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Basic and Clinical Research

Comparison Between Unsintered Hydroxyapatite/Poly-L-Lactic Acid Mesh and Titanium Mesh in Bone Regeneration of Rabbit Mandible

Moroi, Akinori DDS*; Ueki, Koichiro DDS, PhD; Okabe, Katsuhiko DDS, PhD; Marukawa, Kohei DDS, PhD§; Sotobori, Megumi DDS*; Mukozawa, Aya DDS*; Miyazakia, Mao DDS*

Author Information
doi: 10.1097/ID.0b013e31828336be
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Abstract

Treatment of cysts, tumors, and fractures of the jaw can result in bone defects. Such defects must be required with bone grafts or bone substitutes to ensure good structural and function outcomes.1–4 Guided bone regeneration (GBR) has been established as a reliable therapeutic procedure. GBR involves the insertion of a mechanical barrier to form a space into which only cells with osteogenic potential can migrate.1 The GBR is used to ensure the development of adequate bone volume before endosteal implant placement.2,3,5–8 For this application, the epithelial and granulation tissues are removed from the region to be regenerated, and a membrane is strategically placed to prevent the rapidly proliferating epithelial and fibroblast cells from repopulating the region adjacent to the implant, thereby enabling bone ingrowth. Polytetrafluoroethylene (ePTFE) is commonly used for GBR.9,10 Unfortunately, there are clinical situations where the ePTFE becomes dehisced and requires removal before bone generation.11 Some studies have shown up to 20% to 50% dehiscence and high infection rates with ePTFE.12–16 To regeneration bone in marginal or segmental defects, the mechanical barrier needs to resist pressure from the surrounding tissue whereas still presenting an appropriate degree of permeability that can preclude soft tissue invasion and, at the same time, ensure that the inner compartment of the defect receives the necessary nourishment.

Titanium mesh has been used in a variety of clinical applications in reconstructive surgery, including alveolar ridge augmentation.16–20 Titanium mesh is a commonly used material, but it has some disadvantages such as difficulty in providing a suitable contour for a given defect and the need for removal, especially when dental implants are planned. The field of bioresorbable materials has eliminated these disadvantages.21,22 Some of biomaterial had an ability to change to flexibility in hot water. Hence, it could be bent easily in hot water, and it stiffness back to the original in ordinary temperature. However, titanium mesh facilitated greater bone regeneration compared with bioresorbable mesh.23 Therefore, recently, resorbable bone fixation devices (Super-FIXSORB-MX, Takiron, Co., Ltd, Osaka, Japan) have been developed for use in orthopedic or craniofacial, oral, and maxillofacial, or plastic and reconstructive surgeries.24–26 These devices are made from composites of uncalcined and unsintered hydroxyapatite (uHA) particles and poly-L-lactic acid (PLLA), and they are produced by a forging process, which is a unique compression modeling, and machining treatment. They have a modulus of elasticity close to that of natural cortical bone, and they can retain a high strength during the period required for bone healing. They can also show optimal degradation and resorption behaviors, osteoconductivity, and bone bonding.

The purpose of this study was to compare the bone regenerative capability of using uHA/PLLA mesh and titanium mesh in rabbit mandible histologically and immunohistochemically.

Material and Method

The experimental protocol was approved by the Institutional Committee for Animal Care, Kanazawa University.

Experimental Animals

Twenty-four male Japanese white rabbits (12–16 weeks, 2.5–3.0 kg) were used in this experiment.

Surgical Procedure

The entire procedure was performed under sterile conditions. First, the animals were anesthetized with sodium pentobarbital (25 mg/kg) by injection into the lateral ear vein. After the hair in the submandibular region was shaved, 1.8 mL of 2% lidocaine containing 1:80,000 epinephrine was administered to the surgical site. A 25-mm horizontal skin incision was made over the submandibular region to expose the margin of the left mandibular body. The skin, muscles, and periosteum were incised along the inferior border of the mandible. Then, 3 × 5 mm marginal bone defects performed from the lateral side to the medial side were made on both sides by fissure bur (Fig. 1) and covered with a 0.7-mm thickness, 10 × 10mm uHA/PLLA mesh (Super-FIXSORB-MX40; Takiron) with 2 × 7 mm screws on 12 sides of the right and a 0.2-mm thickness, 10 × 10 mm titanium mesh (Micro-Titanium Augmentation Mesh; Stryker LEIBINGER GMBH and CO.KG, Freiburg, Germany) with 2 × 7 mm screw on 12 sides of the right, no mesh on 12 sides of the left (opposite) side, and no material was implanted into the mesh in all animals.(Fig. 2)

Fig. 1
Fig. 1:
Mandibular bone defect: Mandible exposed and a 3- × 5-mm bone defect was made at the submandibular region.
Fig. 2
Fig. 2:
Intraoperative findings: (A) the uHA/PLLA mesh group, (B) the titanium mesh group, (C) the control group (no material).

Specimen Collection

The rabbits were sacrificed at 1, 2, and 4 weeks postoperatively, and the specimens containing the titanium mesh were collected for hematoxylin and eosin staining and for immunohistochemical analysis.

Histological Examination

After fixation with 10% phosphate-buffered formalin, the specimens with the titanium mesh were dehydrated in ethanol and Technovit 7200VLC (Kultzer and Co., GmbH, Wehreim, Germany) and then embedded in acrylic resin. The embedded blocks were trimmed by a cutter and ground by abrasive paper. Thereafter, the sections were further ground to a final thickness of about 10 μm. Finally, the specimens were stained with hematoxylin and eosin and examined under microscope. The observation area was located inside the curved mesh under a 3-mm horizontal line above the inferior border of the mesh and distance more than 1 mm from the lateral wall (Fig. 3). In the control, the observation area was located inside the epithelium of the edge of bone defect. The bone area ration was measured with an image software (ImageJ; the Research Services Branch, National Institute of Mental Health, Bethesda, MD).

Fig. 3
Fig. 3:
The observation area was located inside the curved mesh under a 3-mm horizontal line above the inferior border of the mesh outline, in the coronal section. (A) Measurement of the Photomacrograph stained with hematoxylin-eosin; (B) measurement of the illustration.

Immunohistochemical Staining

The prepared sections were deacrylated in 2-methoxyethyl acetate, inhibited by endogenous peroxidase with 0.3% hydrogen peroxide, and blocked in 10% normal serum before staining. For immunostaining, commercially available monoclonal anti-BMP-2 antibodies (Dako North America, Inc., CA) were used. Sections were incubated overnight with these primary antibodies at 4°C in a humidified chamber. A biotinylated goat anti-mouse IgG antibody (Wako Jyunyaku, Inc., Osaka, Japan) was used to complete the immunostaining. Finally, a light Meyer’s hematoxylin counter stain was applied. The sections were then dehydrated in alcohol and mounted for light microscopy to count the number of positively stained active cells in the regeneration site. The observation area was located at the level of 2 to 3 mm above the most inferior point of the mesh curve in the coronal section (Fig. 2). BMP-2 labeling index (%) was determined as the number of BMP-2 stained cells per voluntary 1000 cells in this area that were counted manually using a high magnification photomicrograph (×400). The measurements were performed 5 times by an author (A.M.) to confirm the reproducibility of the scores, and the mean values were used as the results.

Statistical Analysis

Data of all sides were statistically analyzed with Stat View 4.5 (ABACUSConcepts, Inc., Berkeley, CA). The uHA/PLLA mesh and titanium mesh groups each consisted of 4 sides at 1, 2, and 4 weeks (uHA/PLLA, n = 12; titanium = 12). As the control group, each of the 4 sides at 1, 2, and 4 weeks (total n = 12) were selected. Differences between the groups were analyzed by nonpaired comparison using Scheffe F test. Time-dependent changes were examined by analysis of variance (ANOVA). Difference were considered significant at P < 0.05.

Results

Healing progressed uneventfully in all the animals, and no postoperative complications were noted during the 4-week observation period. After resting for 3 to 6 days postoperatively, the animals could move and leap without any notable pain or limitation.

Histological findings were observed at the end of the mother bone (upper area of the bone defects) and the closed area of the mesh (lower area of the bone defects).

After 1 week, fibrous connective tissue was found at the end of the mother bone in the uHA/PLLA mesh, titanium mesh, and control side. New bone formation was also found in all the sides, although blood components still remained in all the sides. On the other hand, at the closed area of mesh, slight connective tissue and new bone formation were observed on the uHA/PLLA mesh side but not on the titanium mesh and control sides. Blood components still remained in all the sides, similar to the end area of the mother bone (Fig. 4).

Fig. 4
Fig. 4:
Photomacrographs after 1 week: (A) the uHA/PLLA mesh group, (B) the titanium mesh group, and (C) the control group. Photomicrographs after 1 week: (D) the uHA/PLLA mesh group, (E) the titanium mesh group, and (F) the control group (hematoxylin and eosin staining ×20). UM indicates the uHA/PLLA mesh; TM, titanium mesh; FT, fibrous tissue.

After 2 weeks, fibrous connective tissues and blood components disappeared in the uHA/PLLA and titanium mesh sides, but they still remained partially in the control side at the end area of the mother bone. New bone formation increased in all sides. On the other hand, at the closed area of the mesh, fibrous connective tissues and blood components remained in the uHA/PLLA mesh, titanium mesh, and control sides. New bone formation was observed in the uHA/PLLA and titanium mesh sides but not in the control side (Fig. 5). BMP-2 stained cells were observed in all groups (Fig. 7).

Fig. 5
Fig. 5:
Photomacrographs after 2 weeks: (A) the uHA/PLLA mesh group, (B) the titanium mesh group, and (C) the control group. Photomicrographs after 2 weeks: (D) the uHA/PLLA mesh group, (E) the titanium mesh group, and (F) the control group (hematoxylin and eosin staining ×20). UM indicates uHA/PLLA mesh; TM, titanium mesh; FT, fibrous tissue.

After 4 weeks, fibrous connective tissues and blood components could not be seen in all sides, and bone formation increased at the end of mother bone. On the other hand, at the closed area of the mesh, fibrous connective tissues and blood components were not found in the uHA/PLLA and titanium mesh sides, but fibrous tissues still remained slightly in the control side (Fig. 6). Especially, in the uHA/PLLA group, tight bonding between the surface of the mesh and new bone was observed. Absorption of uHA/PLLA did not occur after 1, 2, and 4 weeks. BMP-2 stained cells decreased in all groups (Fig. 7).

Fig. 6
Fig. 6:
Photomicrographs after 4 weeks: (A) the uHA/PLLA mesh group, (B) the titanium mesh group, and (C) the control group (hematoxylin and eosin staining ×20). UM indicates uHA/PLLA mesh; TM, titanium mesh; NB, new bone.
Fig. 7
Fig. 7:
Photomicrographs of the uHA/PLLA mesh group: (A) after 2 weeks, (B) after 4 weeks. Red arrows show the BMP-2 stained cells (immunohistochemical staining ×400).

Bone Area Ratio

The time-course change was significant by repeated measure ANOVA (between subjects; F = 45.089, df = 2, P < 0.0001; within subjects; F = 1301.416, df = 2, P < 0.0001). After 1 week, there was no significant difference between the groups. However, after 2 weeks, the uHA/PLLA and titanium groups were significantly larger than the control group (P = 0.0001 and P = 0.0001, respectively), although there was no significant difference between the uHA/PLLA and titanium groups. After 4 weeks, a similar tendency was shown; the uHA/PLLA group and titanium group were significantly larger than the control group (P = 0.0410 and P = 0.0139, respectively), although there was no significant difference between the uHA/PLLA and titanium groups (Fig. 8).

Fig. 8
Fig. 8:
This graph is an expression of the ratio of the new bone area. After 1 week, there was no significant difference between the groups. After 2 and 4 weeks, the uHA/PLLA and titanium groups were significantly larger than the control group. There was no significant difference between the uHA/PLLA and titanium groups. *Significant difference atP < 0.05.

The Labeling Index of BMP-2 Positive Cells

With regard to change on time-course, there was no significant difference between subjects, but there was a significant difference within subjects (F = 288.802, df = 2, P < 0.0001) by repeated-measure ANOVA. The labeling index significantly showed the highest value after 2 weeks in the uHA/PLLA group (P < 0.0001), the titanium group (P = 0.0001) and the control group (P < 0.0001). However, there was no significant difference between the groups after 1, 2, and 4 weeks (Fig. 9).

Fig. 9
Fig. 9:
Number of BMP-2-positive cells in 1000 cells. There was no significant difference between the groups in each period. The labeling index significantly showed the highest value after 2 weeks in the each groups.

Discussion

In the present study, application of a mesh clearly showed a beneficial effect on bone regeneration in a defect compared with the control group. Control group new bone formation was more than 80% on bone defect in 4 weeks that the early stages of healing was over in control group. The BMP-2 labeling index showed maximum value after 2 weeks and decreased after 4 weeks in all groups. This suggested that bone formation completed after 4 weeks in all groups and could not increase further after more than 4 weeks. Therefore, 1, 2, and 4 weeks were observation points in this study.

Titanium mesh can be shaped to reconstruction alveolar defects. The inherent rigidity of the titanium mesh maintains the space created under the mesh. This should result in an increase in bone volume compared with conventional barriers. However, the titanium mesh has to be removed before performing implant surgery. One of the main problems in using occlusive membranes is their lack of stiffness, which can procedure a collapse of the barrier toward the bone defects, reducing the space needed for the bone regeneration.16–19 Membranes such as e-PTFE do not have adequate rigidity, making it difficult to maintain the space made at the bone defect.27–29

Although membranes made of biodegradable synthetic polymers, such as PLLA, polyglycolide (PGA), polycaprolactone, and their copolymers, do not require a second surgery, their present limitations regarding their ability to provide space for bone formation, early/late absorption, mechanical strength, and inflammatory reaction during biodegradation.30–34

The use of resorbable materials to stabilize the maxilla-facial skeleton has been reported recently. Synthetic polymers have had a considerable impact on orthognathic procedures. Bioabsorbable polymers currently used to produce osteofixation devices include homopolymers and copolymers. The most commonly used polymers are homopolymers of PLLA and PGAs and copolymers of PGA-polylactide or copolymers of L- and D-lactide, and poly-L/D-lactide.35 There are methods to obtain strong malleable devices from PLLA or poly-L/D-lactide, such as self-reinforced composite (Biosorb FX; Bionximplants, Ltd, Tampere, Finland), as-polymerized PLLA, and drawn PLLA (Fixsorb-MX).36,37

Fixsorb-MX, a bioabsorbable ultrahigh-strength PLLA developed for internal fixation of fractures, was fabricated by a drawing technique developed by Matsusue et al.36,37 The bending strength and antipull-out strength of Fixsorb are higher than those of the human cortex and lower than those of titanium palates. In vitro, Fixsorb plates can maintain 80% of the early bending strength until 12 weeks postoperative. Fixsorb requires a longer period to disappear than PGA/polylactide copolymers. However, it has a higher strength such that it can be used for loading regions.36,37 To produce the PLLA for use in the miniplate system, after dissolution and molding of the PLLA as a biomechanical polymer (molecular weight, about 400 kd), it was mechanically processed into rods made though uniaxial extension into various forms.

As a newly developed product, the uHA/PLLA plate system (Super-FIXSORB-MX) that has completed clinical tests in orthopedic, oral, and maxillofacial surgeries exhibit total resorbability and osteological bioactivity such as the ability to directly bond to bone and has good osteoconductivity and good biocompatibility and high stiffness that is retainable for a long period of time to achieve bone union.38,39 The screw and plate of the uHA/PLLA system each contain 30 and 40 wt % of uHA. The uHA/PLLA plate (Super-FIXSORB-MX) was higher than the PLLA plate (Fixsorb-MX) and human cortical bone in the bending strength (uHA/PLLA: 200–270 MPa; PLLA: 200–250 MPa; cortical bone: 100–200 MPa) and the shearing strength (uHA/PLLA: 120–145 MPa; PLLA: 90–95 MPa; cortical bone: 100 MPa). Shikinami et al26 documented the complete process of bioresorption and bone replacement of rods made of forged composites of uHA/PLLA implanted in the femoral medullary cavities of rabbits. From the results, it was found that morphological changes during biodegradation and bone replacement in the proximal medullary cavity up to 4.5 years and molecular weight and the bending strength had decreased to 50 kd and 200 MPa after 6 months. Therefore, if the strength of the absorbable plate decreases and the bony healing between segments is not complete at least 6 months after osteotomy, the skeletal stability cannot sustain for a long time. However, they have a modulus of elasticity close to that of natural cortical bone, and they can retain a high strength during the period required for bone healing. They can also show optimal degradation and resorption behavior, osteoconductivity, and bone bonding capability, because of the HA ingredient. Furthermore, the uHA/PLLA plate and screw could be recognized in the computed tomography image, although the PLLA plate was completely radiolucent. Therefore, it is easy to judge whether the uHA/PLLA plate or screw breaks or becomes displaced. On the other hand, the uHA/PLLA could be bent with a forceps in 60°C hot water. The stability of bent uHA/PLLA seemed to be higher than bent PLLA, although this study could not defect the difference between the constituent materials per se.

Furthermore, an uHA/PLLA mesh type with similar material properties has been developed recently.

Although various resorbable meshes have been developed, there are few reports on the comparison of bone regeneration activities between the meshes.40–42 The comparison with the titanium mesh may be most important and it can provide useful information for clinicians. For these reasons, the titanium mesh has been the standard mesh for GBR or bone reconstruction and the use of barriers made of the titanium micromesh has been advocated.

Hoogeveen et al42 concluded that a degradable membrane composed of poly(DL-lactide-[Latin Small Letter Open E]-caprolactone) was not suitable for clinical application, because ePTFE and collagen membranes performed equally well and even better than the poly(DL-lactide-[Latin Small Letter Open E]-caprolactone) membrane during experimental studies, although the materialism in this study was no meshes with rigidity. The study of Gutta et al23 showed that the titanium macroporous mesh (Stryker-Leibinger, Kalamazoo, MI; pore size 1.2 mm) facilitated greater bone regeneration compared with the microporous (pore size 0.6 mm) and resorbable meshes (70/30 copolymer of poly[L-lactide-co-D,L-lactide]) with pore size 1.0 mm (Macropore, Inc., San Diego, CA).

Kinoshita et al43 developed a novel macroporous GBR membrane made of copolymer LLA and CL (75:25) containing 30% β-TCP material (P[LLA-CL]/β-TCP). They concluded in the animal study that a macroporous biodegradable P(LLA-CL)/β-TCP membrane has enough mechanical strength to endure soft-tissue compressive force, has sufficient maneuverability to form any shape desired, provides space for bone formation, and causes limited inflammatory reaction in the surrounding tissue, although the comparison with titanium mesh was not provided. However, an osteoconduction effect of β-TCP was not observed, probably because β-TCP was embedded in the polymer during new bone formation.

In this study, the uHA/PLLA mesh and the titanium mesh could induce bone formation, although the resorption of the uHA/PLLA mesh could not be observed within 4 weeks. BMP-2 has effect in osteoblast differentiation; so, BMP-2 increases before new bone formation in this area. The uHA have bone conduction capacity and expect to promote new bone formation around them. Therefore, the observation area was located at the most inferior point of the mesh curve in the coronal. In BMP-2 expression, there was no significant difference between the uHA/PLLA mesh and the titanium mesh. This suggested that bone conduction capacity of uHA/PLLA is equivalent to bone conduction capacity of the titanium mesh.

In other studies, bone regeneration could be obtained with the resorbable mesh; however, the resorbable mesh could induce no new bone formation greater than the titanium mesh.23,42 This suggested that the presence of uHA allows bone inductive activity to be elevated much more than the conventional resorbable mesh. After 1 week, the closure area of the mesh, slight connective tissue, and new bone formation were observed on the uHA/PLLA mesh side but not on the titanium mesh and control sides. This suggested that fibroblasts or osteoblasts could exist in the early stage on the surface of the uHA/PLLA mesh. After 4 weeks, tight bonding between the surface of the uHA/PLLA and new bone was recognized completely but only partially on the surface of the titanium mesh. This suggested an enhanced bonding ability to new because of the presence of uHA. Bioresorption mesh reduced the stiffness so early in the process of absorption that epithelial and fibroblast cells invasion to bone defects. In 4 weeks, uHA/PLLA mesh remained with stiffness and shape, and bone defects under mesh were stable.

Although uHA/PLLA mesh with a thickness of 0.7 mm was used in this study, one with a thickness of 0.5 mm has been developed for alveolar bone augmentation. Therefore, the application will extend to alveolar bone defects in the future. However, the uHA/PLLA is resorbed approximately 3 to 5 years after surgery,26 so that partial removal of the mesh may be necessary when the dental implant surgery is carried out within that period.

This study compared 2 difference mesh materials per se. However, autogenous bone is often used with the GBR membrane or mesh to promote bone formation or for their ability to provide space for bone formation in the membrane or mesh. The application of growth factors that enhance bone formation is attractive because of the absence of patient morbidity.44–51 Substitutable bone materials can also be used with the mesh.52,53 Therefore, the effects of the uHA/PLLA mesh in combination with various substitutable bone materials or growth factors, etc, need to be examined further.

Conclusions

The titanium mesh group was significantly larger than the control group regarding the bone area ratio postoperatively at 2 (P = 0.0001) and 4 weeks (P = 0.0410). The uHA/PLLA group was also larger than the control group regarding the bone area ratio postoperatively at 2 (P < 0.0001) and 4 weeks (P = 0.0139). There were no significant differences between the uHA/PLLA group and titanium mesh group postoperatively at 2 and 4 weeks regarding the BMP-2 labeling index and bone area ratio. This study suggested that the uHA/PLLA mesh and titanium mesh could increase new bone formation more than the absence of a mesh in bone defects. However, there was no significant difference between uHA/PLLA mesh and the titanium mesh in bone augmentation.

Disclosure

The authors claim to have no financial interest, either directly or indirectly, in the products or information listed in the article.

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Keywords:

BMP-2; bone defect; acryl resin

© 2013 by Lippincott Williams & Wilkins, Inc.