Treatment of critical bone defects using calcium phosphate cement and mesoporous bioactive glass providing spatiotemporal drug delivery.

Calcium phosphate cements (CPC) are currently widely used bone replacement materials with excellent bioactivity, but have considerable disadvantages like slow degradation. For critical-sized defects, however, an improved degradation is essential to match the tissue regeneration, especially in younger patients who are still growing. We demonstrate that a combination of CPC with mesoporous bioactive glass (MBG) particles led to an enhanced degradation in vitro and in a critical alveolar cleft defect in rats. Additionally, to support new bone formation the MBG was functionalized with hypoxia conditioned medium (HCM) derived from rat bone marrow stromal cells. HCM-functionalized scaffolds showed an improved cell proliferation and the highest formation of new bone volume. This highly flexible material system together with the drug delivery capacity is adaptable to patient specific needs and has great potential for clinical translation.

[Cleft lip and palate : One of the most frequent congenital malformations]. / Lippen-Kiefer-Gaumen-Spalte : Eine der häufigsten angeborenen Fehlbildungen.

With a frequency of 1 per 500 live births, a cleft lip and palate is one of the most frequent congenital malformations. Untreated, it leads to disturbances in feeding, speech, hearing, tooth position and esthetics. A multifactorial genesis is assumed. The fusion of the different facial processes takes place in the first 3 months of pregnancy and a cleft can develop during this time. Surgical treatment includes the early anatomical and functional restoration of the affected structures within the first year of life in order to enable normal intake of food, articulation, nasal breathing and middle ear ventilation. Breastfeeding is possible in children with a cleft formation but alternative feeding methods, such as finger feeding, often have to be used. In addition to the surgery for primary closure of the cleft, otorhinolaryngological (ENT) interventions, speech therapy, orthodontic treatment as well as other surgical interventions are part of the interdisciplinary treatment concept.

A Holistic Approach for the Identification of Success Factors in Secondary Cleft Osteoplasty.

Cleft lip and palate belong to the most frequent craniofacial anomalies. Secondary osteoplasty is usually performed between 7 and 11 years with the closure of the osseus defect by autologous bone. Due to widespread occurrence of the defect in conjunction with its social significance due to possible esthetic impairments, the outcome of treatment is of substantial interest. The success of the treatment is determined by the precise rebuilding of the dental arch using autologous bone from the iliac crest. A detailed analysis of retrospective data disclosed a lack of essential and structured information to identify success factors for fast regeneration and specify the treatment. Moreover, according to the current status, no comparable process monitoring is possible during osteoplasty due to the lack of sensory systems. Therefore, a holistic approach was developed to determine the parameters for a successful treatment via the incorporation of patient data, the treatment sequences and sensor data gained by an attachable sensor module into a developed Dental Tech Space (DTS). This approach enables heterogeneous data sets to be linked inside of DTS, archiving and analysis, and is also for future considerations of respective patient-specific treatment plans.

Toward Biofabrication of Resorbable Implants Consisting of a Calcium Phosphate Cement and Fibrin-A Characterization In Vitro and In Vivo.

Cleft alveolar bone defects can be treated potentially with tissue engineered bone grafts. Herein, we developed novel biphasic bone constructs consisting of two clinically certified materials, a calcium phosphate cement (CPC) and a fibrin gel that were biofabricated using 3D plotting. The fibrin gel was loaded with mesenchymal stromal cells (MSC) derived from bone marrow. Firstly, the degradation of fibrin as well as the behavior of cells in the biphasic system were evaluated in vitro. Fibrin degraded quickly in presence of MSC. Our results showed that the plotted CPC structure acted slightly stabilizing for the fibrin gel. However, with passing time and fibrin degradation, MSC migrated to the CPC surface. Thus, the fibrin gel could be identified as cell delivery system. A pilot study in vivo was conducted in artificial craniofacial defects in Lewis rats. Ongoing bone formation could be evidenced over 12 weeks but the biphasic constructs were not completely osseous integrated. Nevertheless, our results show that the combination of 3D plotted CPC constructs and fibrin as suitable cell delivery system enables the fabrication of novel regenerative implants for the treatment of alveolar bone defects.

Prevalence of hypodontia and supernumerary teeth in a German cleft lip with/without palate population.

BACKGROUND: The distribution of dental abnormalities among cleft patients concerning cleft type frequently poses ambiguity wherefore the aim of this study was to evaluate the prevalence of hypodontia and supernumerary teeth in an exemplary German cleft population dependent on the cleft type. METHODS: Radiographs and dental records of cleft patients, which had been treated and followed up in the Department of Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus Campus, Dresden, Germany (investigation period of 22 years) were evaluated concerning hypodontia and supernumerary teeth dependent on the cleft type. Out of 386 records, 108 patients met the inclusion criteria: non-syndromic cleft of the alveolus with or without palate (CL/P), at least one clear panoramic x-ray, sufficient dental records. Statistical analysis was performed using x-square and binominal test (p ≤ 0.05). RESULTS: Hypodontia was more frequent (54/50%) than supernumerary teeth (36/33.3%) and was more common in bilateral clefts of the lip and palate (BCLP) (70.1%) than in unilateral clefts of the lip and palate (UCLP) (51.6%) or clefts of the lip and alveolus (CLA) (34.5%) (p << 0.001). There was an average of 0.9 missing teeth per patient, thereof the upper lateral incisor was most often affected (23.2%). In contrast, supernumerary teeth were more frequent in CLA (51.7%; p = 0.014) than UCLP (29.0%) and BCLP patients (17.6%). CONCLUSION: The prevalence for numerical dental anomalies was significantly different among the cleft types. Hypodontia significantly increased with the extend of the cleft, whereas the prevalence of supernumerary teeth decreased.

3D Printing of Bone Grafts for Cleft Alveolar Osteoplasty - In vivo Evaluation in a Preclinical Model.

One of the most common hereditary craniofacial anomalies in humans are cleft lip and cleft alveolar bone with or without cleft palate. Current clinical practice, the augmentation of the persisting alveolar bone defect by using autologous bone grafts, has considerable disadvantages motivating to an intensive search for alternatives. We developed a novel therapy concept based on 3D printing of biodegradable calcium phosphate-based materials and integration of osteogenic cells allowing fabrication of patient-specific, tissue-engineered bone grafts. Objective of the present study was the in vivo evaluation of implants in a rat alveolar cleft model. Scaffolds were designed according to the defect's geometry with two different pore designs (60° and 30° rotated layer orientation) and produced by extrusion-based 3D plotting of a pasty calcium phosphate cement. The scaffolds filled into the artificial bone defect in the palate of adult Lewis rats, showing a good support. Half of the scaffolds were colonized with rat mesenchymal stromal cells (rMSC) prior to implantation. After 6 and 12 weeks, remaining defect width and bone formation were quantified histologically and by microCT. The results revealed excellent osteoconductive properties of the scaffolds, a significant influence of the pore geometry (60° > 30°), but no enhanced defect healing by pre-colonization with rMSC.

Current concepts in cleft care: A multicenter analysis.

The current surgical techniques used in cleft repair are well established, but different centers use different approaches. To determine the best treatment for patients, a multi-center comparative study is required. In this study, we surveyed all craniofacial departments registered with the German Society of Maxillofacial Surgery to determine which cleft repair techniques are currently in use. Our findings revealed much variation in cleft repair between different centers. Although most centers did use a two-stage approach, the operative techniques and timing of lip and palate closure were different in every center. This shows that a retrospective comparative analysis of patient outcome between the participating centers is not possible and illustrates the need for prospective comparative studies to establish the optimal technique for reconstructive cleft surgery.

A worldwide comparison of the management of surgical treatment of advanced oral cancer.

INTRODUCTION: Microvascular surgery following tumor resection has become an important field of oral and maxillofacial surgery (OMFS). Following the results from management of T1/T2 floor-of-mouth and tongue squamous cell carcinoma (SCC) in German-speaking countries, Europe, and worldwide, this paper presents specific concepts for the management of resection and reconstruction of T3/T4 SCC of the maxillary and mandibular alveolar process and tongue. METHODS: The DÖSAK questionnaire was distributed in three different phases to a growing number of maxillofacial units worldwide. Within this survey, clinical patient settings were presented to participants and center-specific treatment strategies were evaluated. RESULTS: A total of 188 OMFS units from 36 different countries documented their treatment strategies for T3/T4 maxillary and mandibular alveolar process and tongue SCC. The extent of surgical resections and subsequent reconstructions is more consistent than with T1/T2 tumors, although the controversy surrounding continuity resections and mandible-sparing procedures remains. For continuity resection of the mandible the fibula free flap is the most frequently used bone replacement, whereas maxilla reconstruction concepts are less consistent, ranging from locoregional coverage concepts and different microvascular reconstruction options to treatment via obturator prosthesis. CONCLUSION: Results from treatment strategies for T3/T4 tumors underline the limited evidence for the appropriate amount of resection and subsequent reconstruction process, especially in cases involving the mandible. Prospective randomized trials will be necessary in the long term to establish valid treatment guidelines.

A worldwide comparison of the management of T1 and T2 anterior floor of the mouth and tongue squamous cell carcinoma - Extent of surgical resection and reconstructive measures.

INTRODUCTION: Microvascular surgery following tumor resection has become an important field of oral maxillofacial surgery (OMFS). Following the results on general aspects of current reconstructive practice in German-speaking countries, Europe and worldwide, this paper presents specific concepts for the management of resection and reconstruction of T1/T2 squamous cell carcinoma (SCC) of the anterior floor of the mouth and tongue. METHODS: The DOESAK questionnaire was distributed in three different phases to a growing number of maxillofacial units worldwide. Within this survey, clinical patient settings were presented to participants and center-specific treatment strategies were evaluated. RESULTS: A total of 188 OMFS units from 36 different countries documented their treatment strategies for T1/T2 anterior floor of the mouth squamous cell carcinoma and tongue carcinoma. For floor of mouth carcinoma close to the mandible, a wide variety of concepts are presented: subperiosteal removal of the tumor versus continuity resection of the mandible and reconstruction ranging from locoregional closure to microvascular bony reconstruction. For T2 tongue carcinoma, concepts are more uniform. CONCLUSION: These results demonstrate the lack of evidence and the controversy of different guidelines for the extent of safety margins and underline the crucial need of global prospective randomized trials on this topic to finally obtain evidence for a common guideline based on a strong community of OMFS units.

Application of tissue-engineered bone grafts for alveolar cleft osteoplasty in a rodent model.

OBJECTIVES: The clinical standard for alveolar cleft osteoplasty is augmentation with autologous bone being available in limited amounts and might be associated with donor site morbidity. The aim of the present study was the creation of tissue-engineered bone grafts and their in vivo evaluation regarding their potential to promote osteogenesis in an alveolar cleft model. MATERIALS AND METHODS: Artificial bone defects with a diameter of 3.3 mm were created surgically in the palate of 84 adult Lewis rats. Four experimental groups (n = 21) were examined: bovine hydroxyl apatite/collagen (bHA) without cells, bHA with undifferentiated mesenchymal stromal cells (MSC), bHA with osteogenically differentiated MSC. In a control group, the defect remained empty. After 6, 9 and 12 weeks, the remaining defect volume was assessed by cone beam computed tomography. Histologically, the remaining defect width and percentage of bone formation was quantified. RESULTS: After 12 weeks, the remaining defect width was 60.1% for bHA, 74.7% for bHA with undifferentiated MSC and 81.8% for bHA with osteogenically differentiated MSC. For the control group, the remaining defect width measured 46.2% which was a statistically significant difference (p < 0.001). CONCLUSIONS: The study design was suitable to evaluate tissue-engineered bone grafts prior to a clinical application. In this experimental set-up with the described maxillary defect, no promoting influence on bone formation of bone grafts containing bHA could be confirmed. CLINICAL RELEVANCE: The creation of a sufficient tissue-engineered bone graft for alveolar cleft osteoplasty could preserve patients from donor site morbidity.

Microsurgical reconstruction of the head and neck region: Current concepts of maxillofacial surgery units worldwide.

INTRODUCTION: Microvascular surgery following tumor resection has become an important field of oral maxillofacial surgery (OMFS). Following the surveys on current reconstructive practice in German-speaking countries and Europe, this paper presents the third phase of the project when the survey was conducted globally. METHODS: The DOESAK questionnaire has been developed via a multicenter approach with maxillofacial surgeons from 19 different hospitals in Germany, Austria and Switzerland. It was distributed in three different phases to a growing number of maxillofacial units in German-speaking clinics, over Europe and then worldwide. RESULTS: Thirty-eight units from Germany, Austria and Switzerland, 65 remaining European OMFS-departments and 226 units worldwide responded to the survey. There is wide agreement on the most commonly used flaps, intraoperative rapid sections and a trend towards primary bony reconstruction. No uniform concepts can be identified concerning osteosynthesis of bone transplants, microsurgical techniques, administration of supportive medication and postoperative monitoring protocols. Microsurgical reconstruction is the gold standard for the majority of oncologic cases in Europe, but worldwide, only every second unit has access to this technique. CONCLUSION: The DOESAK questionnaire has proven to be a valid and well accepted tool for gathering information about current practice in reconstructive OMFS surgery. The questionnaire has been able to demonstrate similarities, differences and global inequalities.

Microsurgical reconstruction of the head and neck--current concepts of maxillofacial surgery in Europe.

INTRODUCTION: Microvascular surgery following tumour resection has become an important field of oral maxillofacial surgery (OMFS). This paper aims to evaluate current microsurgical practice in Europe. METHODS: The questionnaire of the DOESAK collaborative group for Microsurgical Reconstruction was translated into English, transformed into an online based survey and distributed to 200 OMFS units with the aid of the European Association for Cranio-Maxillo-Facial Surgery (EACMFS). RESULTS: 65 complete and 72 incomplete questionnaires were returned. Hospitals from the United Kingdom, France, Italy, the Netherlands, Spain, Belgium, Greece, Slovenia and Lithuania participated. 71% of contributing centres were university hospitals, 87% out of these perform microvascular tumour surgery at least on a two-weekly base. Overall complication rate was at around five percent. Most frequently used transplants were the radial forearm flap and the fibular flap. The perioperative management varied widely. Success factors for flap survival, however, were uniformly rated, with the surgical skill being the most important factor, followed by the quality of postoperative management. Medication seems to play a less important role. CONCLUSION: Within Europe microvascular surgery is a common and safe procedure for maxillofacial reconstructive surgery in the field of OMFS. While there is a major accordance for the surgical procedure itself and the most frequently used flaps, perioperative management shows a wide variety of protocols with low presumed impact on surgical outcome.

Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability.

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability.

Tissue-engineered bone grafts for osteoplasty in patients with cleft alveolus.

Alveolar bone grafting is an integral part of the treatment concept in cleft palate patients. As an alternative to autogenous bone, tissue-engineered grafts have found some clinical application. The aim of the present study has been to compare ossification in the cleft area using tissue-engineered grafts in a case series of patients with ossification after transplantation of autogenous spongious bone as the gold standard in alveoloplasty. Eight children with complete cleft lips and cleft palates were included in the study. In four children (group A), the cleft defect was filled with tissue-engineered bone (autogenous osteoblasts cultured on demineralized bone matrix Osteovit(®)); as control in another 4 children (group B), the alveoloplasty was performed using spongious iliac bone. Preoperative and 6 months postoperative cone-beam computed tomography was performed, and volumes of the remaining cleft defects were calculated using 3D navigation software. Wound healing was uneventful in both groups. Six months postoperatively the mean volume of the cleft was 0.55±0.24cm(3) after grafting of tissue-engineered bone (group A) and 0.59±0.23cm(3) after transplantation of autogenous spongiosa. In group A, 40.9% of the cleft defect was ossified; in the control group (group B), 36.6%. Tissue-engineered bone is a promising alternative in alveolar bone grafting and no disadvantages were observed in comparison to the gold standard.

Resorbable triangular plate for osteosynthesis of fractures of the condylar neck.

We describe a new design of resorbable plate for use in the treatment of fractures of the condylar neck, and report the outcome of initial treatment in two patients.

Mandibular traction--an alternative treatment in infants with Pierre Robin sequence.

PURPOSE: In the Pierre Robin sequence, retrognathia and glossoptosis lead to airway obstruction in infants with or without cleft palate. Mandibular distraction has gained acceptance for the treatment of airway obstruction. However, surgical interventions can result in complications. In our institution, mandibular traction is the standard treatment in cases of severe respiratory distress. PATIENTS AND METHODS: A retrospective study was performed of all infants treated for Pierre Robin sequence at our institution from 1979 to 2007. The diagnosis and type of treatment (positioning/palatal plate or mandibular traction) were evaluated. The palatal plate had several knobs at the anterior alveolar ridge to direct the tongue forward. Mandibular traction was applied using weights transmitted onto the mandible by a custom-made plate fixed at the mandible with circumferential wiring. RESULTS: Nineteen children required airway treatment because of repeated cyanotic episodes and respiratory adaptation disorders. Of these 19 children, 8 had been diagnosed with pure Pierre Robin sequence and 11 also had other congenital abnormalities. Of the 19 patients, 10 (56%) were treated nonoperatively by lateral or prone positioning and/or wearing a palatal plate to stimulate the tongue. In 8 patients, conservative management was not sufficient, and continuous mandibular traction was performed for 2 to 5 weeks using weights of 50 to 200 g. One patient required a tracheostomy because of tracheomalacia. CONCLUSIONS: Surgical therapy using mandibular traction is a minimally invasive alternative to more invasive procedures because no serious complications such as scars or damage to the nerves were encountered.

Prefabricated bony radial forearm flap for secondary mandible reconstruction after radiochemotherapy.

BACKGROUND: Primary reconstruction of the mandible is the golden standard of surgical treatment after ablative tumor surgery. Many different microvascular bone grafts are used to reduce wound healing complications at the severely compromised recipient site. The loss of primary grafts due to radiotherapy or osteoradionecrosis can make secondary mandibular reconstruction necessary. To address this problem, we developed the technique of the prefabrication of a radial forearm flap with cancellous bone. The aims were to establish these techniques into the clinical routine and to create a safe and reliable flap with low donor site morbidity. METHODS: In patients who had undergone ablative tumor surgery radiochemotherapy, and primary reconstruction, prefabricated bony radial forearm flaps (PBRFFs) were applied for secondary reconstruction of the mandible. Cylinders of cancellous bone taken from the iliac crest were implanted in the lower forearm to allow the necessary vascularization. After a healing period of 4 weeks, the PBRFF was elevated and grafted into the mandibular defect. RESULTS: All grafts healed uneventfully. However, 1 case required revision of the venous anastomosis after 2 days. The transplants improved the contour of the lower face enabling a good correction of the facial asymmetry. During the follow-up of up to 4 years, the radiographic controls showed good bony consolidation between the graft and the stumps of the mandible as well as formation of cortical bone around the cancellous bone cylinders. CONCLUSION: These results demonstrate that the PBRFF is a safe and reliable graft which provides alternate solution in which other microvascular bone grafts have already failed. In the future, the iliac bone graft may be replaced with scaffold seeded with stem cells for further reduction of donor site morbidity.

O-phospho-L-serine: a modulator of bone healing in calcium-phosphate cements.

Bone substitution materials are seen as an alternative to autogenous bone transplants in the reconstruction of human bone structures. The aim of the present animal study was to evaluate the clinical handling and the conditions of bone healing after the application of a phosphoserine and collagen-I-modified calcium-phosphate cement (Biozement D). The application of phosphoserine is supposed to influence the texture of the extracellular matrix. Standardised bone defects were created in the lower jaw of 10 adult minipigs. These defects were reconstructed with a pasty calcium-phosphate cement mixture. After a healing time of 4 months, the animals were sacrificed. The mandibles of all animals were resected and non-decalcified histological sections of the areas of interest were prepared. The experiment was evaluated by means of qualitative histology and histomorphometry. The hydroxyapatite cement entirely hardened intraoperatively. Modelling and handling of the cement was facile and the margin fit to the host bone was excellent. Histology showed that resorption started in the periphery and proceeded exceptionally fast. The bony substitution, especially in phosphoserine-endowed cements, was very promising. After a healing period of 4 months, phosphoserine cements showed a bone regeneration of nearly two-thirds of the defect sizes. In the applied animal experiment, the newly developed hydroxyapatite collagen-I cement is well suited for bone substitution due to its easy handling, its excellent integration and good resorption characteristics. The addition of phosphoserine is very promising in terms of influencing resorption features and bone regeneration.

Finite element representation of bone substitute remodelling in the jaw bone.

The finite element (FE) method was originally developed on a physical basis for the computation of structure-mechanical problems. Meanwhile, it has been widely applied to medical issues. This study sought a suitable method to build a FE model for remodelling processes in osseous defects supplemented with bone substitute material. For this purpose, the second right premolars were extracted from four pig mandibles (Sus scrofa domesticus) and the extraction alveoli were provided with synthetic bone substitute material. After 70 days, a segmented osteotomy of this area was performed for specimen collection. Radiographs of the specimens were taken in defined planes before and after fixation and embedded with Technovit 9100. Fixation-related shrinkage was quantified from the radiographs using reference lines. Computer tomographic (CT) and microCT images of the fixed and embedded specimens were obtained. From these data, a FE model was built. The construction of a FE model is sufficient to represent bone remodelling after supply of bone substitute material. The use of microCT data permits building a clearly more precise model.

The biomaterial influences the ossification after sinus floor elevation using tissue-engineered bone grafts.

Sinus floor elevation is the standard procedure that allows dental implant insertion in the atrophic posterior maxilla. Instead of autogenous bone, tissue-engineered bone grafts can be used, but clear comparative clinical studies also assessing the influence of the biomaterial are missing. In six patients, tissue-engineered bone grafts were used in eight sinus floor elevations. After culturing osteoblast-like cells from biopsies of the maxilla, they were seeded on scaffolds made either from demineralised bovine bone matrix (DBBM) or from solvent-dehydrated mineralised bone (SDBB), and grafted. In all patients primary wound healing was without complications, except for one patient in the SDBB group. After 12 months, implant insertion was possible only in the SDBB group; in the DBBM group, fibrous connective tissue was found in an attempt of implant insertion. After 5 months, implant placement was performed in one patient of each group. However, the two implants inserted in the DBBM group were lost after 6 weeks. Histology of the bone cores in the DBBM group at 5 months showed lamellar bone and osteoid, and at 12 months showed fibrous connective tissue. Inflammation and some resorption of the scaffold was found 5 months after SDBB grafting, and after 12 months cancellous bone formation encapsulating SDBB remnants were observed. These preliminary data suggest that the preparation method of the bovine bone matrix, in particular the mineral content, and therefore the mechanical stability may have some influence on the generation of new bone.