Bone graft substitutes in periodontal and peri-implant bone regeneration.

Regenerative medicine provides different therapy alternatives alongside gold standard autogenous grafts for the treatment of periodontal or peri-implant osseous defects. Continuing progress in the field of alloplastic bone substitutes has yielded promising solutions to the appropriate indications with the membrane technique either alone or in combination with enamel matrix derivatives. Their clinical outcomes, however, still require critical discussion.

The application of bone graft substitutes for alveolar ridge preservation after orthodontic extractions and for augmentation of residual cleft defects.

The use of bone substitute materials in orthodontics is to be considered prior to orthodontic space closure after tooth extraction during the treatment of marked crowding as well as for treatment of residual defects in cleft-lip-and-palate children. In both cases the common objective is structure preservation or augmentation of the alveolar ridge. The demands to be made on the synthetic bone graft substitute comprise not just complication-free and safe use but also the chance of early tooth movement into the treated defect area with sufficient stability of the new tooth position.

The clinical application of a new synthetic bone grafting material in oral and maxillofacial surgery.

A novel bone formation material based on hydroxyapatite-xerogel is presented. With the use of the innovative sol-gel technology this material is produced in the low-temperature range by the addition of silicon dioxide; in its structure it mimics to a great extent the natural bone matrix. This results in high osteoconductivity and an osteoprotective effect as well as in complete biodegradation corresponding to bone formation in the course of natural bone remodelling. Two case reports are presented.

Wound management after the application of bone grafting substitutes in the orofacial region.

Surgical dressing after the application of bone grafting material depends on the type and size of the defect. A complete and tension-free wound closure has proved to be successful. In this context the infection problem needs special attention. Bone graft substitutes with an adequate surface structure, porosity and chemical properties, in combination with sufficient blood circulation, hold osteoconductive potential. They serve as a guide rail for the osteoblast-induced formation of new bone tissue, which at best may lead to complete replacement of the grafting material.

The biodegradation of hydroxyapatite bone graft substitutes in vivo.

Hydroxyapatite (HA) ceramics are widely used for bone reconstruction. They are osteoconductive and serve as structural scaffolds for the deposition of new bone. Generally, scaffold materials should be degradable as they affect the mechanical properties of the reconstructed bone negatively. Degradation by osteoclasts during the bone remodelling process is desirable but often does not take place. In the current study we analysed by light microscopy the degradation of two granular HA implants in critically sized defects in the mandibula of Goettingen mini-pigs five weeks after implantation. Bio-Oss consists of sintered bovine bone and NanoBone is a synthetic HA produced in a sol-gel process in the presence of SiO2. We found that both biomaterials were degraded by osteoclasts with ruffled borders and acid phosphatase activity. The osteoclasts created resorption lacunae and resorptive trails and contained mineral particles. Frequently, resorption surfaces were in direct contact with bone formative surfaces on one granule. Granules, especially of NanoBone, were also covered by osteoclasts if located in vascularised connective tissue distant from bone tissue. However, this usually occurred without the creation of resorption lacunae. The former defect margins consisted of newly formed bone often without remnants of bone substitutes. Our results show that the degradation of both biomaterials corresponds to the natural bone degradation processes and suggest the possibility of complete resorption during bone remodelling.

The manufacture of synthetic non-sintered and degradable bone grafting substitutes.

A new synthetic bone grafting substitute (NanoBone, ARTOSS GmbH, Germany) is presented. This is produced by a new technique, the sol-gel-method. This bone grafting substitute consists of nanocrystalline hydroxyapatite (HA) and nanostructured silica (SiO2). By achieving a highly porous structure good osteoconductivity can be seen. In addition, the material will be completely biodegraded and new own bone is formed. It has been demonstrated that NanoBone is biodegraded by osteoclasts in a manner comparable to the natural bone remodelling process.

Bone functions and the requirements for bone grafts and substitutes in the orofacial region.

Bone is the largest calcium storage, has distinctive plasticity and adaptability and is part of the supporting tissue. An adequate composition is thus necessary. The bone matrix consists of organic and anorganic structures. Osteoblasts, osteoclasts and osteocytes are responsible for bone formation, resorption and metabolism. The periosteum, endosteum and bone tissue are a functional unit and provide protection, nutrition and growth. Bone is subject to continuous remodelling.

Critical considerations on the diagnostic appraisal, adaptation and remodelling of bone graft substitutes.

The diagnostic assessment of skeletal defects has a long-standing tradition. As a result of the development of new bone grafting materials, the demands on diagnostic assessment have also increased. The mode and quality of diagnostic appraisal are crucial to further clinical use and outcome prediction. Alongside traditional clinical and biological techniques, molecular biological methods have gained a broad scope of application and will be used even more frequently in the future.

[Novel calcium phosphate formula for filling bone defects. Initial in vivo long-term results]. / Neuartiges Knochenaufbaumaterial auf Kalziumphosphatbasis. Erste In-vivo-Langzeitergebnisse.

BACKGROUND: Up to now hydroxyapatite (HA) and beta-tricalciumphosphate (beta-TCP) ceramics have been routinely sintered at temperatures between 1100 degrees and 1500 degrees C. Our new calcium ceramic is fabricated by a sol-gel process at 200 degrees C. The aim of this investigation was to test the biodegradation of and the induction of bone formation by this material. MATERIAL AND METHODS: Eighteen 1-year-old Goettingen minipigs were divided into three groups. Critical size defects (>5 cm(3)) in the mandible were treated differently in all three animals (group 1: filling with 40% beta-TCP plus 60% HA, group 2: pure HA was applied, group 3 served as controls: only gelatinous material was given). Macroscopic and microscopic investigations of the former defects were made 8 months postoperatively. RESULTS. In groups 1 and 2 biodegradation of more than 93% of the new calcium phosphate formula was found 8 months postoperatively and considered to be very good. No difference was observed between pure HA (group 2) and the combination of HA and beta-TCP (group 1). In both groups complete bone formation was seen macroscopically in the former defects. In the control group only incomplete bone formation with 48.4% of the defect area was noted. This difference was significant ( p<0.001). DISCUSSION: The new calcium phosphate formula made by a sol-gel method at 120 degrees C seems to be suitable for filling bone defects and is of interest for orthopedic surgery, traumatology, craniomaxillofacial surgery, and dentistry.

Do folic acid and thiocyanate have a preventive effect on exogenously induced disturbances of embryonic cranial development?

The preventive influence of folic acid and thiocyanate on procarbazine-induced disturbances of embryonic cranial development was investigated on experimental animals. Low dosages of folic acid or thiocyanate demonstrated no prophylactic effect. When thiocyanate was administered alone, an increased cleft rate was unexpectedly found for the secondary palate. The combined application of folic acid and thiocyanate showed a cleft-prophylactic effect in the secondary palate in addition to growth protection in the primary palate. It can be assumed that thiocyanate has a positive effect on chondral and osseous growth of the palate during the post-sensitive phase of embryogenesis, while in the sensitive phase, it can function as a carrier for teratogenous and toxic substances.

The influence of procarbazine and thiocyanate on embryonic bone maturation

The substance procarbazine (Natulan®) is a teratogen known to induce cleft palates in rats on day 14 post-conception. The application of thiocyanate (SCN-) alone to rats on day 10 and 14 of pregnancy had no effects on fetal bone maturation. However, when procarbazine was used, the maturation and growth of fetal bones was delayed. Upon additional application of thiocyanate, the effects of procarbazine (Natulan) were increased. Thus, no antiteratogenic effect of thiocyanate occurs. We propose that charge and metabolites of teratogenic agents play a key role in developing the effects of thiocyanate (AU)

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Sex-related differences in procarbazine-induced cleft palate and microgenia and the anti-teratogenic effect of prenatal folic acid supplementation in rats.

Sex-related differences in the frequency of cleft palates and microgenia in rat fetuses prenatally treated with procarbazine (200 mg/kg on day 14 of gestation (GD14), group 1), and the anti-teratogenic effect of prenatal folic acid supplementation (4 mg/kg on GD14 through GD17, group 2) were studied in LEW.1A rats. In group 1, complete clefts were observed in 69% of the male and in 36% of the female fetuses while incomplete clefts (present only in the hard palate) were exhibited by 31% of the males and 43% of the females. Microgenia occurred in all males but only in 64% of the female fetuses. In group 2, the prenatal folic acid supplementation significantly reduced the occurrence frequency of complete clefts to 9% in males and to 0% in females. In contrast, incomplete clefts increased to 82% in males and 91% in females. Microgenias were reduced to 73% and 57% in male and female fetuses, respectively. Since incomplete clefts present in the hard palate are assumed to be residues of spontaneous intra-uterine repair processes of exogenously induced complete palatal clefts, we conclude that prenatal supplementation with folic acid at a dose of 4 mg/kg promotes the intra-uterine repair of cleft palates and offers a partial protection against procarbazine teratogenicity. Furthermore, it is deduced that gender-specific differences exist in the susceptibility to procarbazine and in the anti-teratogenic effect of folic acid on procarbazine-induced microgenia.

[Stimulating regeneration of bone defects by implantation of bioceramics and autologous osteoblast transplantation]. / Stimulation der Regeneration von Knochendefekten durch Einsatz einer Biokeramik und autologer Osteoblastentransplantation.

QUESTION: Does artificial stimulation of osteoconduction and osteogenesis lead to improved bone formation in defects of critical size? MATERIAL AND METHODS: Full-thickness, critical-sized defects in the anterior mandible were created in 24 adult mini-pigs. These defects were treated with a new kind of bioactive ceramic (60% hydroxylapatite and 40% beta-tricalcium phosphate), applied as a unique sol gel [9]. The bioceramic was tested alone and in combination with autologous osteoblasts. In a control group, periosteum was the only bone-producing source. After 5 weeks, the animals were sacrificed and the defects analyzed clinically, histologically, and by X-ray examination. The effects of periosteum, bioceramics, and osteoblasts were investigated in particular. RESULTS: The new bioceramic was degraded at the same speed as new bone was laid down. The rate of newly formed bone was highest in the bioceramic group at 72.3% (control group with periosteal covering only 59.3%). Additional transplantation of autologous osteoblasts did not result in faster bone production. CONCLUSION: It seems that this bioactive ceramic is successful as a bone replacement material and will be suitable as a carrier for osteoinductive substances such as bone morphogenetic proteins.

Is it possible to prevent cleft palate by prenatal administration of folic acid? An experimental study.

OBJECTIVE: In this study, folic acid was tested for its antiteratogenic effects on experimentally induced cleft palate in animals. DESIGN: Eleven pregnant Lew 1 A dams (75 fetuses) received 200 mg/kg procarbazine via gastric tubing on postconception (p.c.) day 14 to induce a cleft palate (CP); seven of the pregnant dams (45 fetuses) were additionally given 4 mg/kg folic acid subcutaneously from the 14th to the 17th day p.c. As a control group, three more pregnant dams (24 fetuses) were not treated with the drugs mentioned above. All fetuses were delivered by Caesarian section on day 20 p.c. OUTCOMES MEASURED: All fetuses were weighed and examined macroscopically with a stereomicroscope. Each fetal head was cut into 35 frontal sections and scrutinized histologically. RESULTS: None of the control fetuses (n = 24) exhibited a cleft. Without folate administration, 90% of the fetuses (27 of 30) that received procarbazine exhibited a CP. After additional prenatal folate administration, this rate remained virtually unchanged (91%; 41 of 45). However, the proportion of complete (total) CP (4%) was significantly (p <.0001) lower than in the group without folate (53%). Cleft-associated microgenia and microglossia were also significantly less frequent when folate was administered prenatally: microgenia was reduced by 22% (p =.029) and microglossia by 24% (p =.032). CONCLUSIONS: On the basis of these results, folate has a partial ameliorating effect on the teratogenicity of procarbazine given to pregnant rats. Additional studies are necessary on the effect of folate in different species, also taking cleft lip and CP into consideration.

Cheilognathopalatoschisis and its prophylaxis in animal experiments.

Cheilognathopalatoschisis (cleft lip, -maxilla, and -palate) is the second most frequent malformation in humans. The ontogenetic causes are mostly multifactorial. Some researchers have succeeded in lowering the frequency of occurrence of such clefts in children of predisposed women by giving the latter an applied symptomatic replacement therapy with multivitamin preparations or other substance classes during early pregnancy. However, the dosage of these substances was only anecdotal and their effect unspecific. Many research groups world-wide are conducting animal experiments in order to investigate the efficacy of vitamins and other substances as prophylactics. The experiments are usually conducted with laboratory rats and mice, and clefts are often induced by applying chemical noxa. The results of these trials, however, are controversial. Where some authors were able to prove protective effects of the vitamins or other substances they employed, others found evidence that such replacement therapy has no prophylactic effect. This paper provides insight into such studies with experimental animals, and compares their results.

Disturbances of palatogenesis and their prophylaxis in animal experiments.

The goal of this study using experimental animals was to induce disturbances of palatogenesis which are comparable to human maxillary clefts. Simultaneously, an in vivo method of testing presumed antiteratogenic substances is presented. 13 gravid Wistar rats bearing 98 fetuses received 200 mg/kg of procarbazine on day 14 post conception (p. c.) to induce malformations. 7 of these gravid animals, bearing 48 fetuses, additionally received 200 mg/kg thiamine daily from day 13-19 p. c. to prevent malformations. On day 20 p. c., the fetuses were teratologically screened: all fetuses were externally examined, the skeletons of 1/3 were visualized using cartilage/bone staining methods, and the heads of 2/3 were histologically examined in 24 sequential frontal sections. At birth, the procarbazine-damaged fetuses exhibited a high rate of cleft palate, primarily involving the secondary palate (94%), which was accompanied by retardation and delayed ossification of the viscerocranium. 66% of the fetuses showed pronounced brachygenia. The disturbances of palatogenesis were frequently accompanied by disturbed odontogenesis, which chiefly manifested itself near the cleft of the frontal maxilla as a reduction in size (63%), retardation (38%) or absence (31%) of the tooth germ. In the trial group additionally treated with thiamine, the findings did not differ significantly from these. The animal model presented here proved suitable for studying palatogenesis and localization-specific testing of substances presumed to have antiteratogenic effects. A prophylactic effect of thiamine initially tested as a highly-dosed monotherapy was not verifiable.

Application of thiamine in preventing malformations, specifically cleft alveolus and palate, during the intrauterine development of rats.

OBJECTIVE: Animal experiments were conducted to test the reproducibility of previously documented antiteratogenic effects of thiamine on cleft formation in the craniofacial system. DESIGN: Thirteen gravid Wistar rats carrying 98 fetuses were given the hydrazine derivative procarbacine (200 mg/kg BW) on the fourteenth day postconception (PC) to induce malformations, chiefly cleft alveolus and palate (day of determining presence of sperm was called the first day PC). Seven of the treated gravid rats carrying 48 fetuses were additionally given a daily dose of 200 mg/kg thiamine from the thirteenth to the nineteenth day PC. OUTCOME MEASURES: A comparative analysis of the fetuses in both experimental groups was conducted externally and, for the skeleton, macroscopically using special staining techniques; the heads were analyzed using successional histologic sections; bodies were examined stereomicroscopically using the razor-blade sectioning technique. RESULTS: In 12 of the 16 parameters evaluated, no statistically significant differences were found between experimental groups. In some cases, we even observed an amplifying effect of thiamine on the development of malformations in the rat strain used in our study. CONCLUSIONS: Because several previous authors have repeatedly described treatment with thiamine as one of the sufficient prophylactic measures in slowing the development of viscerocranial malformations, especially cleft alveolus and palate, it is of utmost importance that the timing of treatment and dosage of thiamine be taken into consideration not only in animal experiments but also when applying results to humans.

[Degree of inflammation of the mouth mucosa in leukemia patients under cytostatic therapy]. / Entzündungsgrad der Mundschleimhaut bei Leukämiepatienten unter Zytostatikatherapie.

The aim of this study is the registration and the chronological control of inflammatory alterations in the oral mucosa of patients with acute leukaemia under cytostatic treatment. Thirteen patients with acute myeloid leukaemia or acute lymphatic leukaemia were investigated in three oral regions (gingiva, buccal and palatine mucosa) before, during and after cytotoxic drug application for a period of 4-6 weeks by means of exfoliative cytology. Before therapy, patients with leukaemia showed a significant increase in the number of cells from deeper epithelial layers and a significant decrease of the keratinization index for all investigated regions. This is a consequence of the general inflammatory alteration in all mucosal areas. During cytotoxic drug application these findings were modified only for the palatine mucosa. Immediately after the end of cytotoxic drug application only the buccal mucosa showed a slight but not significant tendency for normalization. At this time, only for the palatine mucosa was there a significant tendency toward regression. The study underlines the necessity for intensive dental care of patients with acute leukaemia after treatment with cytotoxic drug, even when the oral mucosa is clinically inconspicuous, as the inflammatory activity may take place subclinically in strongly stressed or vulnerable regions of mucosa.

[The ameloblastic fibro-odontoma--an odontogenic mixed tumor progressing into an odontogenic sarcoma]. / Das ameloblastische Fibroodontom--ein odontogener Mischtumor mit Ubergang in ein odontogenes Sarkom. Eine Kasuistik.

A case report is given on the rare course of an ameloblastic odontoma which originated from the right mandible in a girl at the age of 14. During the follow-up of 12 years there where 4 recurrences with a change in the histological findings. While ameloblastic epithelial complexes were found to be ever decreasing, there was, on the other hand, an increase in the mesenchymal component with foci of a marked proliferation of spindle cellular fibroblastic elements. Finally the condition progressed to an ameloblastic odontosarcoma appearing as a pleomorphic fibrosarcoma with a local metastasis. The clinical behaviour correlated with the histopathological findings.