Skip to main content
Browse Subject Areas

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

The minipig intraoral dental implant model: A systematic review and meta-analysis

  • Marta Liliana Musskopf ,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing (MLM); (CS)

    Affiliation Division of Comprehensive Oral Health–Periodontology, Laboratory for Applied Periodontal & Craniofacial Research, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America

  • Amanda Finger Stadler,

    Roles Data curation, Investigation, Methodology, Validation, Writing – review & editing

    Affiliation Division of Comprehensive Oral Health–Periodontology, Laboratory for Applied Periodontal & Craniofacial Research, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America

  • Ulf ME Wikesjö,

    Roles Conceptualization, Supervision, Validation, Writing – original draft, Writing – review & editing

    Affiliation Division of Comprehensive Oral Health–Periodontology, Laboratory for Applied Periodontal & Craniofacial Research, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America

  • Cristiano Susin

    Roles Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review & editing (MLM); (CS)

    Affiliation Division of Comprehensive Oral Health–Periodontology, Laboratory for Applied Periodontal & Craniofacial Research, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America



The objective of this report was to provide a review of the minipig intraoral dental implant model including a meta-analysis to estimate osseointegration and crestal bone remodeling.


A systematic review including PubMed and EMBASE databases through June 2021 was conducted. Two independent examiners screened titles/abstracts and selected full-text articles. Studies evaluating titanium dental implant osseointegration in native alveolar bone were included. A quality assessment of reporting was performed. Random-effects meta-analyses and meta-regressions were produced for bone-implant contact (BIC), first BIC, and crestal bone level.


125 out of 249 full-text articles were reviewed, 55 original studies were included. Quality of reporting was generally low, omissions included animal characteristics, examiner masking/calibration, and sample size calculation. The typical minipig model protocol included surgical extraction of the mandibular premolars and first molar, 12±4 wks post-extraction healing, placement of three narrow regular length dental implants per jaw quadrant, submerged implant healing and 8 wks of osseointegration. Approximately 90% of studies reported undecalcified incandescent light microscopy histometrics. Overall, mean BIC was 59.88% (95%CI: 57.43–62.33). BIC increased significantly over time (p<0.001): 40.93 (95%CI: 34.95–46.90) at 2 wks, 58.37% (95%CI: 54.38–62.36) at 4 wks, and 66.33% (95%CI: 63.45–69.21) beyond 4 wks. Variability among studies was mainly explained by differences in observation interval post-extraction and post-implant placement, and implant surface. Heterogeneity was high for all studies (I2 > 90%, p<0.001).


The minipig intraoral dental implant model appears to effectively demonstrate osseointegration and alveolar bone remodeling similar to that observed in humans and canine models.


Per-Ingvar Brånemark studying micro-circulation using a rodent model fortuitously discovered that devices made from titanium while biocompatible also formed an intimate relationship with adjoining bone [1]. This initial discovery was confirmed in humans and every year millions of patients benefit from titanium dental implant-anchored prosthetic rehabilitations. Animal models have been used extensively to study soft and hard tissue responses to dental implant materials and designs over the last 50 years [2]. Thousands of animal studies have been published reporting on novel implant technologies, surgical techniques, and alveolar bone augmentation strategies. The use of rodent models and extra-oral sites in large animal models provide insights into the biology of osseointegration and represent useful screening tools of new designs and technologies; however, they fail to mimic the complexity of the oral environment and uniqueness of the alveolar bone. Only large animal intraoral models allow the use of clinically relevant dental implants and prosthetic components.

Historically, canine and nonhuman primate platforms have been preferred for oral/maxillofacial research, however porcine/minipig models have emerged as an important alternative [3,4]. The minipig has been widely used in biomedical research including cardiovascular, orthopedic, and dermatologic settings due to similarities with humans in the anatomy and physiology [5]. Regarding the oral cavity, minipigs feature deciduous, mixed, and permanent dentitions; the first permanent molar is the first permanent tooth to erupt, and there is an extended mixed dentition period. Whereas the minipig and humans share tooth types, the minipig features 6 maxillary and mandibular incisors rather than 4, and 8 maxillary/mandibular premolars rather than 4. Periodontally healthy minipigs feature shallow to moderate probing depths [3]. Keratinized tissue width averages 2.7±0.8mm [6]. Minipig and humans have similar bone formation and remodeling rates [7]. Pilawski et al. (2021) compared maxillary alveolar bone structure in minipigs and humans using radiography, histology, and immunohistochemistry [8]. Histologically, the collagen organization, osteocyte density, alveolar bone remodeling, and mineral apposition rate were similar. Radiographically, bone architecture, bone mineral density, and bone volume were also comparable [8]. Bone formation in gap defects has been estimated to be 1.2–1.5mm per day in minipigs and 1.0–1.5mm per day in humans [2].

Herein, we report a systematic review and meta-analysis of a minipig intraoral dental implant model used to evaluate dental implant technologies and study peri-implant tissue healing. Histological observations from minipig, canine and human studies are discussed in a clinical perspective.


The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) was followed during the review process and reporting [9].

Focused questions

The literature was systematically searched to answer the following focused questions:

  1. What are the osseointegration and crestal bone remodeling levels in the minipig intraoral dental implant model?
  2. Which factors explain the different results observed in the literature?

Search strategy

An electronic search of MEDLINE (via PubMed) and EMBASE up to June 2021 was conducted using the following combination of MeSH terms:

For PubMed

((((dental implant[MeSH Terms]) OR (dental implantation[MeSH Terms])) OR (tooth implantation[MeSH Terms])) AND ((miniature swine[MeSH Terms]) OR (miniature pig[MeSH Terms]) OR (micropig)))


(’minipig’ OR ’miniature swine’ OR ’mini pig’ OR ’miniature pig’ OR ’micropig’) AND (’tooth implant’ OR ’dental implant’ OR ’tooth implantation’) AND [embase]/lim

A manual search of the list of references of the included studies was performed. No efforts were undertaken to search the grey literature.

Study selection

Original articles using minipigs, intraoral sites, titanium dental implants, and evaluating osseointegration histologically were included. Publications without proper statistical analysis including central tendency measures (means or medians) and variability (standard deviation or data range) were excluded from the analysis.

Animals’ characteristics.

Only studies with data of systemically healthy animals were included. For those studies that also included animals with systemic diseases/conditions, only data from healthy controls were used.

Type of treatments.

Only data derived from implants placed in native bone were included. For studies that placed implants in augmented bone or that carried out implant placement concomitantly with guided bone regeneration, only data from control groups were used.


The primary outcome of interest was bone-implant contact (BIC). Secondary outcomes were distance between the implant platform and the first bone-implant contact (first BIC) and distance between the implant platform and the crestal alveolar bone. Osseointegration was defined as the percentage of BIC measured along the length of the implant within the extension of alveolar bone/total perimeter of the implant. First BIC was defined as the distance between the most coronal BIC and the implant platform. Crestal bone level/loss was defined as the distance between the most coronal extent of crestal bone along the implant and the implant platform.

Data synthesis

Two reviewers (MLM and AFS) independently screened titles and abstracts through the databases. Any disagreement was solved by consensus between the reviewers or by a third reviewer (CS). One examiner (MLM) extracted data from the selected studies, and data was reviewed for completeness and accuracy (CS).

Studies characteristics and quality of reporting

Studies characteristics, including sample, preparatory and implant placement protocols, histology performed, and main findings are summarized in table format. Quality assessment of the studies included in the meta-analyses was evaluated based on selected items from ARRIVE checklist (see S1 Table) [10].

Statistical analysis

Meta-analyses were performed for histological parameters for which data could be extracted from at least 3 studies. Articles reporting means and standard deviations were included in the meta-analysis. Studies that only reported medians, data range and sample size were also included, and means and standard deviations were calculated using appropriate formulas [11]. Studies that only presented results in graphic format were not included. Data analysis was performed using statistical software (Stata 17 for Mac, Stata Corporation, College Station, TX, USA). Random effects models were used to estimate the effect sizes and 95% confidence intervals (CI) [12]. Random-effects meta-regression analysis was carried out to investigate factors (moderators) that could help explain between-study heterogeneity. Animal strain and age, healing after extraction and implant placement, staging, type of healing, loading and implant surface were considered. The restricted maximum likelihood method was used. The heterogeneity of effects among studies was assessed by calculating I2 and was broadly categorized as low, moderate and high following the I2 statistics cut-off points suggested by Higgins et al. (2003): 25%, 50%, and 75% [13]. Publication bias was investigate using funnel plots and Egger’s test for funnel plot asymmetry [14]. Exploratory analyses investigating quality of reporting and study funding were done. A total score for quality of reporting was generated by adding scores for each item as follows: 0 = not reported; 1 = unclear; 2 = reported. Funding was categorized as public, private, combined public and private, and unclear.

Ethics approval was not required for this systematic review and meta-analysis.


Studies selection and characteristics

The bibliographic search yielded 279 publications (Fig 1) and a clear increase in the number of articles published overtime was observed. Agreement between reviewers was 85% for titles and 80% for abstracts selection. Fifty-five studies [1569] were included in the quantitative analysis and the most frequent reason for exclusion from the review was lack of BIC data (47.27% of studies) (S2 Table). No additional studies were found in the reference list of studies included.

Studies are summarized in S3 Table. Most studies focused on evaluating new implant surface technologies (47.27%), implant material (10.91%), implant design (7.27%), and surgical protocol (7.27%). The minipig strain most used was the Göttingen (30.90%), followed by Lanyu small-ear pigs (7.27%). The animal’s age ranged from 12 to 72 months and the weight average was 48.99±5.57 kg. Most studies used only females (49.09%). The average number of animals included in the studies was 10.10±5.57 (range 3–30).

Premolars and first molars were usually extracted to provide space for posterior implant placement; few studies extracted incisors or placed implants in diastemas. Immediate implant placement occurred in only 5 studies (9.09%). For delayed implant placement studies, healing following extractions ranged between 8 and 32 wks; most studies allowed for 12 wks of healing post-extraction (36.36%). The average number of implants placed per animal was 6.49±3.63 (range: 2–20), and most studies placed implants in the mandible only (64%). Most studies used implants with 3.5mm in diameter (range: 3.3–6.0mm) and 8mm in length (range: 5-15mm). The average healing time following implant placement was 8.87±10.76 wks (range: 1–96). Delayed implant placement and submerged healing were used in 80% and 64% of studies, respectively. Transmucosal healing was used in 20 out of 55 (36.4%) studies; 14 out of 20 (70%) studies used healing abutments or stock abutments/healing caps. Four (20%) studies used stock abutments and provisional restorations, and two (10%) studies used stock abutments and metallic/ceramic crowns. Approximately 60% of studies reported the use of antibiotics following implant placement. Chemical plaque control was reported by 2 (3.64%) studies and in 4 (7.27%) studies a professional dental cleaning was performed during the follow up time.

All studies used the cutting-grinding technique for histologic preparation of undecalcified samples and 90% used light microscopy for histological evaluation. A buccal-lingual orientation was used in 55% of the studies and section thickness ≥50μm was used in 51% of the studies (range: 50-150μm) when light microscopy was used. Only 15 studies (27.3%) reported that more than one section was used for histological analysis. Toluidine blue staining was used in 45% of studies.

Quality of reporting

Reporting of selected items from the ARRIVE checklist are presented in Fig 2 and S4 Table. Fig 2A presents the distribution of the abovementioned items for the selected studies. Overall, 94.54% of studies described the experimental groups, 74.55% reported animal loss, 56.36% allocated treatment using randomization, and 65.45% described the surgical protocol for implant placement. Most studies described the surgical protocol for implant placement as following the manufacturer’s protocol. Details of animal used were fully described by 40% of the studies. Low quality was related to absence of sample size calculation (94.54% of studies), calibration (83.64% of studies), and masking/blinding (69.09% of studies). Implant loss, an important adverse event, was reported in 76.36% of studies, ranging between 0 and 47 implants, and on average 6.29±11.42 were reported lost.

Fig 2.

a. Quality assessment of the 55 studies included in the systematic review. b. Bubble plot of BIC% and quality assessment scores.

Primary outcome

Table 1 presents BIC according to healing period. Overall, BIC was 59.88% (95%CI: 57.43–62.33). BIC increased significantly during the first month of healing levelling off afterwards (Fig 3A). A high degree of variability was observed in each healing period (Fig 3B). Meta-regressions were used to explore between-study heterogeneity, and crude and adjusted BIC estimates are presented according to important covariates in Table 2. In the unadjusted analysis, between-study heterogeneity could be explained by animal age, alveolar ridge healing time, immediate implant placement, implant loading, implant healing time, and implant surface.

Fig 3.

a. Predicted bone-implant contact (BIC) over time. b. Box plot of bone-implant contact (BIC) according to healing time.

Table 1. Osseointegration (BIC %) according to observation interval (wks).

Table 2. Unadjusted and adjusted osseointegration (BIC %) estimates according to covariates (meta-regression).

In the adjusted analysis, healing time following extractions, healing time after implant placement, and implant surface remained statistically significant factors. Studies that used more than 12 wks of healing following extraction and more than 5 wks of healing after implant placement had significantly higher BIC. Studies testing implants with SLA surface had significantly higher BIC than studies testing other surfaces. An exploratory meta-regression showed an inverse relationship between quality of reporting and BIC (coef = -0.99±0.35, p = 0.004). The scatterplot of the effect sizes against the quality of reporting showed that BIC decreased from approximately 65% for studies with low quality to 50% for studies with high quality (Fig 2B). No significant differences were observed for study funding (p = 0.06).

Heterogeneity was high for all random effect models (I2 > 90%). Evidence of publication bias was observed in the funnel plot (Fig 4) and the Egger test was statistically significant (p<0.001).

Secondary outcomes

Table 3 presents first BIC and crestal bone level according to implant site. Nine studies reported combined buccal and lingual sites first BIC averaging 1.24mm (95%CI: 0.83–1.66). Four studies reported buccal and lingual sites separately first BIC averaging 1.5mm. Four studies reported crestal bone level separately for buccal and lingual sites mean bone level approximating 1.5mm. No studies reported crestal bone level combining buccal and lingual sites.

Table 3. Crestal bone level and first BIC according to implant site (in mm).


In summary, the present systematic review included 55 studies evaluating osseointegration and crestal bone remodeling using a minipig intraoral dental implant model. Most studies evaluated novel dental implant surfaces. Great variability in minipig strain and age, sample size, healing time, and surgical approach was observed. Approximately 90% of studies reported undecalcified histology and incandescent light microscopy histometrics. The quality of reporting assessment identified that most studies did not sufficiently report several methodological items, including animal characteristics and husbandry, sample size calculation, examiner calibration. masking/blinding, and statistical analysis. Studies typically extracted the mandibular premolar and first molar teeth and allowed 12 wks post-extraction healing. Three narrow, 8–10 mm implants were placed in contralateral jaw quadrants and allowed to osseointegrate submerged for 8 wks. The overall mean BIC was approximately 60% for the minipig intraoral dental implant model; BIC increased steadily during the first 5–6 wks and remained stable onwards. Between-study heterogeneity could be explained by healing time post-extraction and after implant placement, and implant surface. Few studies evaluated bone remodeling around the implant platform; the mean first BIC distance was approximately 1.2mm and crestal bone level was 1.5mm.

Few studies have evaluated dental implant osseointegration in humans [7077]. For instance, Lang et al. (2011) compared osseointegration of two sandblasted acid-etched surface mini-implants (SLA and SLActive, Straumann®, Basel, Switzerland) in the posterior mandible [71]. BIC increased from 12.2–14.8% wk 2, to 32.4–48.3% wk 4, to 62% wk 6. Cecchinato et al. (2012) evaluated osseointegration of a fluoride-treated nanostructured mini-implant (Osseospeed®, Astra, Charlotte, NC USA) in individuals with and without history of periodontitis [72]. Overall BIC averaged 58.4±13.0% following 12 wks of osseointegration. Still others observed a mean BIC ranging from 45% to 75% following 12 wks of osseointegration depending on site characteristics and surgical/loading protocols [73,74,76]. Collectively, these estimates of osseointegration are comparable with mean BICs observed in minipigs ranging from 40.9% to 69.1% depending on observation interval. Nevertheless, whereas large animal models may provide estimates of osseointegration comparable with that in humans, it is prudent to caution that bone formation/remodeling [78] and osseointegration [79] appears faster than in humans.

From a regulatory standpoint, several agencies, including the United States Food and Drug Administration, follow the technical specifications related to preclinical evaluation of dental implant systems outlined by the International Organization for Standardization [80]. The specifications indicate that predicate implant devices intended for human clinical use should be tested in intraoral sites with opposing teeth. The animals should have a non-herbivorous pattern of masticatory jaw movements and allow for long-term oral hygiene to be maintained. Although domestic pigs have been used to test dental implants [8184], their increased size and weight at an early age leads to challenges in husbandry and handling [85]. Nonhuman primate and canine models also fulfill these requirements, however their use has been logistically challenging opposed by public opinion [2,86,87]. In comparison to canines, minipigs require more specialized facilities and veterinary care; animal availability and cost might be an issue depending on age/sex and number of authorized vendors.

For decades the canine model has been the preferred platform in implant dentistry due to its availability, handling, anatomic and biologic similarities. Several studies have observed comparable osseointegration rates for the canine and minipig intraoral implant models [88]. A meta-analysis comparing titanium and zirconia implants reported an overall BIC of 60.4% (95%CI: 52.8–67.9%) for titanium implants using a wide range of healing intervals [89]. Abrahamsson et al. (2004) observed a BIC approximating 60% at 12 wks evaluating sandblasted and acid-etched implants [90]. Cochran et al. (1998) reported a mean BIC of 68% for SLA and 78% for titanium plasma sprayed implants at 12 months indicating stable long-term osseointegration [29]. Our laboratory has demonstrated BICs ranging between 63% and 78% for anodized implants at 8 wks in a series of studies evaluating surgical techniques, implant materials, surface characteristics, and restorative approaches [9193].

The quality assessment of reporting in this review show a need for more stringent reporting that readers can evaluate the quality of the studies and researchers replicate methodologies. Only one study was judged to provide a complete description of the methods and results; most studies exhibited multiple omissions. Future reports using the minipig intraoral dental implant model should follow the ARRIVE guidelines [10]. Special attention should be given to sample size calculation, randomization, and examiner masking/blinding to minimize the number of underpowered studies and risk of bias. We did not formally apply established risk of bias tools for animal research such as SYRCLE [94] due to the difficulty to adapt its use to large animal studies and large number of studies that did not report methodology appropriately. Nevertheless, an exploratory analysis showed an inverse relationship between quality of reporting and osseointegration, which may indicate some inflation in the estimates.

This systematic review underscores the safety and efficacy of the surgical procedures and implant technologies tested by most studies using the minipig intraoral dental implant model as measured by clinically acceptable levels of osseointegration, crestal remodeling and short-term survival rates. In perspective, the cumulative implant failure rate in humans for commercially available implants with moderately rough surfaces reviewed herein has been estimated to be approximately 4% after 10 or more years in function [95]. This provides indirect evidence that the osseointegration level observed within 3–4 months following implant placement in minipigs could translate into meaningful long-term clinical outcomes for patients barring technical and biological complications.

The experimental design complexity, including multiple experimental groups and healing times, observed in this review underscores the tension between a desire to reduce the number of animals used in research, one of the pillars of the 3Rs by Russel and Burch [96], while collecting as much data as possible within a single experiment. However well intentioned, this approach is clearly generating a high level of data heterogeneity, which contributes to unreliable results and potentially to reporting bias. The use of simplified study designs such as the split-mouth design with multiple observations per experimental group/animal (duplicates, triplicates) would likely yield most robust results.


Despite reported great variability observed, preferred characteristics for the minipig intraoral dental implant model have emerged, including observation intervals, implant placement approaches, number and size of implants, and outcomes assessment. Osseointegration estimates were comparable to other large animal models and human studies indicating that the minipig model can provide meaningful information for clinical applications.

Supporting information

S1 Table. Items evaluated in the quality assessment–adapted from ARRIVE checklist.


S2 Table. Excluded full-texts and reasons (n = 70).


S3 Table. Description of the 55 studies included in the systematic review.


S4 Table. Quality assessment of included studies (based on ARRIVE checklist).



The authors would like to thank Angelines Gasser for her support during the study execution.


  1. 1. Buser D, Sennerby L, De Bruyn H. Modern implant dentistry based on osseointegration: 50 years of progress, current trends and open questions. Periodontol 2000. 2017;73(1):7–21. pmid:28000280
  2. 2. Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater. 2007;13:1–10. pmid:17334975
  3. 3. Wang S, Liu Y, Fang D, Shi S. The miniature pig: a useful large animal model for dental and orofacial research. Oral Dis. 2007;13(6):530–7. pmid:17944668
  4. 4. Ruehe B, Niehues S, Heberer S, Nelson K. Miniature pigs as an animal model for implant research: bone regeneration in critical-size defects. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108(5):699–706. pmid:19782620
  5. 5. Taguchi T, Lopez MJ. An overview of de novo bone generation in animal models. J Orthop Res. 2021;39(1):7–21. pmid:32910496
  6. 6. Gould TR, Robertson PB, Oakley C. Effect of free gingival grafts on naturally-occurring recession in miniature swine. J Periodontol. 1992;63(7):593–7. pmid:1380548
  7. 7. Mardas N, Dereka X, Donos N, Dard M. Experimental model for bone regeneration in oral and cranio-maxillo-facial surgery. J Invest Surg. 2014;27(1):32–49. pmid:23957784
  8. 8. Pilawski I, Tulu US, Ticha P, Schupbach P, Traxler H, Xu Q, et al. Interspecies Comparison of Alveolar Bone Biology, Part I: Morphology and Physiology of Pristine Bone. JDR Clin Trans Res. 2021;6(3):352–60. pmid:32660303
  9. 9. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol. 2021;134:178–89. pmid:33789819
  10. 10. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412. pmid:20613859
  11. 11. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13. pmid:15840177
  12. 12. Cohen J. A power primer. Psychol Bull. 1992;112(1):155–9. pmid:19565683
  13. 13. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. pmid:12958120
  14. 14. Harbord RM HR, Sterne JAC. Updated tests for small-study effects in meta-analyses. The Stata Journal. Stata Journal 2009;9(2):197–210.
  15. 15. Hoornaert A, Vidal L, Besnier R, Morlock JF, Louarn G, Layrolle P. Biocompatibility and osseointegration of nanostructured titanium dental implants in minipigs. Clin Oral Implants Res. 2020;31(6):526–35. pmid:32058629
  16. 16. Kammerer T, Lesmeister T, Palarie V, Schiegnitz E, Schroter A, Al-Nawas B, et al. Calcium Phosphate-Coated Titanium Implants in the Mandible: Limitations of the in vivo Minipig Model. Eur Surg Res. 2020;61(6):177–87. pmid:33601367
  17. 17. Karl M, Palarie V, Nacu V, Grobecker-Karl T. A Pilot Animal Study Aimed at Assessing the Mechanical Quality of Regenerated Alveolar Bone. Int J Oral Maxillofac Implants. 2020;35(2):313–9. pmid:32142568
  18. 18. Thome G, Sandgren R, Bernardes S, Trojan L, Warfving N, Bellon B, et al. Osseointegration of a novel injection molded 2-piece ceramic dental implant: a study in minipigs. Clin Oral Investig. 2021;25(2):603–15. pmid:32914271
  19. 19. Romero-Ruiz MM, Gil-Mur FJ, Rios-Santos JV, Lazaro-Calvo P, Rios-Carrasco B, Herrero-Climent M. Influence of a Novel Surface of Bioactive Implants on Osseointegration: A Comparative and Histomorfometric Correlation and Implant Stability Study in Minipigs. Int J Mol Sci. 2019;20(9). pmid:31075984
  20. 20. Susin C, Finger Stadler A, Musskopf ML, de Sousa Rabelo M, Ramos UD, Fiorini T. Safety and efficacy of a novel, gradually anodized dental implant surface: A study in Yucatan mini pigs. Clin Implant Dent Relat Res. 2019;21 Suppl 1:44–54. pmid:30860675
  21. 21. Susin C, Finger Stadler A, Fiorini T, de Sousa Rabelo M, Ramos UD, Schupbach P. Safety and efficacy of a novel anodized abutment on soft tissue healing in Yucatan mini-pigs. Clin Implant Dent Relat Res. 2019;21 Suppl 1:34–43. pmid:30859699
  22. 22. Herrero-Climent M, Romero Ruiz feminine MM, Calvo PL, Santos JVR, Perez RA, Gil Mur FJ. Effectiveness of a new dental implant bioactive surface: histological and histomorphometric comparative study in minipigs. Clin Oral Investig. 2018;22(3):1423–32. pmid:29022215
  23. 23. Hou PJ, Ou KL, Wang CC, Huang CF, Ruslin M, Sugiatno E, et al. Hybrid micro/nanostructural surface offering improved stress distribution and enhanced osseointegration properties of the biomedical titanium implant. J Mech Behav Biomed Mater. 2018;79:173–80. pmid:29306080
  24. 24. Mehl C, Kern M, Neumann F, Bahr T, Wiltfang J, Gassling V. Effect of ultraviolet photofunctionalization of dental titanium implants on osseointegration. J Zhejiang Univ Sci B. 2018;19(7):525–34. pmid:29971991
  25. 25. Rios-Santos JV, Menjivar-Galan AM, Herrero-Climent M, Rios-Carrasco B, Fernandez-Palacin A, Perez RA, et al. Unravelling the effect of macro and microscopic design of dental implants on osseointegration: a randomised clinical study in minipigs. J Mater Sci Mater Med. 2018;29(7):99. pmid:29946992
  26. 26. Kuo T.-F. LH-C, Tseng C.-F., Yang J.-C., Wang S.-F., Yang T.C.-K., Lee S.-Y. Evaluation of Osseointegration in Titanium and Zirconia-Based Dental Implants with Surface Modification in a Miniature Pig Model. Journal of Medical and Biological Engineering 2017;37(3):313–20.
  27. 27. Brockmeyer P, Krohn S, Thiemann C, Schulz X, Kauffmann P, Troltzsch M, et al. Primary stability and osseointegration of dental implants in polylactide modified bone—A pilot study in Goettingen minipigs. J Craniomaxillofac Surg. 2016;44(8):1095–103. pmid:27346283
  28. 28. Chiang HJ, Hsu HJ, Peng PW, Wu CZ, Ou KL, Cheng HY, et al. Early bone response to machined, sandblasting acid etching (SLA) and novel surface-functionalization (SLAffinity) titanium implants: characterization, biomechanical analysis and histological evaluation in pigs. J Biomed Mater Res A. 2016;104(2):397–405. pmid:26418567
  29. 29. Cochran D, Stavropoulos A, Obrecht M, Pippenger B, Dard M. A Comparison of Tapered and Nontapered Implants in the Minipig. Int J Oral Maxillofac Implants. 2016;31(6):1341–7. pmid:27861658
  30. 30. Eom TG, Kim HW, Jeon GR, Yun MJ, Huh JB, Jeong CM. Effects of Different Implant Osteotomy Preparation Sizes on Implant Stability and Bone Response in the Minipig Mandible. Int J Oral Maxillofac Implants. 2016;31(5):997–1006. pmid:27632253
  31. 31. Mehl C, Gassling V, Schultz-Langerhans S, Acil Y, Bahr T, Wiltfang J, et al. Influence of Four Different Abutment Materials and the Adhesive Joint of Two-Piece Abutments on Cervical Implant Bone and Soft Tissue. Int J Oral Maxillofac Implants. 2016;31(6):1264–72. pmid:27861650
  32. 32. Ou KL, Weng CC, Wu CC, Lin YH, Chiang HJ, Yang TS, et al. Research of StemBios Cell Therapy on Dental Implants Containing Nanostructured Surfaces: Biomechanical Behaviors, Microstructural Characteristics, and Clinical Trial. Implant Dent. 2016;25(1):63–73. pmid:26473440
  33. 33. Ou KL, Hsu HJ, Yang TS, Lin YH, Chen CS, Peng PW. Osseointegration of titanium implants with SLAffinity treatment: a histological and biomechanical study in miniature pigs. Clin Oral Investig. 2016;20(7):1515–24. pmid:26507647
  34. 34. Stavropoulos A, Cochran D, Obrecht M, Pippenger BE, Dard M. Effect of Osteotomy Preparation on Osseointegration of Immediately Loaded, Tapered Dental Implants. Adv Dent Res. 2016;28(1):34–41. pmid:26927486
  35. 35. Botzenhart U, Kunert-Keil C, Heinemann F, Gredes T, Seiler J, Berniczei-Royko A, et al. Osseointegration of short titan implants: A pilot study in pigs. Ann Anat. 2015;199:16–22. pmid:24780612
  36. 36. Huang MS, Chen LK, Ou KL, Cheng HY, Wang CS. Rapid Osseointegration of Titanium Implant With Innovative Nanoporous Surface Modification: Animal Model and Clinical Trial. Implant Dent. 2015;24(4):441–7. pmid:25946663
  37. 37. López-García M G-CA, López-Peña M, San Román F, Thams U, Muñoz Guzón FM. Influence of implantation side on the integration of dental implants. A study on miniature pigs. Int J Stomatol Occlusion Med 2015;8:41–6.
  38. 38. Korn P, Schulz MC, Hintze V, Range U, Mai R, Eckelt U, et al. Chondroitin sulfate and sulfated hyaluronan-containing collagen coatings of titanium implants influence peri-implant bone formation in a minipig model. J Biomed Mater Res A. 2014;102(7):2334–44. pmid:23946280
  39. 39. Schulz MC, Korn P, Stadlinger B, Range U, Moller S, Becher J, et al. Coating with artificial matrices from collagen and sulfated hyaluronan influences the osseointegration of dental implants. J Mater Sci Mater Med. 2014;25(1):247–58. pmid:24113890
  40. 40. Sivan-Gildor A, Machtei EE, Gabay E, Frankenthal S, Levin L, Suzuki M, et al. Novel implant design improves implant survival in multirooted extraction sites: a preclinical pilot study. J Periodontol. 2014;85(10):1458–63. pmid:24694078
  41. 41. Stramandinoli-Zanicotti RT, Sassi LM, Schussel JL, Torres MF, Matos Ferreira SA, Carvalho AL. Effect of radiotherapy on osseointegration of dental implants immediately placed in postextraction sites of minipigs mandibles. Implant Dent. 2014;23(5):560–4. pmid:25192164
  42. 42. Vasak C, Busenlechner D, Schwarze UY, Leitner HF, Munoz Guzon F, Hefti T, et al. Early bone apposition to hydrophilic and hydrophobic titanium implant surfaces: a histologic and histomorphometric study in minipigs. Clin Oral Implants Res. 2014;25(12):1378–85. pmid:24118429
  43. 43. Verket A, Lyngstadaas SP, Ronold HJ, Wohlfahrt JC. Osseointegration of dental implants in extraction sockets preserved with porous titanium granules—an experimental study. Clin Oral Implants Res. 2014;25(2):e100–8. pmid:23190181
  44. 44. Linares A, Domken O, Dard M, Blanco J. Peri-implant soft tissues around implants with a modified neck surface. Part 1. Clinical and histometric outcomes: a pilot study in minipigs. J Clin Periodontol. 2013;40(4):412–20. pmid:23432822
  45. 45. Eom TG, Jeon GR, Jeong CM, Kim YK, Kim SG, Cho IH, et al. Experimental study of bone response to hydroxyapatite coating implants: bone-implant contact and removal torque test. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(4):411–8. pmid:22749706
  46. 46. Gahlert M, Roehling S, Sprecher CM, Kniha H, Milz S, Bormann K. In vivo performance of zirconia and titanium implants: a histomorphometric study in mini pig maxillae. Clin Oral Implants Res. 2012;23(3):281–6. pmid:21806681
  47. 47. Gottlow J, Dard M, Kjellson F, Obrecht M, Sennerby L. Evaluation of a new titanium-zirconium dental implant: a biomechanical and histological comparative study in the mini pig. Clin Implant Dent Relat Res. 2012;14(4):538–45. pmid:20586785
  48. 48. Saulacic N, Bosshardt DD, Bornstein MM, Berner S, Buser D. Bone apposition to a titanium-zirconium alloy implant, as compared to two other titanium-containing implants. Eur Cell Mater. 2012;23:273–86; discussion 86–8. pmid:22492019
  49. 49. Stadlinger B, Hintze V, Bierbaum S, Moller S, Schulz MC, Mai R, et al. Biological functionalization of dental implants with collagen and glycosaminoglycans-A comparative study. J Biomed Mater Res B Appl Biomater. 2012;100(2):331–41. pmid:22102613
  50. 50. Elian N, Bloom M, Dard M, Cho SC, Trushkowsky RD, Tarnow D. Effect of interimplant distance (2 and 3 mm) on the height of interimplant bone crest: a histomorphometric evaluation. J Periodontol. 2011;82(12):1749–56. pmid:21513475
  51. 51. Linares A, Mardas N, Dard M, Donos N. Effect of immediate or delayed loading following immediate placement of implants with a modified surface. Clin Oral Implants Res. 2011;22(1):38–46. pmid:21039892
  52. 52. Ruehe B, Heberer S, Bayreuther K, Nelson K. Effect of dehiscences to the bone response of implants with an Acid-etched surface: an experimental study in miniature pigs. J Oral Implantol. 2011;37(1):3–17. pmid:20557147
  53. 53. Assenza B, Scarano A, Perrotti V, Vozza I, Quaranta A, Quaranta M, et al. Peri-implant bone reactions around immediately loaded conical implants with different prosthetic suprastructures: histological and histomorphometrical study on minipigs. Clin Oral Investig. 2010;14(3):285–90. pmid:19495815
  54. 54. Duyck J, Corpas L, Vermeiren S, Ogawa T, Quirynen M, Vandamme K, et al. Histological, histomorphometrical, and radiological evaluation of an experimental implant design with a high insertion torque. Clin Oral Implants Res. 2010;21(8):877–84. pmid:20528892
  55. 55. Schliephake H, Hefti T, Schlottig F, Gedet P, Staedt H. Mechanical anchorage and peri-implant bone formation of surface-modified zirconia in minipigs. J Clin Periodontol. 2010;37(9):818–28. pmid:20573183
  56. 56. Stadlinger B, Hennig M, Eckelt U, Kuhlisch E, Mai R. Comparison of zirconia and titanium implants after a short healing period. A pilot study in minipigs. Int J Oral Maxillofac Surg. 2010;39(6):585–92. pmid:20172693
  57. 57. Stadlinger B, Lode AT, Eckelt U, Range U, Schlottig F, Hefti T, et al. Surface-conditioned dental implants: an animal study on bone formation. J Clin Periodontol. 2009;36(10):882–91. pmid:19735467
  58. 58. Stadlinger B, Bierbaum S, Grimmer S, Schulz MC, Kuhlisch E, Scharnweber D, et al. Increased bone formation around coated implants. J Clin Periodontol. 2009;36(8):698–704. pmid:19531092
  59. 59. Traini T, Neugebauer J, Thams U, Zoller JE, Caputi S, Piattelli A. Peri-implant bone organization under immediate loading conditions: collagen fiber orientation and mineral density analyses in the minipig model. Clin Implant Dent Relat Res. 2009;11(1):41–51. pmid:18657155
  60. 60. Stadlinger B, Pilling E, Huhle M, Khavkin E, Bierbaum S, Scharnweber D, et al. Suitability of differently designed matrix-based implant surface coatings: an animal study on bone formation. J Biomed Mater Res B Appl Biomater. 2008;87(2):516–24. pmid:18546193
  61. 61. Stadlinger B, Pilling E, Huhle M, Mai R, Bierbaum S, Scharnweber D, et al. Evaluation of osseointegration of dental implants coated with collagen, chondroitin sulphate and BMP-4: an animal study. Int J Oral Maxillofac Surg. 2008;37(1):54–9. pmid:17983729
  62. 62. Germanier Y, Tosatti S, Broggini N, Textor M, Buser D. Enhanced bone apposition around biofunctionalized sandblasted and acid-etched titanium implant surfaces. A histomorphometric study in miniature pigs. Clin Oral Implants Res. 2006;17(3):251–7. pmid:16672019
  63. 63. Nkenke E, Fenner M, Vairaktaris EG, Neukam FW, Radespiel-Troger M. Immediate versus delayed loading of dental implants in the maxillae of minipigs. Part II: histomorphometric analysis. Int J Oral Maxillofac Implants. 2005;20(4):540–6. pmid:16161738
  64. 64. Rimondini L, Bruschi GB, Scipioni A, Carrassi A, Nicoli-Aldini N, Giavaresi G, et al. Tissue healing in implants immediately placed into postextraction sockets: a pilot study in a mini-pig model. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;100(3):e43–50. pmid:16122646
  65. 65. Buser D, Broggini N, Wieland M, Schenk RK, Denzer AJ, Cochran DL, et al. Enhanced bone apposition to a chemically modified SLA titanium surface. J Dent Res. 2004;83(7):529–33. pmid:15218041
  66. 66. Nkenke E, Lehner B, Weinzierl K, Thams U, Neugebauer J, Steveling H, et al. Bone contact, growth, and density around immediately loaded implants in the mandible of mini pigs. Clin Oral Implants Res. 2003;14(3):312–21. pmid:12755781
  67. 67. Zechner W, Tangl S, Furst G, Tepper G, Thams U, Mailath G, et al. Osseous healing characteristics of three different implant types. Clin Oral Implants Res. 2003;14(2):150–7. pmid:12656873
  68. 68. Dostalova T, Himmlova L, Jelinek M, Grivas C. Osseointegration of loaded dental implant with KrF laser hydroxylapatite films on Ti6Al4V alloy by minipigs. J Biomed Opt. 2001;6(2):239–43. pmid:11375735
  69. 69. Basquill PJ, Steflik DE, Brennan WA, Horner J, Van Dyke TE. Evaluation of the effects of diagnostic radiation on titanium dental implant osseointegration in the micropig. J Periodontol. 1994;65(9):872–80. pmid:7990025
  70. 70. Ivanoff CJ, Hallgren C, Widmark G, Sennerby L, Wennerberg A. Histologic evaluation of the bone integration of TiO(2) blasted and turned titanium microimplants in humans. Clin Oral Implants Res. 2001;12(2):128–34. pmid:11251662
  71. 71. Lang NP, Salvi GE, Huynh-Ba G, Ivanovski S, Donos N, Bosshardt DD. Early osseointegration to hydrophilic and hydrophobic implant surfaces in humans. Clin Oral Implants Res. 2011;22(4):349–56. pmid:21561476
  72. 72. Cecchinato D, Bressan EA, Toia M, Araujo MG, Liljenberg B, Lindhe J. Osseointegration in periodontitis susceptible individuals. Clin Oral Implants Res. 2012;23(1):1–4. pmid:22092689
  73. 73. Donati M, Botticelli D, La Scala V, Tomasi C, Berglundh T. Effect of immediate functional loading on osseointegration of implants used for single tooth replacement. A human histological study. Clin Oral Implants Res. 2013;24(7):738–45. pmid:22540676
  74. 74. Nakajima Y, Piattelli A, Iezzi G, Fortich Mesa N, Ferri M, Botticelli D. Influence of the Presence of Alveolar Mucosa at Implants: A Histological Study in Humans. Implant Dent. 2018;27(2):193–201. pmid:29319546
  75. 75. Yonezawa D, Piattelli A, Favero R, Ferri M, Iezzi G, Botticelli D. Bone Healing at Functionally Loaded and Unloaded Screw-Shaped Implants Supporting Single Crowns: A Histomorphometric Study in Humans. Int J Oral Maxillofac Implants. 2018;33(1):181–7. pmid:29340352
  76. 76. Omori Y, Iezzi G, Perrotti V, Piattelli A, Ferri M, Nakajima Y, et al. Influence of the Buccal Bone Crest Width on Peri-Implant Hard and Soft Tissues Dimensions: A Histomorphometric Study in Humans. Implant Dent. 2018;27(4):415–23. pmid:29878920
  77. 77. Amari Y, Piattelli A, Apaza Alccayhuaman KA, Mesa NF, Ferri M, Iezzi G, et al. Bone healing at non-submerged implants installed with different insertion torques: a split-mouth histomorphometric randomized controlled trial. Int J Implant Dent. 2019;5(1):39. pmid:31802302
  78. 78. Štembírek J KM, Putnová I, Stehlík L, Buchtová M. The pig as an experimental model for clinical craniofacial research. Lab Anim. 2012;46(4):269–79. pmid:22969144
  79. 79. Boticelli D LN. Dynamics of osseointegration in various human and animal models—a comparative analysis. Clin Oral Implants Res. 2017;28(6):742–8. pmid:27214566
  80. 80. Dentistry—Preclinical evaluation of dental implant systems—Animal test methods, (2005).
  81. 81. Perez-Albacete Martinez C, Vlahovic Z, Scepanovic M, Videnovic G, Barone A, Calvo-Guirado JL. Submerged flapless technique vs. conventional flap approach for implant placement: experimental domestic pig study with 12-month follow-up. Clin Oral Implants Res. 2016;27(8):964–8. pmid:26147852
  82. 82. Gredes T, Kubasiewicz-Ross P, Gedrange T, Dominiak M, Kunert-Keil C. Comparison of surface modified zirconia implants with commercially available zirconium and titanium implants: a histological study in pigs. Implant Dent. 2014;23(4):502–7. pmid:25025856
  83. 83. Bousdras VA, Sindet-Pedersen S, Cunningham JL, Blunn G, Petrie A, Naert IE, et al. Immediate functional loading of single-tooth TIO2 grit-blasted implant restorations: a controlled prospective study in a porcine model. Part I: Clinical outcome. Clin Implant Dent Relat Res. 2007;9(4):197–206. pmid:18031441
  84. 84. Sennerby L, Odman J, Lekholm U, Thilander B. Tissue reactions towards titanium implants inserted in growing jaws. A histological study in the pig. Clin Oral Implants Res. 1993;4(2):65–75. pmid:8218745
  85. 85. Swindle MM, Makin A, Herron AJ, Clubb FJ Jr., Frazier KS. Swine as models in biomedical research and toxicology testing. Vet Pathol. 2012;49(2):344–56. pmid:21441112
  86. 86. Pellegrini G, Seol YJ, Gruber R, Giannobile WV. Pre-clinical models for oral and periodontal reconstructive therapies. J Dent Res. 2009;88(12):1065–76. pmid:19887682
  87. 87. Kantarci A, Hasturk H, Van Dyke TE. Animal models for periodontal regeneration and peri-implant responses. Periodontol 2000. 2015;68(1):66–82. pmid:25867980
  88. 88. Hao CP, Cao NJ, Zhu YH, Wang W. The osseointegration and stability of dental implants with different surface treatments in animal models: a network meta-analysis. Sci Rep. 2021;11(1):13849. pmid:34226607
  89. 89. Roehling S, Schlegel KA, Woelfler H, Gahlert M. Performance and outcome of zirconia dental implants in clinical studies: A meta-analysis. Clin Oral Implants Res. 2018;29 Suppl 16:135–53. pmid:30328200
  90. 90. Abrahamsson I, Berglundh T, Linder E, Lang NP, Lindhe J. Early bone formation adjacent to rough and turned endosseous implant surfaces. An experimental study in the dog. Clin Oral Implants Res. 2004;15(4):381–92. pmid:15248872
  91. 91. Wikesjo UM, Susin C, Qahash M, Polimeni G, Leknes KN, Shanaman RH, et al. The critical-size supraalveolar peri-implant defect model: characteristics and use. J Clin Periodontol. 2006;33(11):846–54. pmid:16965525
  92. 92. Wikesjo UM, Qahash M, Polimeni G, Susin C, Shanaman RH, Rohrer MD, et al. Alveolar ridge augmentation using implants coated with recombinant human bone morphogenetic protein-2: histologic observations. J Clin Periodontol. 2008;35(11):1001–10. pmid:18976397
  93. 93. Lee J, Hurson S, Tadros H, Schupbach P, Susin C, Wikesjo UM. Crestal remodelling and osseointegration at surface-modified commercially pure titanium and titanium alloy implants in a canine model. J Clin Periodontol. 2012;39(8):781–8. pmid:22671935
  94. 94. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43. pmid:24667063
  95. 95. Wennerberg A, Albrektsson T, Chrcanovic B. Long-term clinical outcome of implants with different surface modifications. Eur J Oral Implantol. 2018;11 Suppl 1:S123–S36. pmid:30109304
  96. 96. Russell WMS BR. The Principles of Humane Experimental Technique. Ltd. MC, editor. London, UK1959.