Journal of Dental Research

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Effects of Implant Healing Time on Crestal Bone Loss of a Controlled-load Dental Implant
C.C. Ko, W.H. Douglas, R. DeLong, M.D. Rohrer, J.Q. Swift, J.S. Hodges, K.-N. An and E.L. Ritman J DENT RES 2003 82: 585 DOI: 10.1177/154405910308200803 The online version of this article can be found at: http://jdr.sagepub.com/content/82/8/585

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RESEARCH REPORTS
Biomaterials & Bioengineering

C.C. Ko1*, W.H. Douglas1, R. DeLong1, M.D. Rohrer2, J.Q. Swift3, J.S. Hodges4, K.-N. An5, and E.L. Ritman6
1MDRCBB, Department of Oral Science, 2Division of Oral Pathology, Department of Oral Science, 3Maxillofacial Surgery Division, University of Minnesota, and 4Division of Biostatistics and School of Dentistry, University of Minnesota, Minneapolis 55455; 5Orthopedics Biomechanics Laboratory, Mayo Clinic, MN 55905; and 6Department of Physiology & Biophysics, Mayo Medical School, Rochester, MN 55905; *corresponding author, koxxx007@umn.edu

Effects of Implant Healing Time on Crestal Bone Loss of a Controlled-load Dental Implant

J Dent Res 82(8):585-591, 2003

INTRODUCTION

ABSTRACT
The universally accepted concept of delay-loaded dental implants has recently been challenged. This study hypothesizes that early loading (decreased implant healing time) leads to increased bone formation and decreased crestal bone loss. We used 17 minipigs to study implants under a controlled load, with non-loaded implants for comparison. Radiographic and histological assessments were made of the osseointegrated bone changes for 3 healing times (between implant insertion and loading), following 5 months of loading. The effect of loading on crestal bone loss depended on the healing time. Early loading preserved the most crestal bone. Delayed loading had significantly more crestal bone loss compared with the non-loaded controls (2.4 mm vs. 0.64 mm; P < 0.05). The histological assessment and biomechanical analyses of the healing bone suggested that loading and bioactivities of osteoblasts exert a synergistic effect on osseointegration that is likely to support the hypothesis that early loading produces more favorable osseointegration. KEY WORDS: dental implant, early loading, crestal bone loss, biomechanics, micro-CT.

successful dental implant requires that osteointegration be achieved and A cervical bone height be maintained. The hypothesis that strategic early loading encourages such bony responses has not been directly validated. Advocacy of early loading rests largely on clinical reports of in vivo tests (Lefkove and Beals, 1990; Hruska and Borelli, 1993; Lazzara et al., 1998; Piattelli et al., 1998; Szmukler-Moncler et al., 1998; Brnemark et al., 1999; Randow et al., 1999). Brunski et al. (1989), using computer-controlled implant loading applied after a 12-month immobilization healing period, suggested that high mechanical strains lead to micro-damage resorption and crestal bone loss. Other early-loading studies allowed subjects/animals to determine their own masticatory pathway and occlusal forces (Brunski et al., 1979; Piattelli et al. , 1998; Randow et al. , 1999). Although inconclusive, promising observations included denser bone and less crestal bone loss around the early-load implants compared with their delayed-loaded counterparts (Piattelli et al., 1998; Randow et al., 1999). These results are similar to those from orthopedic studies that reported stiffer and more highly mineralized bone resulting from weight-bearing fracture repair (Woo et al., 1984; Woodard et al., 1987; Chao et al., 1989; Gilbert et al., 1989; Aro and Chao, 1990). Few experimental data exist that describe mandibular bone response as a function of implant-healing time under controlled-loading conditions. In this study, we used an intra-oral hydraulic device (Ko et al., 2002) to control in vivo load and healing time quantitatively. The study design had internal controls, which assessed the healing bone's condition before being loaded, and external controls, which assessed the bone after being loaded. Radiographic and histological assessments were made of the osseointegrated bone changes. The hypothesis was that an early application of a mechanical stimulus (decreased implant-healing time) leads to increased bone formation.

METHODS
Experimental Design
Three groups (experimental, internal and external controls) were formed from 17 Sinclair pigs (Sinclair Research Center Inc., Columbia, MO, USA) averaging 1.5 yrs old and 65 kg body weight. Each group was divided into subgroups for nonloaded implant-healing times of 1, 2, or 4 mos (Fig. 1). Right and left 4th premolars were extracted from each pig. After 2 mos of healing, dental implants were placed in the healed extraction sites. Timing of the extraction depended on the pig's assigned group. All procedures were approved by the Animal Care Committee at the University of Minnesota (9910A22661). The experimental group consisted of 12 pigs (4 per healing period) with one implant per mandibular side (unilateral). At the completion of the healing

Received April 9, 2002; Last revision April 22, 2003; Accepted April 25, 2003 A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org.

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2 mos after the extraction. The implant threads at the neck had smaller inter-thread distances (0.29 mm) than did threads at the middle and apical regions (0.54 mm), which had a parallel profile. One-stage surgical procedures used a non-threaded, transmucosal, internal-hex abutment. During the insertion, the crestal bone was trimmed to create a flat surface following the standard clinical procedure used in humans. The implant-abutment gap was kept at 1 mm, mesial-distally, above the flattened bone level. The intra-oral device included a membrane and a servomotor connected via a subcutaneously embedded PVC catheter that could be connected and disconnected every day. This allowed the animals to move freely but to be implant-loaded in vivo. Standard dental bridges protected the implants from uncontrolled chewing effects.

Measurements on Crestal Bone Loss

Radiographs were taken of the experimental and external control groups before and after the five-month loading or non-loading period. The amounts of mesial and distal crestal bone loss along the implant surfaces (CBL) were measured and compared (Fig. 2A).

Figure 1. Study design: surgical schedules, healing and loading times of the implants. The experimental group included 12 pigs; for each pig, 1 implant was used as the experimental implant, and the implant in the contralateral side was used as an internal control. The experimental animals were divided into 3 equal subgroups with one-, two-, and fourmonth implant healing periods. The daily load was applied for 5 mos for all experimental implants. For the internal control on the contralateral side, the implant was allowed to heal for 1, 2, or 4 mos, the same as the experimental implant in the same pig. Since both the internal control and the experimental implants were recovered at the same time, control implants were placed at appropriate times before the animals' death. Five animals with 2 bilateral implants were used as external controls to provide a baseline of bone loss. These also were divided into 3 groups with the same healing periods as the experimental implants. The external control implants stayed in the jaw for the appropriate healing period plus an additional 5 mos with no loading.

Statistics
The statistical analysis used a mixed linear model (MIXED procedure in SAS version 6.12) with the log(CBL+0.5 mm) as the outcome (dependent) variable. The 0.5 mm factor allowed for zero bone loss. The fixed effects were Loading (no or yes) and Month (1, 2, or 4) and their interaction. The random effect was the pig. This design permits the following comparisons to be made: (1) loading vs. no loading (experimental vs. external control), comparing bone adaptation at the end of the implant period; (2) implant healing time (1, 2, or 4 mos) within the experimental group; and (3) length of implant healing time within the external controls. The latter describes crestal bone changes due to non-load healing times and should aid in the delineation between loading and healing effects.

period, a cyclic load (1 Hz and 6.5 N) was applied daily (excluding weekends) for 5 mos to all implants. The small force was rationalized in a previous report (Ko et al., 2002). An intra-oral hydraulic device applied the cyclic load to the experimental implant for 10 min each day. After the five-month fixed loading time, the animals were killed, and the implant and surrounding bone were removed for evaluation. For internal control, we used the same 12 experimental group pigs with the implant inserted on the contralateral extraction site (Fig. 1). The implant was placed at the appropriate time to allow for healing periods of 1, 2, or 4 mos prior to the animals' death and recovery of the non-loaded implants and surrounding bone. Stevenel's Blue and van Gieson's Picro-Fuchsin stains were applied to the harvested tissues so that cell appearance histology of the interfacial tissues could be investigated just before the load. For external control, we used 5 additional pigs. Two implants, 1 per mandibular side, were inserted and allowed to heal for the same 1, 2, or 4 mos as for the experimental group. An additional 5 mos of non-loaded healing time was added, corresponding to the 5 mos of loading for the experimental group, totaling 6, 7, or 9 mos of healing time.

Evaluation of Healing Bone Conditions

To study the mechanism by which healing time affected cervical bone loss under functional loading, we analyzed healing bone condition (e.g., histomorphometry, elasticity, bony architecture, etc.) using the internal control implants. The interfacial bone's histomorphometry was studied with Stevenel's Blue and van Gieson's Picro-Fuchsin stains, which differentially stain calcified bone a bright red with intensity depending on the maturity of the bone, and non-calcified bone and osteoid bright green. The thickness of the unmineralized osteoid seam adjacent to the implant surface was quantified, and the appearances of osteoblasts were compared for different healing times. Elastic moduli were measured by nanoindentation (Ko et al., 1995; Chang et al., 2003). Bone architectures around the implants were evaluated by microcomputed tomography (CT) imaging, which scans implant-bone structures with a resolution of 20 m (Jorgensen et al., 1998; Peyrin et al., 1998). Local mechanical strains were estimated with the use of simplified 2D homogenization finite element models, and the material properties were measured by nanoindentation (see Appendix, www.dentalresearch.org). Interfacial healing bone's porosity, estimated from individual CT slices (i.e., 20-m-thick images, which are not shown) within the 3D images, was found to be 50%, 20%, and 10% for the one-, two-, and four-month healing times, respectively. Detailed boundary conditions and numerical

Implant Design and Surgical Procedures

Smooth titanium threaded dental implants (Walter Lorenz Co., Jacksonville, FL, USA) with tapered neck portions (2) and an intra-oral device (Ko et al., 2002) were placed in the extraction site

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Figure 2. Bone loss comparisons between and among different healing groups. (A) Diagram for measurements showing mesial-distal cross-section of the implant-bone and hydraulic device. Two crestal bone loss measurements per implant (a and b, in mm) were taken along the implant surface from the subtracted radiographic images. (B) Averaged crestal bone loss for experimental and external control groups. The symbol n represents number of measurements obtained, 2 from each implant. The data (CBL, in mm) were averaged for the 3 healing-time subgroups. The loading effect on crestal bone loss significantly depends on healing time (loading-by-month interaction, p = 0.03), increasing as time proceeds. * indicates a significant difference between the experiment and the control. (C) Representative digitally subtracted images. Representative radiographs from experimental and control implants show distinct crestal bone loss associated with delayed loading (four-month group). The displayed control implant healed for 4 mos. Grey represents non-changed areas. Blue and pink indicate bone loss, and red-yellow-green indicate bone gain. We created the images by subtracting the after-loading image from the before-loading image using the S3D x-ray method (University of Minnesota). The images were aligned by optimization of optical topology of the selected areas of x-ray films. Neither the before nor the after image was distorted to match landmarks. The bone loss observed, in general, agrees with the conventional warping method (not shown here).

model convergence were reported previously (Ko et al., 2002). Principal strains (tensile and compressive) and maximum shear strains were compared with the amount of bone loss for each healing stage.

RESULTS
Three animals (1 four-month experimental implant and 2 external controls) died of pulmonary infections unrelated to the surgical procedures. The loading effect on crestal bone loss depended on healing time (loading-by-month interaction, p = 0.03), increasing as healing time got longer (Fig. 2B). Post hoc tests showed a significant difference between loading and non-loading for 4 mos of healing (p = 0.008), but not for 1 mo (p = 0.90) or 2 mos (p = 0.36) of healing. Crestal bone loss during loading for the one-month healing group was slightly larger than that for

the unloaded controls. The two- and four-month healing groups had 2 and 4 times as much bone loss as the external controls, respectively. Differences in average bone loss between the experimental and external control groups were not significant (p = 0.11). The crestal bone of the loaded one-month healing implants was radiographically denser and more opaque than in the other groups, indicating that loading at 1 mo stimulates bone formation more effectively (Fig. 2C). The 3D osseous architecture of CT images showed qualitatively higher bone density, thicker trabeculae, and fewer inter-trabecular spaces surrounding the one-month experimental implants than the twoand four-month experimental implants (Fig. 3). Trabeculae appeared to orient along the long axis of the implant, matching the direction of loading, suggesting that adaptation occurred in response to the early loading. The tendency to such an adaptation pattern under functional loading decreased as the

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Figure 3. Micro-computed tomography (CT) images for qualitative assessments of bony architectures. Upper: After healing but before being loaded, the healing bone near the internal control implant grew more dense as the healing time increased. At one-month healing, the detected bony struts were thin. Perhaps there were thicker unmineralized osteoid seams surrounding the struts, as shown in Fig. 4. Four months healing resulted in mature, thicker, trabeculi with less inter-trabecular space; however, trabeculi were randomly aligned without the preferred orientation. Lower: After five months loading (experimental implant), however, bone density decreased as the non-loaded healing period increased. The one-month healing bone appeared to deposit much more dense calcified bone in response to loading than the two- and four-month healing bone. The bone struts in the one-month and two-month experimental groups were aligned in the direction at which the load was applied. The trabecular bone in the four-month experimental group, however, displayed a random pattern, unrelated to loading direction. The bar on the right lower corner of each image indicates a scale of 1 mm.

healing time increased. Unmineralized osteoid tissues adjacent to the implants were more abundant and thicker in the one-month (covering 17 + 3% of bone area) and two-month (8.4 + 2.3%) healing group tissues than in the four-month healing group tissue (4 + 3%), providing more viable tissue at the early healing stage (Fig. 4). Histomorphometric results showed that the one-month healing tissue consisted of newly forming bone in various degrees of maturity, with numerous spindle-shaped osteoblasts. The fourmonth healing tissue contained new bone with uniform maturity and fewer cuboidal osteoblasts. Nanoindentation showed that the healing bone's stiffness gradually increased with increasing healing time. Mean elastic moduli obtained from the 3 healing groups were 7.3 GPa, 7.9 GPa, and 8.4 GPa for the one-, two-, and four-month groups, respectively; thus, early-healing bone is more compliant under functional loading. The finite element analysis (Appendix, www.dentalresearch.org) suggested that the highest local minimum principal strain in healing bone was located at the

crestal region, and was -71.4 , -56.2 , and -39.2 for the one-month, two-month, and four-month loading groups, respectively. At the same location, maximum principal strain was 26.2 , 25.7 , and 16.3 , respectively; maximum shear strain was 48.8 , 39.3 , and 27.5 , respectively.

DISCUSSION
This study tested the hypothesis that early loading on dental implants stimulates favorable bone integration. Two parameters of functional loading (loading magnitude and implant healing time) were objectively and quantitatively controlled. Shorter healing time promoted denser bone and less crestal bone loss, both of which support the above hypothesis. Characterization of healing bone properties (biological and mechanical) and estimates of in vivo strains provided preliminary insight about how and why functional loading affects alveolar bone response. The present load regime applied an axial loading for a single 10-minute period daily. Clearly, lateral forces act on

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implants because of occlusal morphology. However, the maximum lateral (off-axis) force of 30 N is one-tenth of the maximum vertical (axial) force of 400 N (Fontijn-Tekamp et al., 1998; Richter, 1998). With only 10 min of axial load, our results strongly suggest that loading and healing time synergistically affect osseointegration. Bone changes appeared to be a mechanical adaptation following long-term exercise (5 months' loading), as supported by x-ray and CT observations. Increasing daily loading time or adding off-axial load would not likely affect overall outcomes. This study does not determine whether excessive forces would give different results. From finite element analysis (Appendix, www.dentalresearch.org), a force of 1950 N (300 times 6.5 N) would raise tissue strain from the current 70 to 24,000 , which could cause microdamage of the interfacial bone (Brunski et al., 1989). This is very unlikely to happen. Our results indicate that healing time affects crestal bone loss only for the loaded implants. Delayed loading resulted in twice the amount of bone loss as early loading, consistent with the results reported by Randow et al. (1999). The range of bone loss of 1.71 to 2.99 mm in delayedloading implants was within the range of 0.4 to 4 mm reported by Isidor (1996). For earlyloading implants, bone loss Figure 4. Histology of implant-bone interface with Stevenel's Blue and Van Gieson's picro-fuschin stain. Calcified bone stains a bright red, with variations in intensity depending on the maturity of the bone. Non-calcified bone ranged from 0.0 mm to 1.6 mm, and osteoid stain bright green; osteoblasts stain blue. The implant (black) is on the right side of the images. The in good agreement with percentage of osteoid seams over the mineralized areas was 17%, 8.4%, and 4% for the one-, two-, and fourBrnemark et al. (1999). The month healing tissue, respectively. These data were sampled within 300 m by 300-m squares adjacent to the control (non-load) implants implant surfaces. For the one-month healing tissue, the newly forming bone was in various degrees of maturity, showed no adaptive pattern with numerous spindle-shaped osteoblasts with undistinguishable boundaries between cells and denser nuclei. The four-month healing tissue contained new bone with uniform maturity and relatively fewer osteoblasts, being (e.g., denser bone) and had bone cuboidal. The bar on the right upper corner of each image indicates a scale of 10 m. loss (0.3 to 1.0 mm) similar to that of the early-loading implants, which suggests that immobilization, becomes susceptible to resorption. We biological width (soft-tissue sealing) is probably stable, as described by Cochran et al. (1997) and Hermann et al. (2000). estimated that tissue strain is halved when loading started at the fourth month of healing, due to the stiffened interface. The The absence of exudation and the absence of continuous decreased strain may decrease loading efficacy for stimulating radiolucencies around peri-implant spaces suggested that infectious resorption was not the major cause of bone loss. bone formation. However, the tissue strain estimated in this study was much smaller than the 1000 found for stimulating It is unclear why healing alveolar bone, after prolonged
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non-surgically altered bone (Rubin and Lanyon, 1985) and smaller than other suggested strain thresholds ranging from 1500 to 3500 (Frost, 1983; Turner et al., 1997). We hypothesize that strain thresholds promoting bone formation may differ between normal and wounded alveolar bone because their cell populations and tissue compositions are different. This hypothesis remains to be tested in future studies. Nevertheless, our 70 concurs with recent reports by Rubin and co-workers (Qin et al. , 1998; Rubin et al., 2001), who found that 70 could provide an anti-resorptive effect on an isolated turkey ulna. Rubin et al. and Qin et al. used a higher frequency of loading (30 Hz), while we used a low frequency (1 Hz). Although our studies and Rubin's studies found the same strains, because the frequencies differed, the strains may not act on the same types of cells or tissue structures. Analysis of our histomorphometric data indicated that the enriched osteoid in early healing disappears in prolongedhealing tissue. Individual osteoblasts in prolonged-healing tissues appear more distinguishable from neighbor cells, are more cuboidal, and apparently "park" on the surface of mature bone. Osteoblasts in early-healing tissue show boundaries indistinguishable from those of neighboring cells and contain much denser nuclei stain. The osteoblasts usually lie on a thick (15-20 m) osteoid and seem to actively produce more mineral matrix for maturation than do prolonged-healing osteoblasts, perhaps providing better proliferation activity for mechanical stimuli. Studies in distraction osteogenesis show that, in healing bone, mechanical stimuli more readily produce bone morphogenic proteins in the early stage than in the delayed stage (Sato et al., 1999). There may be a link between cell appearance and gene expression under functional implant loading. Gene expression under various loading magnitudes should be studied for this relationship to be characterized. Extrapolation of current animal data to human implants needs to be carefully considered, because pig bone remodels slightly faster than human bone. However, with the small strain values of 70 estimated in our pig model, far below the microdamage strains of 24,000 (Brunski et al., 1989), it is not unlikely that the same loading would benefit humans clinically.

ACKNOWLEDGMENTS
The authors thank Mr. Manuel Chan for his assistance in data analysis, Mr. H.S. Prasad for histopathological sectioning, and Dr. C.-L. Lin for finite element analyses. This study was supported, in part, by the Whitaker Foundation RG97-0455, Minnesota Dental Research for Biomaterials and Biomechanics, Graduate School University of Minnesota, and by NIH/NIDCR P30-DE09737.

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