Segmental mandibular bone reconstruction with a carbonate-substituted hydroxyapatite-coated modular endoprosthetic poly(ɛ-caprolactone) scaffold in Macaca fascicularis.

A bio-degradable scaffold incorporating osteoinductive factors is one of the alternative methods for achieving the regeneration of a mandibular bone defect. The current pilot study addressed such a bone reconstruction in a non-human primate model, Macaca fascicularis monkeys, with an engineered poly(ɛ-caprolactone) (PCL) scaffold, provided with a carbonate-substituted hydroxyapatite coating. The scaffolds were implanted into unilaterally created mandibular segmental defects in 24 monkeys. Three experimental groups were formed: (1) scaffolds with rhBMP-2 (n = 8), (2) scaffolds with autologous mixed bone marrow cells (n = 8), and (3) empty scaffolds as a control group (n = 8). Evaluation was based on clinical observation as well as micro-CT, mechanical, and histological analyses. Despite a high infection rate, the overall results showed that the currently designed PCL scaffolds had insufficient load-bearing capability, and complete bone union was not achieved after 6 months of implantation. Nevertheless, the group of PCL scaffolds loaded with rhBMP-2 showed evidence of bone-regenerative potential, in contrast to PCL with autologous mixed bone marrow cells and the control group.

The use of a polycaprolactone-tricalcium phosphate scaffold for bone regeneration of tooth socket facial wall defects and simultaneous immediate dental implant placement in Macaca fascicularis.

Bone regeneration and aesthetic outcomes may be compromised when immediate implants are placed at extraction sites with dehiscence defects. The aim of this study was to compare, in a monkey model, peri-implant bone regeneration and implant stability after immediate implant placement into tooth sockets with facial wall defects in two treatment groups. In eight control monkeys, the bony defect was reconstructed with autogenous particulate bone, whereas in 10 test monkeys a polycaprolactone-tricalcium phosphate (PCL-TCP) scaffold was used. The monkeys were sacrificed after 6 months and the specimens were analyzed by histology and histomorphometry. Better maintenance of facial bone contour was noted in the test group; however, bone regeneration was seen only at areas adjacent to a bony wall of the defect. The mean bone-to-implant contact was 27.6 ± 19.1% (control group) versus 6.8 ± 7.9% (test group). The mean bone area percentage was 11.8 ± 10.1% (control group) versus 6.8 ± 6.9% (test group). Implant survival was 100% at 6 months for both the groups. It was concluded that although the use of a PCL-TCP scaffold showed better maintenance of the alveolar contour as compared to autogenous particulate bone at 6 months, there was minimal bone regeneration within the defect.

Effect of postoperative radiation therapy on mandibular reconstruction using a modular endoprosthesis - a pilot study.

The endoprosthetic system has been shown to be a potential option for mandibular reconstruction. The objective of this pilot in vivo animal study was to determine the effects of postoperative radiation using brachytherapy on bone and soft tissue healing in mandibles reconstructed with the endoprosthesis. Six adult Macaca fascicularis mandibles were reconstructed with a cemented endoprosthesis after segmental body resection. The animals were divided into two groups. The test group was subjected to radiation therapy 1 month postoperation while the control group did not receive any radiation. Results showed no major radiation side effects. Mucosal ulcerations and wound dehiscence at the radiated sites healed within 4 weeks. One animal from each group had prosthesis failure and was unable to complete the study. Micro-CT findings indicated no significant differences between the total bone volume percentage (TBV%) of the study and control groups. Histomorphometrical analysis using grading scales also showed no significant differences between the two groups. Under the study conditions, postoperative brachytherapy did not affect the tissue response around the endoprosthesis within the early 6 months postradiation period. The endoprosthesis, therefore, remains a viable reconstructive option when postoperative radiation is prescribed.

Subcutaneous tissue response to titanium, poly(ε-caprolactone), and carbonate-substituted hydroxyapatite-coated poly(ε-caprolactone) plates: a rabbit study.

The aim of this study was to evaluate the soft tissue response to poly(ε-caprolactone) (PCL) implants with and without carbonate-substituted hydroxyapatite (CHA) coating compared to the commonly used titanium alloy (Ti-6Al-4V)-machined surface. Experimental materials were implanted subcutaneously in New Zealand white rabbits for 5 weeks. The tissue attachment strength, as evaluated by a tissue peel test, histological and histomorphology analysis, as well as scanning electron microscopy were compared between groups. The peel test result revealed no statistically significant difference between groups. Histological analysis found fibrous capsule formation around all implant materials. The fibrous capsule around PCL implants with and without CHA coating was significantly thinner compared with the capsule thickness around the titanium implants. However, the inflammatory cells, as present at the fibrous capsule-implant interface, were found to be significantly lower in the Ti-group. In conclusion, the current data do not prove that PCL or PCL with a CHA coating results in a superior soft tissue response compared with a machined titanium implant.

Biocompatibility and bone formation with porous modified PMMA in normal and irradiated mandibular tissue.

UNLABELLED: A cemented mandibular endoprosthesis is a potentially viable option for mandibular reconstruction after ablative surgery. The commonly used PMMA cement has the inherent weakness of a lack of bioactivity. Improvement by the addition of porosities and bioactive compounds like calcium phosphates may resolve this issue. OBJECTIVE: The objective of this study was to assess the bone and tissue response to two modified PMMA cements with post-operative radiation as an additional influencing factor. MATERIALS & METHODS: An in vivo animal study was performed using a mandibular rabbit model. A porous PMMA cement (A) and a porous cement incorporated with Beta-tricalcium phosphate particles (b-TCP) (B) were placed in bilateral mandibular defects with exposed roots and mandibular nerve of 20 animals. Half of the animals underwent additional post-operative radiation. RESULTS: The animals were healthy with only a minor complication in one rabbit. Temperature analysis showed no significant risk of thermal necrosis with the maximal in vivo cement temperature at 37.8°C. Histology demonstrated: (1) good bone ingrowth around the defect as well as within the pores of the cement and defect bridging was achieved in 70% of the specimens after 12-15 weeks of implantation, (2) no pulpal injury with minor secondary cementum response, (3) an intact mandibular nerve with no inflammation, (4) extensive degradation and resorption of the b-TCP particles by 12-15 weeks, and (5) presence of an intervening thin fibrous tissue at the bone-to-cement interface. Histomorphometrical analysis revealed that there was no difference between the different cements and the presence or absence of post-operative radiation. The 12-15 weeks specimens showed significantly more bone ingrowth and bone maturity than the 4-7 weeks specimens. CONCLUSION: Both modified PMMA cements have good biocompatibility, bioactivity and support bone ingrowth and additional post-operative radiation did not show any negative effects.

The modular endoprosthesis for mandibular body replacement. Part 2: finite element analysis of endoprosthesis reconstruction of the mandible.

INTRODUCTION: Problems with loosening of the modules for the modular endoprosthesis were encountered in animal studies for mandibular body replacement. We performed a finite element analysis to look at the stress distribution and areas of stress concentration in a human sized mandible. Variations were made to the stem and defect length to look at how the forces changed. The hypothesis was: (1) reconstruction with a modular endoprosthesis did not lead to areas of stress concentration beyond the material strength of cortical bone and titanium alloy; (2) changes in dimensions of the endoprosthesis did not cause a corresponding linear increase to the stresses. MATERIALS AND METHODS: The endoprosthesis was modelled to create a male, female part with stems and a connection screw (Case I). The stem length was halved (Case II) and defect length doubled (Case III). Geometric data of a human sized mandible were obtained, a continuity defect created digitally at the right molar area and the models combined. Boundary conditions were set and the model loaded to get a bite force of 300 N at the incisor region. An intact mandible was used as a control. RESULTS: The right side of the reconstructed mandible became less rigid and flexed more. The highest stresses were within the endoprosthesis at two areas of stress concentration: (1) shear stress at the superior surface of the stems close to the junction of the stem and the module body; (2) compressive stresses at the bottom bevel of the dove-tailed connection. The stress distribution for Case I and II did not differ much except for the magnitude which was slightly higher for Case II. There was a tendency for outward bending at the module connection for Case III which potentially might cause loosening of the module connection. Displacements of the mandible were less than 1 mm throughout. CONCLUSION: The endoprosthesis with its present dimensions would be expected to perform adequately at a bite force of 300 N. An increase in defect length caused a tendency for bending at the stem and the module connection. With a decrease in stem length, there were little differences except a slight increase in magnitude.

The modular endoprosthesis for mandibular body replacement. Part 1: mechanical testing of the reconstruction.

INTRODUCTION: In this paper we present the results of the mechanical testing of a new generation modular endoprosthesis, which has been designed to improve the results of mandibular reconstruction. MATERIALS AND METHODS: The new cementless endoprosthesis consists of a male part, a female part (both with screws on the stems), connected via a dove-tailed connection and secured with a coronal screw. The endoprosthesis was fitted into standardized blocks of synthetic bone (Synbone AG, Malans, Switzerland). The set-up was fixed to an ElectroPuls testing machine at one end and loaded at the other end 25 mm away. Three specimens were loaded continuously until failure to determine the average load to failure of the construct. Five specimens were then loaded cyclically between 10 and 150 N until either failure or 500,000 cycles. A finite element analysis was also performed on the set-up. RESULTS: Of the five specimens in the fatigue testing, only one survived while the other four either were bent or fractured at the stem of the clamped portion. The specimen that survived had very good bony contact with the prosthesis at the lower border. The connection of the modules via the dove-tailed design did not show any loosening. Finite element analysis showed areas of stress concentration at the superior surface of the stems to 188.8 MPa. This was well below the yield strength of titanium alloy of 897 MPa. Statistical analysis performed for specimens 1 to 4 to calculated lower tolerance bounds on cycles to failure, representing the estimated minimum achievable cycles to failure at 90, 95, and 99% of the population at 90 and 95% confidence levels, showed that the estimated mean cycles to failure was 10,132 cycles at the mean, minimum and maximum loads of 120 N and 18.4 N respectively. CONCLUSION: Good bony contact seems to be essential at the lower border for long-term survival of the reconstruction. Small gaps increase the bending forces and thus shear stresses at the stem. The new design of the modular endoprosthesis is prone to stress concentrations at the superior surface of the stems. This is accentuated by the sharp screw threads of the stems. The loosening of the module connection seemed to have been stopped with the dove-tailed design.

Soft tissue adaptation to modified titanium surfaces.

Surface modification of titanium alloy implants to enhance soft tissue adherence is important to minimize soft tissue dehiscence. This study aimed to confirm if a dual acid etched "Osseotite®" titanium surface contributes to soft tissue adherence in muscle. It also aims to explore if a radio frequency magnetron sputtered hydroxyapatite (HA)/bioglass (BG) coating can serve this purpose and provides soft tissue adherence in mucosal tissue. The study was carried out in 18 Macaca fascicularis animals, 14 Osseotite® coated Ti6Al4V bullets inserted intramuscularly and 12 HA/BG coated Ti6Al4V plates inserted into the submucosa. These were compared with machined Ti6Al4V surfaces as controls. The histological and histomorphometrical results revealed that no significant difference existed in muscle tissue response between machined and Osseotite® surfaces. On the other hand, the HA/BG coated submucosal plates showed statistically significant differences with a thinner capsule quantity (p < 0.0001), an increased capsule quality (p < 0.0001) and interface quality score (p < 0.05). In conclusion, the deposited HA/BG coatings facilitated soft tissue (mucosa) adaptation at 1 month of implant installation, whereas the acid etched Osseotite® surface did not enhance muscular adaptation.

Replacement of the condyle and ascending ramus by a modular endoprosthesis in Macaca fascicularis--part 4: evaluation of the temporomandibular joints.

PURPOSE: To assess, using cone-beam computed tomography and histologic examination, whether the fixation of a condyle-ascending ramus mandibular modular endoprosthesis results in a physiologic condylar replacement in Macaca fascicularis. MATERIALS AND METHODS: The right condyle and ascending ramus were resected in 8 adult monkeys and replaced with a modular endoprosthesis, fixed with polymethyl methacrylate bone cement (Palacos). Four monkeys were sacrificed at 3 months and another 4 at 6 months postoperatively. The reconstructed and contralateral temporomandibular joints were harvested en bloc and studied using cone-beam computed tomography and descriptive histologic examination. Heterotopic bone formation was quantified using a modified grading scale. The condyle cartilage thickness in the contralateral temporomandibular joint was measured using histomorphometric methods. The results were compared with those of the unoperated control monkeys. RESULTS: Bone resorption in the glenoid fossa and pathologic changes in the articular disc were noted on the reconstructed side in most specimens. Nevertheless, cone-beam computed tomography findings, histologic findings, and condyle cartilage thickness measurements of the contralateral temporomandibular joint were not significantly different from those of the control specimens. CONCLUSION: Replacement of the condyle and ascending ramus using a modular endoprosthesis in Macaca fascicularis resulted in adaptive remodeling of the glenoid fossa at up to 6 months postoperatively. Long-term studies are required to further assess the potential of this mode of reconstruction.

Replacement of the condyle and ascending ramus by a modular endoprosthesis in Macaca fascicularis--part 3: evaluation of peri-implant bone remodeling.

PURPOSE: To assess whether the fixation of a condyle-ascending ramus mandibular modular endoprosthesis, using bone cement, will result in stress-related bone resorption in the Macaca fascicularis. MATERIALS AND METHODS: The right condyle and ascending ramus were resected in 8 adult monkeys and replaced by a modular endoprosthesis, fixed with polymethylmethacrylate bone cement (Palacos). Four monkeys were sacrificed at 3 months and another 4 at 6 months postoperatively. The bone mineral density was assessed using dual-energy x-ray absorptiometry in the region anterior to the stem and using micro-computed tomography in the buccal, lingual, and inferior regions adjacent to the stem. RESULTS: The bone mineral density of the 3-month specimens was greater than that at 6 months in the buccal, lingual, and inferior regions adjacent to the stem. However, the difference was statistically significant only in the inferior aspect. No significant difference was found in the bone mineral density in the region anterior to the stem between the 3- and 6-month specimens. CONCLUSION: A minimal reduction in bone density around the stem of the endoprosthesis was observed between 3 and 6 months after placement. This reduction did not result in any adverse clinical events.

Replacement of the condyle and ascending ramus by a modular endoprosthesis in Macaca fascicularis-part 2: microcomputed tomographic and histologic evaluation of the ramus and stem.

PURPOSE: The present study presents the microcomputed tomographic and histologic evaluation of the peri-implant tissues of a modular endoprosthesis used to replace the condyle and ascending ramus in Macaca fascicularis. MATERIALS AND METHODS: The right condyle and ascending ramus were resected in 8 adult monkeys and replaced by a modular endoprosthesis, fixed with polymethylmethacrylate bone cement (Palacos). Four monkeys were sacrificed at 3 months and 4 at 6 months postoperatively. Microcomputed tomographic scanning was performed to analyze the bone volume at the bone-cement interface. Histologic and histomorphometric assessments were done using a modified hard and soft tissue grading scale and by studying the total bone contact at the interface. RESULTS: The combined (buccal, lingual, and inferior) mean bone volume percentage of the 6-month group was significantly greater than that of the 3-month group (P < .05). The 6-month specimens showed a reduced inflammatory response and more abundant bone formation around the stem. The total soft tissue histologic score was significantly greater in the 6-month group (P < .05). A total bone contact percentage of 15.4% to 85.2% was achieved in 3 specimens. CONCLUSIONS: Satisfactory bone growth was found at the bone-cement interface at the stem region, although direct bone contact with the cement was not achieved in all cases. Soft tissue contact with the prosthetic ramus, in the form of a fibrous capsule, was present in some areas. At 6 months, minimal interfacial inflammation was found in this monkey model.

Bone cements and their potential use in a mandibular endoprosthesis.

Bone cement was first used in the 1950s. Since then many modifications have been made and alternatives developed to the original polymethylmethacrylate (PMMA) cement. In view of the use of bone cement in a novel mandibular endoprosthetic system, we performed a review of the current literature on this material. Different cements are described and their potential use in a mandibular endoprosthetic system discussed. The PMMA-based cements are currently the most suitable choice. Plain PMMA has the longest track record and is the default choice for the initial development phase of this system. If there is a significant risk of infection, then an antibiotic-loaded PMMA cement can be selected. However, modified PMMA cements, composite resin cements, osteoinductive calcium phosphate compounds, and cementless fixation are options that offer advantages over PMMA cements, and further research should be conducted to study their suitability.

Replacement of the condyle and ascending ramus by a modular endoprosthesis in Macaca fascicularis--part 1: a clinical and radiographic study.

PURPOSE: To evaluate the feasibility of replacing the condyle and ascending ramus with a novel modular endoprosthesis in Macaca fascicularis. MATERIALS AND METHODS: Eight male adult monkeys (Macaca fascicularis) were used in this study. The right condyle and ascending ramus posterior to the lower second molar were resected. An endoprosthesis consisting of 2 modules was inserted to replace the resected segment and fixed in place using polymethylmethacrylate bone cement (Palacos). Four monkeys were sacrificed at 3 months and another 4 at 6 months postoperatively. The operated side of the mandible was then harvested, including the endoprosthesis and the stump of the mandible to which it was attached. Lateral mandibular radiographs were taken using standard settings immediately postoperatively and postsacrifice. RESULTS: Two monkeys presented with a fistula at the operated area 1 month postoperatively, but this resolved with a short course of antimicrobial treatment. At the time of sacrifice, no fistulas, dehiscences, or mobility of the endoprostheses was observed. There was no significant change in maximum mouth opening. At 3 months, a linear radiolucency was noted at the cement-bone interface in the 2 monkeys that previously presented with fistulas; whereas at 6 months, none of the 4 animals showed any radiolucency. CONCLUSIONS: The use of a cemented modular endoprosthesis for replacement of the condyle and ramus unit was feasible with minimal complications allowing normal mouth opening and occlusion. Further histologic and microfocus computed tomographic studies will be done to confirm the findings.

Mandibular reconstruction in adults: a review.

Mandibular defects may result from trauma, inflammatory disease and benign or malignant tumours. Mastication, speech and facial aesthetics are often severely compromised without reconstruction. The goal of mandibular reconstruction is to restore facial form and function, implying repair of mandibular continuity and muscle attachments. There should also be room for implant insertion so as to allow for rehabilitation of occlusion and articulation, whereas the function of the inferior alveolar nerve should be restored to assure adequate sensitivity of the lips. Mandibular reconstruction principles and techniques have evolved dramatically over the years. Refinements in techniques continue to improve patient quality of life. This paper reviews current techniques of mandibular reconstruction in adults and discusses the strengths and weaknesses of each.

Upregulation of GADD153 expression in the apoptotic signaling of N-(4-hydroxyphenyl)retinamide (4HPR).

The molecular basis for the pharmacologic effects of N-(4-hydroxyphenyl)retinamide (4HPR) was investigated by studying the gene(s) that this compound may upregulate in cultured human epithelial tumor cells. Treatment of the cultured human nasopharyngeal carcinoma-derived cells (CNE3) with 4HPR caused modest cell-cycle arrest at G(1) and apoptosis. The mRNA levels of a total of 20 genes were downregulated with the majority of them involved in cell cycle-related functions. Only the mRNA level of the growth arrest and DNA-damage inducible gene (gadd153) was upregulated by approximately 7-fold, with a concomitant increase in intracellular protein level. Similar upregulation of gadd153 by 4HPR was observed in HeLa and 2 other tumor cell lines. The 4HPR-induced apoptosis was markedly enhanced in the CNE3 cells that transiently overexpressed the gadd153 protein. Unlike 4HPR, all-trans-retinoic acid (ATRA) had no effect on the mRNA or protein level of gadd153. The ability of 4HPR and ATRA to stimulate the promoter activity of gadd153 was then examined. In the HeLa cells, both 4HPR and ATRA caused a 2- to 4-fold stimulation of the promoter activity of gadd153, but similar to the CNE3 cells, ATRA was incapable of upregulating the protein level of gadd153. This is the first demonstration that gadd153 is a 4HPR-responsive gene in tumor cells and may have a functional role to play in 4HPR-induced apoptosis. Furthermore, our data suggest that the expression of gadd153 can be regulated by 4HPR at the transcriptional level.