Temperature Threshold Values of Bone Necrosis for Thermo-Explantation of Dental Implants—A Systematic Review on Preclinical In Vivo Research

Purpose: Very high or low temperatures will lead to bone damage. The objective of this review was to analyze threshold values for thermal bone necrosis. Methods: Histological animal studies evaluating thermal effects on bone necrosis were selected via electronic and hand searches in English and German language journals until 1 November 2019. The outcome measures were temperature-exposure intervals and laser settings effecting bone damage. Furthermore, investigated parameters were the bone-to-implant contact ratios (BIC) and infrabony pockets around dental implants after thermal treatment. For quality assessment of studies, the CAMARADES study quality checklist was applied. Results: A total of 455 animals in 25 animal studies were included for data extraction after screening of 45 titles from 957 selected titles of the MEDLINE (PubMed), The Cochrane Library, Embase and Web of Science search. The threshold values for bone necrosis ranged between 47 °C and 55 °C for 1 min. A threshold value for cryoinsult and laser treatment has not yet been defined. However, temperatures in the vicinity of 3.5 °C produce a histologically proven effect on the bone and in the surrounding tissue. At 50 °C for 1 min, BIC values significantly decreased and infrabony pockets increased. Bone quality had an influence on the outcome, as cancellous bone suffered higher bone damage from thermal treatment compared to cortical bone. Conclusion: No clear threshold value for bone necrosis is available according to the current literature for warm and cold stimuli. More in-depth and clinical studies are required to provide further insights in assessing the potential of thermal necrosis for implant removal.


Introduction
The exposure of bone to high temperatures will lead to bone damage and necrosis [1]. Not only heat, but also targeted cooling affects the bone structure and vital cells in the surrounding tissue [2,3]. A single cold stimulus at −10 • C inevitably leads to surrounding skin and bone necrosis. [2,3]. This is also called "cryoinsult".
(animal study) OR in vivo OR histopathology AND thermal osteonecrosis) OR thermo necrosis) OR thermal bone damage) OR heat induced osteonecrosis) OR cryoinsult induced osteonecrosis. With regard to The Cochrane Library search, the following combinations were used: histopathology in All Text AND thermal osteonecrosis in All Text OR thermo necrosis in All Text OR thermal bone damage in All Text OR heat induced osteonecrosis in All Text OR cryoinsult induced osteonecrosis in All Text.
For the Web of Science search, the following terms and combinations were applied: topic: (animal study) and topic: (in vivo) and topic: (histopathology) and topic: (thermal osteonecrosis) or topic: (thermo necrosis) or topic: (thermal bone damage) or topic: (heat induced osteonecrosis) or topic: (cryoinsult induced osteonecrosis).
In addition, the electronic search was complemented by a manual search of the reference lists of all included full texts. For the electronic MEDLINE search, a reference management software (Endnote X 8.2, Thomson Reuters) was used. The obtained publications from The Cochrane Library search were also imported into the reference management software and finally screened.

Inclusion Criteria
The inclusion criteria for the studies were as follows: (1) In vivo animal studies (2) Studies investigating thermal bone damage by histopathology (3) Studies at all levels of evidence, except case reports and expert opinion (4) Studies reporting on at least one of the outcome measures (5) Language: German or English

Exclusion Criteria
Studies from which data on selected outcome variables could not directly be retrieved or calculated were not considered. Systematic reviews, studies with missing thermal input, in vitro studies, randomized clinical trials and other clinical studies and cadaver studies were excluded.

Selection of Studies
After elimination of duplicates, 2 calibrated reviewers (KK, AM) independently reviewed titles, abstracts, and full texts in accordance with the inclusion criteria. All titles were included in the abstract screening. If the information in the abstract was not clear enough for selection purposes, the full text was reviewed.

Data Extraction
Data extraction was independently performed on all included studies using data extraction tables. If data for individual parameters of the systematic review was sufficient, a meta-analysis was performed. Any disagreement with regard to inclusion and exclusion was resolved by discussion between the reviewers. In case of missing or unclear data, or if the information was still not sufficient for evaluation, the study was excluded for the present review (Table 1). For quality assessment of studies, the CAMARADES study quality checklist was applied [25]. The bias evaluation included sample size calculation, animal exclusion or the blinded assessment of outcome, blinded induction of the model, statement of potential conflicts, random allocation, compliance with the animal welfare regulations, and whether the studies were published in peer-reviewed journals.

Statistical Analysis
BIC around implants after thermal treatment and infrabony implant pockets after thermal treatment were considered as outcomes to describe differences between test and control groups after thermal treatment. Effect sizes of continuous outcomes for each study were reported as mean differences, along with 95% confidence intervals (CI We planned to conduct a meta-analysis only if studies were comparable, i.e., if treatments, participants, and the underlying clinical question are similar enough for pooling. To evaluate the statistical heterogeneity between studies, the Q-test of homogeneity and I2 statistics as a percentage of the total variability across studies were used. The significance level of the Q-test was set to 0.10, and I2 values were categorized as 25%, 50%, and 75% for low, moderate, and high heterogeneity, respectively [26]. All analyses were performed with RevMan 5.3.5 (Cochrane C., London, UK). Given the clinical heterogeneity across trials, we have abstained from summarizing the study specific effects into one overall effect. Results were expressed by effect sizes for each study and corresponding forest plots.
A total of 455 animals were evaluated across multiple different species, including 224 rats, 117 rabbits, 70 emus, 41 sheep, and 10 dogs. 18 studies assessed temperature/time intervals and seven studies investigated the effect of laser application on bone necrosis. For temperature control, 11 studies used thermocouples and two infrared thermography. Bony regions of interest were 8 mandibles, 6 femurs, 5 tibiae, 4 calvarias, and one maxilla and iliac crest. Histopathological parameters evaluated 24 cortical and 16 cancellous sites. Due to the quality of reported data and the high clinical heterogeneity between studies, no meta-analysis was performed; nevertheless, the effect estimates of each study regarding BIC (Bone-to-Implant Contact) around implants and infrabony implant pockets after thermal treatment were presented (Figures 2 and 3). A total of 455 animals were evaluated across multiple different species, including 224 rats, 117 rabbits, 70 emus, 41 sheep, and 10 dogs. 18 studies assessed temperature/time intervals and seven studies investigated the effect of laser application on bone necrosis. For temperature control, 11 studies used thermocouples and two infrared thermography. Bony regions of interest were 8 mandibles, 6 femurs, 5 tibiae, 4 calvarias, and one maxilla and iliac crest. Histopathological parameters evaluated 24 cortical and 16 cancellous sites. Due to the quality of reported data and the high clinical heterogeneity between studies, no meta-analysis was performed; nevertheless, the effect estimates of each study regarding BIC (Bone-to-Implant Contact) around implants and infrabony implant pockets after thermal treatment were presented (Figures 2 and 3).

Temperature and Exposure Time Leading to Bone Damage
Cold and warm stimuli lead to bone damage and should therefore be separated. Three studies [2,29,31] reported cryoprobes in an emu model. The aim was to induce femoral head necrosis with temperatures ranging from −273 °C to −10 °C. The exposure time varied between 15 s and 9 min, producing bone necrosis in all cases. The lowest necrosis volume was reported at a temperature of A total of 455 animals were evaluated across multiple different species, including 224 rats, 117 rabbits, 70 emus, 41 sheep, and 10 dogs. 18 studies assessed temperature/time intervals and seven studies investigated the effect of laser application on bone necrosis. For temperature control, 11 studies used thermocouples and two infrared thermography. Bony regions of interest were 8 mandibles, 6 femurs, 5 tibiae, 4 calvarias, and one maxilla and iliac crest. Histopathological parameters evaluated 24 cortical and 16 cancellous sites. Due to the quality of reported data and the high clinical heterogeneity between studies, no meta-analysis was performed; nevertheless, the effect estimates of each study regarding BIC (Bone-to-Implant Contact) around implants and infrabony implant pockets after thermal treatment were presented (Figures 2 and 3).

Temperature and Exposure Time Leading to Bone Damage
Cold and warm stimuli lead to bone damage and should therefore be separated. Three studies [2,29,31] reported cryoprobes in an emu model. The aim was to induce femoral head necrosis with temperatures ranging from −273 °C to −10 °C. The exposure time varied between 15 s and 9 min, producing bone necrosis in all cases. The lowest necrosis volume was reported at a temperature of

Temperature and Exposure Time Leading to Bone Damage
Cold and warm stimuli lead to bone damage and should therefore be separated. Three studies [2,29,31] reported cryoprobes in an emu model. The aim was to induce femoral head necrosis with temperatures ranging from −273 • C to −10 • C. The exposure time varied between 15 s and 9 min, producing bone necrosis in all cases. The lowest necrosis volume was reported at a temperature of −10 • C and an exposure time of 9 min. Goetz et al., 2008 concluded that temperatures below 3.5 • C to 1 • C produced histologically proven bone necrosis.
The remaining part of 15 studies analyzed the effect of heat on bone structure at temperatures ranging from 33 • C to 190 • C. Heat stimuli of 44 • C and 1 min had not caused any damages on bone [12]. First tissue reactions, such as hyperemia, started at 47 • C for 1 min. Bone resorption and dead osteocytes have been reported at temperatures up to 50 • C [13]; however, no long-term thermal bone damage could be evaluated due to bone remodeling [14]. Furthermore, Lundskog, 1972  From those studies, the heat boundary stimuli of bone necrosis, which is no relation with species and sites, are likely to be 48 to 50 • C for 1 min, and that is almost compatible with Langskog's report. Nevertheless, one study [39] stated that the threshold value must be 55 • C with an exposure time of 1 min. According to Arnoldi et al., 2012, a high temperature of 180-190 • C for only a very short time of a few seconds did not lead to bone necrosis.

Laser Settings Producing Bone Damage
Stubinger et al. (2011) assessed that, with a cooled Er:YAG laser with an energy output of up to 1000 mJ/pulse and 12 Hz, no thermal damage resulted. One study assessing an Er:YAG laser (cooled) with the settings of 2 W and 20 Hz led to a small bone necrosis layer directly after irrigation [43]. On the other hand, a CO 2 laser (not cooled) at 20 W and 2 kHz produced an active resorption by osteoclasts; however, the histologic changes had less than 40 pm layer thickness after 6 weeks [38]. Pourzarandian et al., 2004 compared the Er:YAG and CO 2 lasers. For the Er:YAG laser, the results after 14 days were a carbonized tissue that covered the treated surface, spots of mineralization, and new bone formation in a percentage of the treated area. Compared to that, there was no significant new bone formation after application of the CO 2 laser.

BIC around Implants after Thermal Treatment
A temperature elevation up to 38.9 • C for 4 min and 1-month follow-up [28] showed similar BIC values around treated implants (mean 43.1% SD 2.80) and untreated implants (45% SD 1.30).
Higher temperature values [17,18] of 60 • C for 1 min led to reduced BIC values around heated implants (mean 25.42% SD 1.49 in cancellous bone, mean 27.23% SD 12.44 in cortical bone) versus untreated implants (mean 38.05% SD 1.38 in cancellous bone, mean 31.94% SD 18.10 in cortical bone). However, only the implants inserted in the cancellous bone [17] presented significant differences. Similarly, at a lower temperature of 50 • C for 1 min, the cancellous bone led to a significantly lower BIC value, whereas around implants that were inserted in more cortical bone [18] no deviating BIC values were evaluated.

Infrabony Implant Pockets after Thermal Treatment
Higher temperature values [17,18] not only led to loss of bone contact, but also the infrabony pockets next to the treated implant increased. Pocket values ranged around heated implants (60 • C for 1 min) at a mean 3.11 SD 0.33 in cancellous bone, mean 1.07 SD 0.44 in cortical bone and around untreated implants at a mean 1.21 SD 0.16 in cancellous bone, mean 0.56 SD 0.49 in cortical bone. The infrabony pockets were significantly larger compared to the control group in the cancellous area of the iliac crest of the sheep at 50 • C for 1 min (Figure 3) [17]. In contrast, the cortical area of the sheep mandible did not present any significant differences between the test and control groups for the same temperature/time interval. On the other hand, at 60 • C for 1 min, treated implants showed larger infrabony pockets for both treated groups, the cortical and cancellous groups (Figure 3). However, only the implants inserted in the cancellous bone [17] presented significant differences. The bone quality has had an influence on the outcome, as the iliac crest presented greater amount of bone pockets compared to the mandible.

Risk of Bias in Individual Studies
For quality assessment of studies, the CAMARADES study quality checklist was applied (Figure 4).

Discussion
The purpose of this review was to define threshold values for thermal bone necrosis in order to assess the potential of thermal necrosis for implant removal. Based on our findings no clear threshold value for bone necrosis is available according to the current literature. The researchers focused on several parameters, such as temperature and exposure time leading to bone damage, laser settings producing bone damage, BIC values around implants, and infrabony implant pockets after thermal treatment.
In recent years, advanced water-cooling systems have been quite effective in reducing heat storage during implant drilling. Therefore, there is currently only a limited number of recent clinical studies on the topic of heat-induced bone necrosis and implant loss available. Several authors have investigated the temperature thresholds leading to jaw necrosis with widely varying results [12,14,30,32]. The differences in the values may be attributed in part to the diversity of the experiments and the many different influencing variables such as blood flow, bone structure, and more [27]. In 1983, Eriksson and Albrektsson stated a temperature of 47 °C with an exposure time of 1 min as the threshold value for bone damage [12]. This value reflects the lower limit of possible damage and corresponds to the threshold values published by Lundskog (50 °C with an exposure time of 30 s) [32]. Berman et al., 1984 concluded that cortical bone is more resistant to heat than cancellous bone [1]. Jacobs et al., 1972 did not explicitly aim to determine a threshold value; however, they produced osteonecrosis at lower temperatures [46]. Other studies describe damage at temperatures from 43 to 68 °C [41,47].
A similar effect to that of heating can be achieved by targeted cooling. Temperatures in the range of 1 °C to 3.5 °C produce a histologically proven effect on the bone and in the surrounding tissue (max. 0.7 mm) [2,3]. An isotherm of 3.5 °C was published by Goetz et al., 2008 which best corresponded to the boundary of the osteonecrotic lesions; however, this was a cadaver study without in vivo results [3]. This review focused only on in vivo animal studies. A single cold stimulus from −10 °C to −20 °C inevitably leads to surrounding skin and bone necrosis.
Furthermore, it is known that osteocytes can be damaged by exposure to temperatures above 45 °C for 15 s [44]. The degree of damage depends on the temperature and the exposure time. Several threshold values for bone necrosis have been announced by multiple studies. In 1972, Lundskog claimed 50 °C for 30 s [32], and in 1953, Rouiller stated 55 °C for 1 min for the exact threshold boarder [39]. Both investigations took place in rabbits. However, Lundskog studied the cortical and cancellous tibia bone and Rouiller preferred the cortical calvaria, metatarsi, and radii. It may be hypothesized

Discussion
The purpose of this review was to define threshold values for thermal bone necrosis in order to assess the potential of thermal necrosis for implant removal. Based on our findings no clear threshold value for bone necrosis is available according to the current literature. The researchers focused on several parameters, such as temperature and exposure time leading to bone damage, laser settings producing bone damage, BIC values around implants, and infrabony implant pockets after thermal treatment.
In recent years, advanced water-cooling systems have been quite effective in reducing heat storage during implant drilling. Therefore, there is currently only a limited number of recent clinical studies on the topic of heat-induced bone necrosis and implant loss available. Several authors have investigated the temperature thresholds leading to jaw necrosis with widely varying results [12,14,30,32]. The differences in the values may be attributed in part to the diversity of the experiments and the many different influencing variables such as blood flow, bone structure, and more [27]. In 1983, Eriksson and Albrektsson stated a temperature of 47 • C with an exposure time of 1 min as the threshold value for bone damage [12]. This value reflects the lower limit of possible damage and corresponds to the threshold values published by Lundskog (50 • C with an exposure time of 30 s) [32]. Berman et al., 1984 concluded that cortical bone is more resistant to heat than cancellous bone [1]. Jacobs et al., 1972 did not explicitly aim to determine a threshold value; however, they produced osteonecrosis at lower temperatures [46]. Other studies describe damage at temperatures from 43 to 68 • C [41,47].
A similar effect to that of heating can be achieved by targeted cooling. Temperatures in the range of 1 • C to 3.5 • C produce a histologically proven effect on the bone and in the surrounding tissue (max. 0.7 mm) [2,3]. An isotherm of 3.5 • C was published by Goetz et al., 2008 which best corresponded to the boundary of the osteonecrotic lesions; however, this was a cadaver study without in vivo results [3]. This review focused only on in vivo animal studies. A single cold stimulus from −10 • C to −20 • C inevitably leads to surrounding skin and bone necrosis.
Furthermore, it is known that osteocytes can be damaged by exposure to temperatures above 45 • C for 15 s [44]. The degree of damage depends on the temperature and the exposure time.
Several threshold values for bone necrosis have been announced by multiple studies. In 1972, Lundskog claimed 50 • C for 30 s [32], and in 1953, Rouiller stated 55 • C for 1 min for the exact threshold boarder [39]. Both investigations took place in rabbits. However, Lundskog studied the cortical and cancellous tibia bone and Rouiller preferred the cortical calvaria, metatarsi, and radii. It may be hypothesized that in the same individual, different regions lead to divergent threshold values. Therefore, it remains unclear if these values are transferable to the jawbone, especially the human jawbone.
Furthermore, defined threshold values for cold stimulus and laser treatment leading to bone necrosis have not yet been published. Bone irritations of −10 • C or a laser setting of a cooled Er:YAG laser with 20 Hz and 2 W evidently led to bone necrosis. In particular, it remains difficult to compare different laser devices, as there is a variety of variable and adjustment possibilities, such as fiber thickness, device, wavelength, distance between objects, energy output, and continuous-wave or pulsating settings.
A critical reflection on this review showed that not all studies used thermocouples for exact temperature measurement. Thermography and thermocouples were described as temperature control systems. Especially with thermocouples their position is finally decisive. Internal systems are located directly at the point of measurement, whereas external remote systems cannot detect the individual temperature loss over the individual distance [48]. Additionally, the reduced thermal conductivity and the inhomogeneous properties of the bone must be considered. In contrast, the infrared thermographic camera only records the surface temperature, so that the temperature at the actual measuring point can only be determined to a limited extent. The different threshold values could either be explained by the different measurement techniques, or the individual bone characteristics during examination.
Furthermore, due to different methods (e.g., different thermal devices, different species and bone areas), the overall threshold values may be considered as an average value. Additionally, the statistical results of this systematic review should be interpreted considering the high degree of study heterogeneity. Due to the heterogeneity of the current literate and in order to avoid misleading results no meta-analysis was performed.
The current literature could not give a clear threshold to clinicians concerning heat generation and osteonecrosis because studies presented widely varying results. It is difficult to apply these numerical results directly to humans. Each animal species has an individual bone metabolism that can differ from humans. Up to now it is completely unclear whether an implant can be loosened in this temperature range without triggering a starving necrosis. In order to avoid thermal bone damage in humans, the limit of 47 • C for 1 min should not be exceeded. However, in order to further explore thermo-explantation, these numerical values can only be used as a guideline and before applied to humans further preclinical studies should follow. Based on these findings more preclinical studies regarding the effect of temperature and time intervals on the development of a limited bone necrosis within the range between 47 • C and 55 • C for 1 min are necessary.

Conclusions
It can be concluded that no clear threshold value for bone necrosis is available according to the current literature. The values ranged between 47 • C and 55 • C for 1 min. A threshold value for cryoinsult and laser treatment has not yet been defined. Bone quality had an influence on the outcome, as cancellous bone suffered higher bone damage compared to cortical bone. It is suggested that more in-depth and clinical studies are required to provide further insights in assessing the potential of thermal necrosis for implant removal.

Conflicts of Interest:
The authors declare no conflict of interest. The sponsors had no role in the design, execution, interpretation, or writing of the study.