepare with consequently lower batch variability and production cost, and are already employed in a wide variety of biomedical applications. ...
Mandibular tissue engineering aims to develop synthetic substitutes for the regeneration of critical size defects (CSD) caused by a variety of events, including tumor surgery and post‐traumatic resections. Currently, the gold standard clinical treatment of mandibular resections (i.e., autologous fibular flap) has many drawbacks, driving research efforts toward scaffold design and fabrication by additive manufacturing (AM) techniques. Once implanted, the scaffold acts as a support for native tissue and facilitates processes that contribute to its regeneration, such as cells infiltration, matrix deposition and angiogenesis. However, to fulfil these functions, scaffolds must provide bioactivity by mimicking natural properties of the mandible in terms of structure, composition and mechanical behavior. This review aims to present the state of the art of scaffolds made with AM techniques that are specifically employed in mandibular tissue engineering applications. Biomaterials chemical composition and scaffold structural properties are deeply discussed, along with strategies to promote osteogenesis (i.e., delivery of biomolecules, incorporation of stem cells, and approaches to induce vascularization in the constructs). Finally, a comparison of in vivo studies is made by taking into consideration the amount of new bone formation (NB), the CSD dimensions, and the animal model.
... Bone morphogenetic proteins (BMP) are naturally occurring osteogenic proteins in bone, essential to bone healing and remodeling. 6 BMP-2 is the most widely studied agent for craniofacial applications 7 including alveolar cleft repair, 8,9 and some surgeons expanded its use off-label to attempt "graft-less" repair in pediatric patients 8,[10][11][12] However, widespread use of BMP-2 remains limited today as evidence has emerged suggesting BMP-2 may result in ectopic bone formation, osteolytic defects, carcinogenesis, severe edema and wound healing complications in noncraniofacial applications. [13][14][15] In addition, it is unknown how previous use of this osteogenic bone factor ages long term or interacts with bone growth factors used in subsequent surgeries, especially those occurring many years later. ...
Objective:
This study investigates the effectiveness of demineralized bone matrix (DBX) to close alveolar clefts in patients previously treated with bone morphogenic protein-2 (BMP-2) who remained with bone nonunion.
Design:
This is an IRB-approved retrospective, single-center study.
Setting:
This study was conducted at a tertiary academic center.
Patients/participants:
We searched for all surgical encounters with the Current Procedural Terminology (CPT) code 42210 from the years 2013-2019. Included patients were diagnosed with cleft alveolus, previous BMP-2 exposure and required revision bone grafting during mixed dentition for persistent alveolar defects.
Interventions:
17 patients underwent revision alveolar bone grafting (ABG) with either DBX (n = 10) or autograft (n = 7) to repair persistent bony cleft.
Main outcome measure(s):
The primary study outcome measured was alveolar bone graft revision failure described as continued alveolar nonunion.
Results:
The median age at revision ABG was 13.1 ± 3.3 years, with a mean follow-up time of 4.9 years (1.1-9.2 years). Patients were 53% male, 47% had a unilateral cleft lip and alveolus. 58.8% of patients were treated with DBX in the cleft, 41.2% treated with autograft from iliac crest. Overall, 11.8% (n = 2) of all revisions failed, requiring a second revision. The average time to reoperation was 2.06 years, and both were re-grafted with autograft. There was no statistically significant difference between the type of bone graft source used and the failure rate obtained (P = .1544).
Conclusions:
DBX and autologous iliac crest bone grafts achieve similar alveolar union rates during revision ABG in patients treated with previous BMP-2 to the alveolar cleft.
... Designing Strategies for Cleft Lip and Palate Care structure [29]. Finally, platelet-rich plasma (PRP) is being studied with regard to its potential for tissue repair in vivo. ...
... Medical researchers have proposed various methods to reduce stula formation including the use of buccal aps (14), bone grafting (15), buccal myomucosal ap (16) Buccal fat pad ap (17), buccal mucosal ap (18), and high growth factor (PRGF) plasma (19). Acellular Dermal Matrix is widely used in multiple plastic surgeries (20). ...
Background
Acellular Dermal Matrix graft is usually used to repair fistulas following a cleft palate and has had positive results. But its use for primary palatoplasty has been less studied. Our aim was to compare the usefulness of using Acellular Dermal Matrix transplantation for primary palatoplasty with intravelar veloplasty in contrast to its lack of use
Materials and methods
A total of 72 children (6 months to 6 years old) with cleft palate were included in the study. The case-control prospective observations were conducted. A group underwent primary palatoplasty with intravelar veloplasty using Acellular Dermal Matrix and the control group had the same surgery without using Acellular Dermal Matrix. Patients were monitored for fistula formation, post-operative infection, and ulcers.
Results
No post-surgical infection and wound opening was seen in any group. In the recipients of Acellular Dermal Matrix and control group three and six fistula was reported in which patients had soft and hard palate involvement and the cleft with length greater than 15 mm.
Conclusions
Considering the double incidence of fistulas in the control group compared to the ADM recipient, it seems that the use of ADM can be effective in reducing the incidence of fistulas. Since fistula is one of the complications of primary palatoplasty surgery and leads to secondary surgeries, the use of ADM can be helpful.
... Moreover, many research groups have reported the repair of alveolar clefts in patients with clefts using BMP proteins. In an interesting study, it has been demonstrated that in patients with congenital facial clefts, rhBMP2 autogenously can be a substitute for iliac crest bone [124,125]. ...
Bone-marrow-derived mesenchymal stem cells (BM-MSCs) are one of the most widely studied postnatal stem cell populations and are considered to utilize more frequently in cell-based therapy and cancer. These types of stem cells can undergo multilineage differentiation including blood cells, cardiac cells, and osteogenic cells differentiation, thus providing an alternative source of mesenchymal stem cells (MSCs) for tissue engineering and personalized medicine. Despite the ability to reprogram human adult somatic cells to induced pluripotent stem cells (iPSCs) in culture which provided a great opportunity and opened the new door for establishing the in vitro disease modeling and generating an unlimited source for cell base therapy, using MSCs for regeneration purposes still have a great chance to cure diseases. In this review, we discuss the important issues in MSCs biology including the origin and functions of MSCs and their application for craniofacial and periodontal tissue regeneration, discuss the potential and clinical applications of this type of stem cells in differentiation to maxillofacial bone and cartilage in vitro, and address important future hopes and challenges in this field.
... As an exogenous, recombinant growth factor, it has a reduced biological activity. So that, a higher concentration is required to produce more effect till reaching plateau [48]. ...
... Clinical studies have demonstrated that BMPs are, at least, equivalent in terms of bone quantity produced as autologous bone grafts for the repair of alveolar cleft. 106,171,178,179 However, controversy exists over the specific quality of bone produced through BMP-driven intervention. 175,180 Bone morphogenetic protein-2. ...
Clefts of the lip and/or palate are the most prevalent orofacial birth defects occurring in about 1:700 live human births worldwide. Early postnatal surgical interventions are extensive and staged to bring about optimal growth and fusion of palatal shelves. Severe cleft defects pose a challenge to correct with surgery alone, resulting in complications and sequelae requiring life-long, multidisciplinary care. Advances made in materials science innovation, including scaffold-based delivery systems for precision tissue engineering, now offer new avenues for stimulating bone formation at the site of surgical correction for palatal clefts. Here, we review the present scientific literature on key developmental events that can go awry in palate development and the common surgical practices and challenges faced in correcting cleft defects. How key osteoinductive pathways implicated in palatogenesis inform the design and optimization of constructs for cleft palate correction is discussed within the context of translation to humans. Finally, we highlight new osteogenic agents and innovative delivery systems with the potential to be adopted in engineering-based therapeutic approaches for the correction of palatal defects.
... For instance, the discovery of rhBMP-2 has prompted a spurt of activity to apply this growth factor into a variety of bone defects. Primarily observed in embryonic and skeletal development, small amounts of these proteins are found in mature skeletons for bone repair and maintenance [22]. ...
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.
... The association of bone graft with human recombinant BMP-2 (hrBMP-2) in vitro and in vivo demonstrated the production of mature bone (Shimakura et al., 2003). Furthermore, clinical studies corroborate that BMPs are, at least, just as efficient as autologous bone graft for the repair of alveolar/palate cleft (Chin et al., 2005;Canan et al., 2012;Ayoub et al., 2016;Hammoudeh et al., 2017). Very recently, 10 years of follow-up evidenced the safe use of BMP-7 for the reconstruction of the alveolar cleft (Ayoub and Gillgrass, 2019). ...
Craniofacial development comprises a complex process in humans in which failures or disturbances frequently lead to congenital anomalies. Cleft lip with/without palate (CL/P) is a common congenital anomaly that occurs due to variations in craniofacial development genes, and may occur as part of a syndrome, or more commonly in isolated forms (non-syndromic). The etiology of CL/P is multifactorial with genes, environmental factors, and their potential interactions contributing to the condition. Rehabilitation of CL/P patients requires a multidisciplinary team to perform the multiple surgical, dental, and psychological interventions required throughout the patient’s life. Despite progress, lip/palatal reconstruction is still a major treatment challenge. Genetic mutations and polymorphisms in several genes, including extracellular matrix (ECM) genes, soluble factors, and enzymes responsible for ECM remodeling (e.g., metalloproteinases), have been suggested to play a role in the etiology of CL/P; hence, these may be considered likely targets for the development of new preventive and/or therapeutic strategies. In this context, investigations are being conducted on new therapeutic approaches based on tissue bioengineering, associating stem cells with biomaterials, signaling molecules, and innovative technologies. In this review, we discuss the role of genes involved in ECM composition and remodeling during secondary palate formation and pathogenesis and genetic etiology of CL/P. We also discuss potential therapeutic approaches using bioactive molecules and principles of tissue bioengineering for state-of-the-art CL/P repair and palatal reconstruction.
... Both pediatric calvarial and maxillary reconstruction lend themselves to augmentation of innate healing processes given limitations with currently used modalities. However, currently employed bone tissue engineering strategies such as bone matrix substitute, synthetic polymer scaffolds, and morphogenic proteins are still limited by subsequent graft resorption, inability to fill critically sized defects, and reported disruption of suture growth 6,9,20,27,37,38 . ...
This study investigates a comprehensive model of bone regeneration capacity of dypiridamole-loaded 3D-printed bioceramic (DIPY-3DPBC) scaffolds composed of 100% beta-tricalcium phosphate (β –TCP) in an immature rabbit model through the time of facial maturity. The efficacy of this construct was compared to autologous bone graft, the clinical standard of care in pediatric craniofacial reconstruction, with attention paid to volume of regenerated bone by 3D reconstruction, histologic and mechanical properties of regenerated bone, and long-term safety regarding potential craniofacial growth restriction. Additionally, long-term degradation of scaffold constructs was evaluated. At 24 weeks in vivo, DIPY-3DPBC scaffolds demonstrated volumetrically significant osteogenic regeneration of calvarial and alveolar defects comparable to autogenous bone graft with favorable biodegradation of the bioactive ceramic component in vivo. Characterization of regenerated bone reveals osteogenesis of organized, vascularized bone with histologic and mechanical characteristics comparable to native bone. Radiographic and histologic analyses were consistent with patent craniofacial sutures. Lastly, through application of 3D morphometric facial surface analysis, our results support that DIPY-3DPBC scaffolds do not cause premature closure of sutures and preserve normal craniofacial growth. Based on this novel evaluation model, this DIPY-3DPBC scaffold strategy is a promising candidate as a safe, efficacious pediatric bone tissue engineering strategy.
... Several studies from the orthodontic and maxillofacial literature, and from our institution, have shown similar rates of bone reconstitution in off-label use of rhBMP-2 for alveolar grafting and augmentation. [16][17][18][19][20] Despite these successes, significant concerns have been raised over the safety of rhBMP-2. Specifically, an initial U.S. Food and Drug Administration warning was issued following accounts of postoperative dysphagia and airway compromise from swelling in patients who had received it around the cervical spine. ...
... Notwithstanding the positive osteogenic effects of rhBMP-2 clinical administration, such strategy has a number of drawbacks that limit this mode of therapy as the definitive solution. Specifically, recombinant growth factors have lower activity than endogenous counterparts, unsustainable concentration over time, and short in vivo half-life [28][29][30][31][32], necessitating the clinical dosage, which is several orders of magnitude greater than the physiologic dose. The extremely high dose has been attributed to growing concerns about biological complications, such as increased malignancy risk [33] and potentially life-threatening edema. ...
Among many applications of therapeutic monoclonal antibodies (mAbs), a unique approach for regenerative medicine has entailed antibody-mediated osseous regeneration (AMOR). In an effort to identify a clinically relevant model of craniofacial defect, the present study investigated the efficacy of mAb specific for bone morphogenetic protein- (BMP-) 2 to repair canine segmental mandibular continuity defect model. Accordingly, a 15 mm unilateral segmental defect was created in mandible and fixated with a titanium plate. Anorganic bovine bone mineral with 10% collagen (ABBM-C) was functionalized with 25 μ g/mL of either chimeric anti-BMP-2 mAb or isotype-matched mAb (negative control). Recombinant human (rh) BMP-2 served as positive control. Morphometric analyses were performed on computed tomography (CT) and histologic images. Bone densities within healed defect sites at 12 weeks after surgery were 1360.81 ± 10.52 Hounsfield Unit (HU), 1044.27 ± 141.16 HU, and 839.45 ± 179.41 HU, in sites with implanted anti-BMP-2 mAb, rhBMP-2, and isotype mAb groups, respectively. Osteoid bone formation in anti-BMP-2 mAb (42.99% ± 8.67) and rhBMP-2 (48.97% ± 2.96) groups was not significantly different but was higher (p<0.05) than in sites with isotype control mAb (26.8% ± 5.35). In view of the long-term objective of translational application of AMOR in humans, the results of the present study demonstrated the feasibility of AMOR in a large clinically relevant animal model.
... Considering the size of the defect and the concentration of rhBMP-2 recommended in the previous studies, it was assumed that the relatively low concentration used in the present study would imply significant effectiveness. Additional studies will be needed to investigate the use of an adequate concentration of rhBMP-2 or a combination with another growth factor because the recommended concentration is already 200,000 times higher than the human physiological volume [49]. ...
In this study, a new concept of a 3D-printed scaffold was introduced for the accurate placement of an implant and the application of a recombinant human bone morphogenetic protein-2 (rhBMP-2)-loaded bone graft. This preliminary study was conducted using two adult beagles to evaluate the 3D-printed polycaprolactone (PCL)/β-tricalcium phosphate (β-TCP)/bone decellularized extracellular matrix (bdECM) scaffold conjugated with rhBMP-2 for the simultaneous use as an implant surgical guide stent and bone graft material that promotes new bone growth. Teeth were extracted from the mandible of the beagle model and scanned by computed tomography (CT) to fabricate a customized scaffold that would fit the bone defect. After positioning the implant guide scaffold, the implant was placed and rhBMP-2 was injected into the scaffold of the experimental group. The two beagles were sacrificed after three months. The specimen block was obtained and scanned by micro-CT. Histological analysis showed that the control and experimental groups had similar new bone volume (NBV, %) but the experimental group with BMP exhibited a significantly higher bone-to-implant contact ratio (BIC, %). Within the limitations of this preliminary study, a 3D-printed scaffold conjugated with rhBMP-2 can be used simultaneously as an implant surgical guide and a bone graft in a large bone defect site. Further large-scale studies will be needed to confirm these results.
... Se reportó una serie de casos en donde utiliza solo rhBMP-2 en la reconstrucción de la fisura alveolar en humanos (Chin et al., 2005). Se obtuvo una reconstrucción ósea exitosa en 49/50 fisuras en pacientes de 6 a 14 años. ...
Bone morphogenetic protein (BMP) is an endogenous protein that has shown significant effects in the promotion of bone formation. BMP also has been described in the reconstruction of traumatic and pathological bone defects, including alveolar cleft, alveolar ridge augmentation, maxillary sinus elevation, and applications in post-extraction alveolus graft, and peri-implant surgery among others. Despite the advantages associated with the use of BMP, currently is applied in combination with collagen matrices, which has certain properties such as low mechanical resistance and a high burst initial release that diminish its effectiveness in bone formation. In this context, the development of novel systems with greater mechanical resistance and prolonged release of BMP, that lead to chemotaxis of mesenchymal cells, following by its differentiation to osteoblasts represents a major challenge that holds outstanding clinical potential for the stimulation of bone formation. In this paper, we describe the use of BMP for the reconstruction of alveolar clefts, and its advantages being administrated in polymeric microparticles as sustain release system with promising applications in the stimulation of bone formation.
... Several studies from the orthodontic and maxillofacial literature, as well as from our institution, have shown similar rates of bone reconstitution in off-label use of rhBMP-2 for alveolar grafting and augmentation. [16][17][18][19][20] Despite these successes, significant concerns have been raised over the safety of rhBMP-2. Specifically, an initial FDA warning was issued following accounts of postoperative dysphagia and airway compromise from swelling in patients who had received rhBMP-2 around the cervical spine. ...
Background:
Alveolar cleft reconstruction using iliac crest bone graft(ICBG) is considered standard of care for children with complete cleft lip and palate at the time of mixed dentition. Harvesting bone may result in donor site morbidity, additional operating time and length of hospitalization. Recombinant human bone morphogenetic protein(rhBMP)-2 with a demineralized bone matrix(DBM) was used as an alternative bone source for alveolar cleft reconstruction. We investigate the outcomes of rhBMP-2/DBM versus ICBG for alveolar cleft reconstruction by reviewing postoperative surgical complications and cleft closure.
Methods:
A retrospective chart review was conducted for 258 rhBMP-2/DBM and 243 ICBG procedures on 414 patients over a 12-year period with a mean follow-up of 2.9 years (rhBMP-2/DBM) and 4.1 years(ICBG). We compared the complications, canine eruption and alveolar cleft closure between the two groups.
Results:
In the rhBMP-2/DBM group, one patient required prolonged intubation due to intraoperative airway swelling not thought to be caused by rhBMP-2, 36 reported facial swelling and one required outpatient steroids as treatment, 12 had dehiscence; however, half of these complications resolved without intervention. 23/228 of the rhBMP-2/DBM and 28/242 of the ICBG groups required repeat surgery for alveolar cleft repair. The findings of canine tooth eruption into the cleft site through the graft were similar between the two groups.
Conclusions:
rhBMP-2/DBM appears to be an acceptable alternative for alveolar cleft repair. We found no increase in serious adverse events with the use of this material. Local complications, such as swelling and minor wound dehiscence predominantly improved without intervention.
... This eliminates donor site morbidity and minimizes hospital stay and postoperative pain and discomfort. [98][99][100] New imaging techniques, such as cone-beam computed tomography, allow more accurate assessment of the volume of the bony defect before surgery and radiographic outcome of the grafted alveolus after surgery when compared to the conventional twodimensional periapical and panoramic radiographs used previously. ...
This chapter is a comprehensive overview regarding the treatment of cleft lip and palate (CLP) patients. Epidemiology with global aspects are discussed. Etioilogy, genetics, and embryology are described in the initial part of the chapter. The importance of an interdisciplinary approach and treatment planning are discussed. The section on surgical treatment includes all aspects of CLP surgery, such as cleft lip repair, cleft palate repair, and alveolar cleft repair. Correction of secondary deformities like maxillary hypopla-sia, oronasal fistulas, and lip–nose deformities is another important part of the chapter. The importance of jaw– orthopedic and speech specialists is emphasized.
... It is also necessary to consider that the use of rhBMP-2 should be seen with caution in patients under 18 years old due to the lack of studies on its effects on the immature skeleton. 17 However, Chin et al 18 and Herford et al 19 found no systemic complications with the use of rhBMP-2 in patients under 18 years old. In addition, Balaji,13 as in the present clinical case, described a successful patient of mandibular reconstruction with rhBMP-2 in an 18-month-old patient. ...
This paper describes 3 patients of off-label use of bone morphogenetic protein 2 (rhBMP-2) in the reconstruction of mandibular continuity defects. In the first patient, rhBMP-2 was associated with iliac crest bone graft for late mandibular reconstruction after resection of osteosarcoma. In the 2 other patients, rhBMP-2 was used alone. In 1 patient the mandibular continuity defect was due to resection for treatment of osteomyelitis and in the other patient a continuity defect was created by unsuccessful osteogenic distraction for correction of mandibular hypoplasia. Despite the good results in those patients, the off-label use of rhBMP-2 is associated with increased rate of complications, so more studies are needed to assess the predictability of the use of rhBMP-2 in mandibular continuity defects. Therefore, at the moment the off-label use of rhBMP-2 should be restricted to complicated bone defects in which the conventional alternatives of reconstruction were unsuccessful.
Objective
This bibliometric study seeks to provide a comprehensive overview of the 100 most frequently cited articles in the domain of cleft orthodontics. The analysis will reveal key influential publications, collaborative author networks, and identify prevailing research themes within the field.
Method
The studies related to Orthodontics in the realm of cleft lip and palate (CLP) were retrieved from the Scopus database on 30th August 2024 using key terms. The results obtained were sorted in descending order of citations and the 100 top-cited articles were hand-filtered. RStudio software version 4.2.0 and Bibliometrix R-package was used for performing scientometrics involving co-citation, co-occurrence, collaboration and co-word analyses, bibliographic coupling and network mapping.
Results
A total of n = 3984 articles were retrieved from which top-100 cited articles were filtered. These documents were published during 1950-2019 with peak production in 1997. The United States and the Netherlands were the most prolific countries involved in the given research. The majority of the highly referenced articles pertained to alveolar bone grafting, and treatment outcomes being the second common focus followed by Infant and early orthopedics (Naso-alveolar moulding, Maxillary Protraction) and facial growth during the given period.
Conclusions
Thematic mapping depicted bone grafting, alveoloplasty (infant orthopedics) and maxillofacial development as the more developed core topics than the psychology and self-perception of patients with CLP. Recent research trends have shifted towards three-dimensional assessment methods.
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.
This chapter focuses on dentoalveolar cleft repair. It focuses on surgical indications, contraindications, pertinent anatomy, virtual surgical planning, operative techniques, postoperative management, complications and key points of dentoalveolar cleft repair. Bone grafting within the maxilla may be classified as primary, secondary, or tertiary depending on the timing of surgical intervention. Primary grafting, however, has been associated with adverse effects on maxillary skeletal growth, and, as a result, secondary grafting procedures are preferred. Bilateral maxillary clefts require limited stripping during alveolar grafting. Occasionally, a premaxillary setback or two‐stage grafting procedure may be useful. Both autogenous and allogenic grafting material have been used with success to reconstruct dentoalveolar clefts. The chapter also provides several case reports with high‐quality images.
Introduction: Alveolar bone grafting aims to restore bony continuity of the alveolus and provide optimal periodontal support for teeth adjacent to the cleft. We created a survey of cleft surgeons to assess the current standard of care regarding this procedure.
Methods: A multiple choice survey was implemented using Qualtrics software and emailed to a list of 708 surgeons from the ACPA membership directory. Correlation between various provider factors and treatment practices was assessed with Fisher's exact test and likelihood ratio tests.
Results: The response rate was 17.5%. Eighty-seven percent of providers preferred to perform grafts prior to secondary canine eruption while 10% favored before central incisor eruption. Eighty-one percent favored palatal expansion prior to bone grafting. Wide variability existed regarding the time to initiate postoperative orthodontics; 43% waited 4 to 6 months. Sixty-four percent of surgeons now utilize cone beam CT to assess graft take. The majority of respondents utilized cancellous bone autograft (92%) from the anterior iliac crest (97%) as graft material. Seventy percent used three or more modalities for post-operative pain control management. Early career surgeons (0-5 years) appeared more likely to use non-autologous materials (p < .01) for grafting.
Conclusion: Alveolar bone grafting prior to secondary canine eruption remains the most common strategy but other protocols are employed. Surgeons utilize multiple modalities for radiographic evaluation and most often use autologous cancellous bone as the primary grafting material. There is no true consensus on the perioperative timing and sequencing of orthodontic manipulation while principles of multimodal perioperative pain control appear widely accepted.
Whitlockite (WH) is a calcium-phosphate-based Mg-containing ceramic with good mechanical properties, rapid resorption, and good osteogenicity. Recently, we successfully synthesized highly porous WH granules using a marine plankton exoskeleton (MP-WH). In the present study, we improved the osteoinductive activity of MP-WH granules by bone morphogenetic protein2 (BMP2) (MP-WH/BMP2). The surface morphology and composition of the fabricated MP-WH/BMP2 granules were characterized using scanning electron microscopy (SEM), X-ray diffraction, and Fourier transform infrared (FT-IR) spectroscopy. The biocompatibility and osteogenic effects were evaluated using human mesenchymal stem cells (hMSCs). BMP2 was absorbed on the surfaces of the MP-WH/BMP2 granules. Immobilized BMP2 was released at a moderate rate over 30 days. hMSCs seeded on MP-WH/BMP2 granules became biocompatible, with a better proliferation and adhesion for MP-WH/BMP2, compared with MP-WH. Bone-specific markers Runx2, type I collagen, osteocalcin, and osteopontin were significantly upregulated following BMP2 incorporation. Similar observations were made regarding the alkaline phosphatase activity. This study suggests that BMP2 incorporation improves the osteoinductive activity of marine-plankton-derived WH granules for bone tissue repair.
This study aimed to evaluate the bone regeneration capacity of a customized alloplastic material and xenograft with recombinant human bone morphogenetic protein-2 (rhBMP-2). We prepared hydroxyapatite (HA)/tricalcium phosphate (TCP) pure ceramic bone blocks made using a 3D printing system and added rhBMP-2 to both materials. In eight beagle dogs, a total of 32 defects were created on the lower jaws. The defective sites of the negative control group were left untreated (N group; 8 defects), and those in the positive control group were filled with particle-type Bio-Oss (P group; 12 defects). The defect sites in the experimental group were filled with 3D-printed synthetic bone blocks (3D group; 12 defects). Radiographic and histological evaluations were performed after healing periods of 6 and 12 weeks and showed no significant difference in new bone formation and total bone between the P and 3D groups. The 3D-printed custom HA/TCP graft with rhBMP-2 showed bone regeneration effects similar to that of particulate Bio-Oss with rhBMP-2. Through further study and development, the application of 3D-printed customized alloplastic grafts will be extended to various fields of bone regeneration.
The aim of this study was to identified and analyzed the top 25 most cited articles among the articles published in The Journal of Craniofacial Surgery (J Craniofac Surg) from 1995 to 2020 in the Web of Science database. Using the advanced search section in the Web of Science, all articles published in the J Craniofac Surg were listed. The distribution of the numbers of publications by years was determined. It was determined that a total of 11,888 articles were published in the J Craniofac Surg between 1995 and 2020. A total of 84,218 citations were made to these articles, and the h-index of these articles was 73. The top 25 most cited articles were determined. The top three countries that made the most cited to these 25 articles were the USA (n: 1112), China (n: 292), and Germany (n: 251), respectively. The top three journals that made the most cited to these 25 articles were the J Craniofac Surg (n: 378), Plast Reconstr Surg (n: 179), and J Oral Maxillofac Surg (n: 120), respectively. The authors think that this study may benefit researchers in this field by identifying the most cited articles in the J Craniofac Surg.
The goals of alveolar cleft repair include (1) stabilization of the maxilla, (2) permitting tooth eruption, (3) eliminating the oronasal fistula, (4) improving aesthetics, and (5) improving speech. Alveolar cleft repair should be considered one of the steps of a larger comprehensive orthodontic management plan. In conjunction with closure of the oronasal fistula, a variety of grafting materials can be used in the alveolar cleft. Autogenous grafts have been found to have greater efficacy compared with allogenic or xenogeneic bone, substitute bone, and alloplasts but with more donor site morbidity.
Alveolar Bone Grafting is a clinical procedure which is performed to maintain the integrity of the alveolar arch in cleft patients. This clinical procedure helps in facilitating eruption of canine and lateral incisors. This chapter discusses the normal anatomy of alveolus, significance of cleft alveolus, surgical steps to ensure separation of a well-defined oral and nasal layer, donor sites for bone grafting, harvesting techniques and final closure of the alveolar cleft. In addition, this chapter further highlights the recent developments in the field of bone regeneration.
Purpose:
This study sought to compare radiographic outcomes and resource utilization between recombinant human bone morphogenetic protein-2 (rhBMP-2) and anterior iliac crest bone graft (AICBG) when used for secondary alveolar grafting.
Materials and methods:
This is a 14-year retrospective study of patients with alveolar clefts treated at the Morgan Stanley Children's Hospital of New York-Presbyterian/Columbia University Irving Medical Center between January 2006 and January 2020. Patients who had alveolar grafting with either rhBMP-2 or AICBG were included in this study. The primary study predictor was the graft material. The study outcomes were bone height, operating room time, and the number of scrubbed personnel (surgeon and assistants). Graft survival was measured at a minimum of 6 months postoperatively. Bone height was scored according to the Bergland scale, and radiographic success was defined as Bergland types 1 or 2.
Results:
The study sample included a total of 115 patients with 130 alveolar clefts. Overall, 13.0% of patients had bilateral repairs, and 17.4% were retreatments. The cumulative success rate was 89.5%. There were no differences in success between materials (rhBMP: 90.3%; AICBG: 89.1%; P = .85). Patients presenting for retreatment were more likely to receive rhBMP-2 than AICBG (48.6 vs 3.8%, P < .01). After controlling for other significant confounders, the rhBMP-2 group required less personnel (P < .01) and operating room time (P < .01). Only 1 patient in the rhBMP-2 group was admitted, whereas all AICBG patients were admitted a minimum of 1 night.
Conclusions:
Compared with AICBG, rhBMP-2 produced a similar height of bone but required less hospital resources. The decision to use harvested ilium or rhBMP-2 is not limited by outcome data at this time. More studies will need to be performed to identify the particular advantages of each graft material. The choice of material is currently both surgeon specific and patient specific and requires thorough informed consent.
For successful outcomes in bone grafting, it is important to have a clear and detailed understanding of the fundamentals and basics in regenerative science. This article summarize the grafting materials and growth factors that are now in use to provide an improved understanding of the properties of each material and indications for subsequent use. The article gives an overview of the fundamentals of bone healing, including the physiology of regeneration. It is hoped that clinicians can make improved decisions that are based in literature when considering treatment options for restoring patients' functional dentition.
Tissue engineering integrates principles of biology and engineering to develop constructs for the repair of damaged and/or absent tissue. The field has grown substantially over the past two decades, with particular interest in bone tissue engineering. Clinically, there are needs in which the sheer quantity of bone required to restore form and function either exceeds the patient's healing capacity or bone's intrinsic regenerative capabilities. Autologous bone grafting remains the standard of care for craniofacial reconstruction, with vascularized osseous or osteocutaneous free flaps as the definitive "gold standard", but is commonly associated with donor site morbidity, graft resorption, increased operating time, and cost. Regardless of the size of a craniofacial defect, from trauma, pathology, and osteonecrosis surgeons and engineers involved with reconstruction need to consider the complex 3-dimensional geometry of the defect and its relationship to local structures. Three-dimensional (3D) printing has garnered significant attention and presents opportunities to use craniofacial bone tissue engineering as a technology that offers a personalized approach to bony reconstruction. Clinicians and engineers are able to work together to produce patient-specific space-maintaining scaffolds tailored to site-specific defects that are osteogenic, osseoconductive, osseoinductive, encourage angiogenesis/vasculogenesis, and mechanically stable upon implantation to prevent immediate failure.In this work, we review biological and engineering principles important in applying 3D printing technology to bone tissue engineering for craniofacial reconstruction as well as present recent translational advancements in 3D-printed bioactive ceramic scaffold technology.
Purpose:
Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although rhBMP-2 is under investigation for alveolar cleft repair, safety concerns remain (e.g. growing suture pathology). Dipyridamole (DIPY) is an adenosine receptor indirect agonist with known osteogenic potential. This study compared DIPY to rhBMP-2 at alveolar cleft defects delivered via 3D-printed bioceramic (3DBC) scaffolds.
Methods:
Skeletally immature New Zealand White rabbits underwent unilateral, 3.5mm x3.5mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with 3DBC scaffolds coated with 1000μm-DIPY (n=6), 10,000μm-DIPY (n=7), and 0.2 mg/mL-rhBMP-2 (n=5). At t=8 weeks, new bone was quantified using Amira 6.1 software. Non-decalcified histology was performed, and new bone was mechanically evaluated. Statistical analysis was performed using a generalized linear mixed model and Wilcoxon rank sum test.
Results:
Negative controls did not heal while new bone formation bridged all 3DBC treatment groups. 1,000μm-DIPY scaffolds regenerated 28.03±7.38%, 10,000μm-DIPY scaffolds regenerated 36.18±6.83% (p=0.104 1,000μm vs. 10,000μm DIPY), and rhBMP-2 coated scaffolds regenerated 37.17±16.69% bone (p=0.124 vs. 1,000μm-DIPY and p=0.938 vs. 10,000μm-DIPY). On histology/electron microscopy, no changes in suture biology were evident for DIPY, while rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either DIPY or rhBMP-2 when compared to native bone.
Conclusion:
Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.
Abstract Recombinant human bone morphogenic proteins (rhBMPs) have been introduced for reconstruction of alveolar defects. The volume of the bone formed at the cleft region may be related to rhBMP-2 dose. Greater side effects have been reported with increased doses of rhBMP-2. The aim of the present study was to assess the bone at the cleft area using low dose of rhBMP-2 combined with autogenous bone graft for reconstruction of the alveolar cleft. Patients with unilateral cleft lip and palate between the 11 to 14 years old were enrolled. After palatal expansion, autogenous graft was placed at the side of cleft in the control group (n = 6). In the BMP group, the rhBMP-2 was injected into the autogenous bone graft at the defect site (n = 5). Cone beam computed tomography (CBCT) images were taken of all patients immediately and 3 months after graft surgery to compare the density, thickness, and height of the bone graft between the 2 groups. Intermolar and interpremolar widths were also measured. The authors found less diminish of density and height of the bone graft 3 months postsurgery in patients with autogenous bone graft combined with rhBMP-2. However, significant difference in the relapse tendency of transverse dimension of the arch or thickness of the bone graft was not observed between the 2 groups. Thus, low dose rhBMP-2 combined with autogenous bone graft can be promising to reach predictable results after alveolar reconstruction in cleft lip and palate patients.
Implant restoration of the dentition poses many challenges in cases of limited bony foundation. Many patients suffer from loss of teeth and supporting bony structures through mechanisms including trauma, congenital abnormalities, or resorption secondary to tooth loss. In addition to classic alveolar ridge augmentation techniques and materials, growth factors are being studied to improve patient outcomes, especially in cases of larger, more challenging defects, in previously failed graft sites, and in stringent aesthetic cases. In this chapter, we will discuss three growth factors which are most commonly studied and US Food and Drug Administration approved: bone morphogenetic protein-2 (BMP-2), platelet-derived growth factor (PDGF), and platelet-rich protein/platelet-rich fibrin (PRP/PRF). Currently, growth factors are utilized in a wide variety of clinical situations, including guided bone regeneration, peri-implant defects, sinus augmentation, and socket augmentation. Furthermore, we will explore the future of growth factor usage, with new factors in various stages of investigation, combinations of materials, and viable cell therapy. Though much work has been done in the last few decades to reveal the clinical relevance of growth factors, much more research, both basic and clinical, must be performed to improve current technologies, develop predictable protocols, and evaluate long-term results.
Introduction:
Exogenous Nel-like molecule type 1 (NELL1) represents a potentially attractive clinical treatment option in the orthodontic and other settings because of its osteoinductive and vasculogenic properties.
Aims:
To explore effects of NELL1on corticotomy-assisted tooth movement and osteogenesis in a rat model.
Methods:
Thirty Sprague-Dawley rats were divided into 6 groups:Control, Sham, Tooth movement only, Vehicle, NELL1-LD (low-dose NELL), NELL1-HD (high-dose NELL). Human recombinant NELL1 protein was applied locally (Groups NELL1-LD and NELL1-HD) into buccal mucosa region of left first upper molar. Then measured the distance and velocity of tooth movement, sacrificed animals at 6 weeks after surgery, and followed by computed tomography and histochemical staining.
Results:
Both NELL1 groups had higher bone mineral density, greater tooth movement distance and velocity than Vehicle group. Proximally and distally, periodontal ligament width was significantly increased in NELL1-LD and NELL1-HD groups. Decortication enhances remodeling, however, rapid bone formation by high-dose NELL1 may affect bone absorption.
Conclusion:
Appropriate dose of NELL1 can be administrated to reduce the total time for tooth movement, and may shorten the treatment time in select populations.
Purpose:
The purpose of this study was to report on a 10-year assessment after the application of recombinant human bone morphogenetic protein 7 (rhBMP-7) for the reconstruction of alveolar clefts.
Patients and methods:
This study was conducted as a prospective phase II clinical trial on 9 unilateral and 2 bilateral alveolar clefts that received rhBMP-7 (Osigraft; Stryker Biotech, UK). The mean age of the patients at surgery was 10.4 years. At 6 months postoperatively, occlusal radiographs were taken to evaluate bone formation at the cleft site. Patients were followed up within the routine cleft care pathway for up to 10 years to monitor the impact of bone morphogenetic protein 7 on orthodontic treatments and maxillary growth. Radiographs were taken according to the standard cleft care protocol.
Results:
The radiographic assessment of the unilateral cleft lip and palate cases suggested good bone formation with a Kindelan score of grade 1 or 2. The bilateral alveolar cleft cases had a score of grade 3 or 4, indicating failure or partial failure. The children with successful grafts underwent a routine orthodontic follow-up without incident. The maxillary growth appeared to be similar to that in cases grafted with autogenous bone. No long-term complications and no abnormal pattern of bone formation were detected.
Conclusions:
The study provides unique evidence on the long-term safety of rhBMP-7 when applied at the area of skeletal immaturity for the reconstruction of alveolar clefts in children.
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).
Alveolar cleft reconstruction has historically relied on autologous iliac crest bone grafting (ICBG), but donor site morbidity, pain, and prolonged hospitalization have prompted the search for bone graft substitutes. The authors evaluated bone graft substitutes with the highest levels of evidence, and highlight the products that show promise in alveolar cleft repair and in maxillary augmentation. This comprehensive review guides the craniofacial surgeon toward safe and informed utilization of biomaterials in the alveolar cleft.
A literature search was performed to identify in vitro human studies that fulfilled the following criteria: Level I or Level II of evidence, ≥30 subjects, and a direct comparison between a autologous bone graft and a bone graft substitute. A second literature search was performed that captured all studies, regardless of level of evidence, which evaluated bone graft substitutes for alveolar cleft repair or alveolar augmentation for dental implants. Adverse events for each of these products were tabulated as well.
Sixteen studies featuring 6 bone graft substitutes: hydroxyapatite, demineralized bone matrix (DBM), β-tricalcium phosphate (TCP), calcium phosphate, recombinant human bone morphogenic protein-2 (rhBMP-2), and rhBMP7 fit the inclusion criteria for the first search. Through our second search, the authors found that DBM, TCP, rhBMP-2, and rhBMP7 have been studied most extensively in the alveolar cleft literature, though frequently in studies using less rigorous methodology (Level III evidence or below). rhBMP-2 was the best studied and showed comparable efficacy to ICBG in terms of volume of bone regeneration, bone density, and capacity to accommodate tooth eruption within the graft site. Pricing for products ranged from 3110 per 5 mL.
The balance between innovation and safety is a complex process requiring constant vigilance and evaluation. Here, the authors profile several bone graft substitutes that demonstrate the most promise in alveolar cleft reconstruction.
The introduction of porous and nonporous hydroxylapatite materials for utilization in the repair of alveolar clefts and skeletofacial deformities has been discussed. We conclude from the review the following. First, autologous particulate bone marrow is still the best material with which to graft alveolar cleft defects. Second, hydroxylapatite should not be used for grafting alveolar cleft defects in growing patients if teeth are expected to erupt through the grafted cleft area or require orthodontic movement into the grafted area. In those situations, autogenous bone is much preferable. Third, hydroxylapatite, if it covers an erupting tooth, will cause destruction of the erupting dentition, and if an orthodontic force attempts to mobilize teeth within the grafted area, external root resorption is to be expected. Fourth, resorbable tricalcium phosphate should not be used as alveolar cleft grafting material in growing children or adult patients. Fifth, porous hydroxylapatite, granules and blocks, should not be used to close alveolar cleft defects in adults. Sixth, nonporous hydroxylapatite granules can be utilized in closing alveolar cleft defects in adults where teeth erupt into the grafted area. Seventh, when utilized as inter- positional grafting material, Interpore 200 in porous blocks is the material of choice and is used in combination with miniplate fixation. Finally, when utilized as extrafacial or extracranial augmentation material, the porous hydroxylapatite blocks are superior to nonporous hydroxylapatite.
CONCLUSIONS AND SUMMARY
Allogeneic bone has a low complication rate with excellent clinical results when used for alveolar cleft bone grafting. It adequately stabilizes the maxillary segments without relapse, giving support to the alar base of the nose. Allogeneic bone forms a scaffold, which the host replaces with new viable bone, and allows the eruption of teeth and orthodontic movement of teeth into the graft site. Use of allogeneic bone obviates a donor surgical site.
The optimum particle size for allogeneic bone grafts is 2 X 2 X 2 mm. Total replacement of allogeneic bone in the graft site takes 6 months to 1 year, and orthodontic treatment should be delayed for at least 3 months after surgery.
Allogeneic bone produces a greater net yield of bone than does autogenous bone. It provides alveolar bone continuity for prosthetic rehabilitation. In summary, it can provide excellent results in first-time operations for clefts in 9- to 11-year-old patients before eruption of the permanent canine tooth.
Whether bilateral or unilateral, when appropriate grafting and soft-tissue procedures accomplish almost normal anatomic reconstruction of the cleft defect, there is usually significant improvement in growth, function, and esthetics. Waiting until 9 years of age to perform the alveolar cleft graft carries some risk of poor bone support of both the lateral incisor, if present, and the central incisor adjacent to the cleft and frequently leads to a poor balance of clinical crown height between the maxillary permanent central incisors.
Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone
formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone
formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino
acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones
corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant
human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing
the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene
family, while the third, BMP-1, appears to be a novel regulatory molecule.
Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.
Autogenous particulate cancellous bone and marrow grafts were studied in bilateral, surgically produced palatal and alveolar clefts in six young rhesus monkeys. Fluorescence and routine light microscopy indicated complete osseous regeneration of the cleft areas. Tooth buds on either side of the surgical area were not disturbed by the grafting procedure.
Wandering histiocytes, foreign body giant cells, and inflammatory connective-tissue cells are stimulated by degradation products
of dead matrix to grow in and repopulate the area of an implant of decalcified bone. Histiocytes are more numerous than any
other cell form and may transfer collagenolytic activity to the substrate to cause dissolution of the matrix. The process
is followed immediately by new-bone formation by autoinduction in which both the inductor cells and the induced cells are
derived from ingrowing cells of the host bed. The inductor cell is a descendant of a wandering histiocyte; the induced cell
is a fixed histiocyte or perivascular young connective-tissue cell. Differentiation of the osteoprogenitor cell is elicited
by local alterations in cell metabolic cycles that are as yet uncharacterized.
Bovine bone morphogenetic protein (bBMP) induces differentiation of mesenchymal-type cells into cartilage and bone. bBMP has an apparent Mr of 18,500 +/- 500 and represents less than 0.001% of the wet weight of bone tissue. A Mr 34,000 protein resembling osteonectin is separated by extraction with Triton X-100. A Mr 24,000 protein and about half of a Mr 22,000 protein are disassociated from bBMP by precipitation in 1.5 M guanidine hydrochloride. Aggregates of bBMP and a Mr 14,000 protein are insoluble in aqueous media; the bBMP becomes soluble when the Mr 14,000 protein is disassociated in 6 M urea and removed from the solution by ultrafiltration. Three separate molecular species with apparent Mrs 18,500, 17,500, and 17,000 are eluted at 0.10, 0.15, and 0.20 M phosphate ion concentrations, respectively, from a hydroxy-apatite column. The Mr 18,500 protein has the amino acid composition of acidic polylpeptide and includes four half-cystine residues; the pI is 4.9-5.1. The Mr 22,000 component is a chromoprotein resembling ferritin. The NH2-terminal amino acid sequence of the Mr 17,500 protein simulates histone H2B. The Mr 17,000 protein may possess calmodulin activity. Aggregates of the Mr 18,500 and other proteins induce formation of large deposits of bone; the Mr 18,500 protein alone is rapidly absorbed and induces formation of small deposits. None of the other proteins induces bone formation.
The closure of a wide alveolar cleft and fistula in cleft patients and the reconstruction of a maxillary dentoalveolar defect in traumatic patients are challenging for both orthodontists and surgeons. This is due to the difficulty in achieving complete closure by using local attached gingiva and the great volume of bone required for the graft. In this article, the authors propose using interdental distraction osteogenesis to create a segment of new alveolar bone and attached gingiva for the complete approximation of a wide alveolar cleft/fistula and the reconstruction of a maxillary dentoalveolar defect. They performed this procedure on one patient with a traumatic maxillary dentoalveolar defect and 10 patients with unilateral or bilateral cleft lips and palates who had varied dentoalveolar clefts/fistulas. Interdental and maxillary osteotomies were performed on one side of the dental arch by the cleft or defect. After a latency period of 3 days, the osteotomized distal segment of the dental arch was then distracted and transported toward the cleft or defect by using a toothborne intraoral distraction device. The alveoli and gingivae on both ends of the cleft or defect were approximated after distraction osteogenesis. The need for extensive alveolar bone grafting was eliminated. A segment of new edentulous alveolus and attached gingiva was created interdentally at a site distant to the cleft or defect. In the cleft patients, teeth were moved orthodontically into the regenerate (newly formed alveolar bone) dental crowding 1 week after distraction. The orthodontic tooth movement was rapidly completed in 3 months, and the edentulous space was eliminated. Interdental distraction osteogenesis minimizes an alveolar cleft/fistula and helps reconstruct a maxillary dentoalveolar defect by approximating the native alveoli and gingivae; it also creates new alveolar bone and gingiva for rapid orthodontic tooth movement.