Publications by authors named "John B Brunski"

29 Publications

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Comparative analyses of the soft tissue interfaces around teeth and implants: Insights from a pre-clinical implant model.

J Clin Periodontol 2021 Mar 13. Epub 2021 Mar 13.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, CA, USA.

Aim: To evaluate the similarities and differences in barrier function of a peri-implant epithelium (PIE) versus a native junctional epithelium (JE).

Materials And Methods: A mouse model was used wherein titanium implants were placed sub-occlusally in healed extraction sites. The PIE was examined at multiple timepoints after implant placement, to capture and understand the temporal nature of its assembly and homeostatic status. Mitotic activity, hemidesmosomal attachment apparatus, and inflammatory responses in the PIE were compared against a JE. Additionally, we evaluated whether the PIE developed a Wnt-responsive stem cell niche like a JE.

Results: The PIE developed from oral epithelium (OE) that had, by the time of implant placement, lost all characteristics of a JE. Compared with a JE, an established PIE had more proliferating cells, exhibited lower expression of attachment proteins, and had significantly more inflammatory cells in the underlying connective tissue. Wnt-responsive cells in the OE contributed to an initial PIE, but Wnt-responsive cells and their descendants were lost as the PIE matured.

Conclusions: Although histologically similar, the PIE lacked a Wnt-responsive stem cell niche and exhibited characteristics of a chronically inflamed tissue. Both features contributed to suboptimal barrier functions of the PIE compared with a native JE.
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http://dx.doi.org/10.1111/jcpe.13446DOI Listing
March 2021

Influence of Nanotopography on Early Bone Healing during Controlled Implant Loading.

Nanomaterials (Basel) 2020 Nov 3;10(11). Epub 2020 Nov 3.

Laboratory for the Study of Calcified Tissues and Biomaterials, Department of Stomatology, Faculty of Dental Medicine, Université de Montréal, Montréal, QC H3C3J7, Canada.

Nanoscale surface modifications influence peri-implant cell fate decisions and implant loading generates local tissue deformation, both of which will invariably impact bone healing. The objective of this study is to determine how loading affects healing around implants with nanotopography. Implants with a nanoporous surface were placed in over-sized osteotomies in rat tibiae and held stable by a system that permits controlled loading. Three regimens were applied: (a) no loading, (b) one daily loading session with a force of 1.5N, and (c) two such daily sessions. At 7 days post implantation, animals were sacrificed for histomorphometric and DNA microarray analyses. Implants subjected to no loading or only one daily loading session achieved high bone implant contact (BIC), bone implant distance (BID) and bone formation area near the implant (BFAt) values, while those subjected to two daily loading sessions showed less BFAt and BIC and more BID. Gene expression profiles differed between all groups mainly in unidentified genes, and no modulation of genes associated with inflammatory pathways was detected. These results indicate that implants with nanotopography can achieve a high level of bone formation even under micromotion and limit the inflammatory response to the implant surface.
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http://dx.doi.org/10.3390/nano10112191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693286PMC
November 2020

Mechano-adaptive Responses of Alveolar Bone to Implant Hyper-loading in a pre-clinical in vivo model.

Clin Oral Implants Res 2020 Dec 15;31(12):1159-1172. Epub 2020 Sep 15.

Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA.

Objectives: Oral implants transmit biting forces to peri-implant bone. In turn, those forces subject peri-implant bone to mechanical stresses and strains. Here, our objective was to understand how peri-implant bone responded to conditions of normal versus hyper-loading in a mouse model.

Material And Methods: Sixty-six mice were randomly assigned to 2 groups; both groups underwent bilateral maxillary first molar extraction followed by complete healing. Titanium alloy implants were placed in healed sites and positioned below the occlusal plane. After osseointegration, a composite crown was affixed to the implant so masticatory loading would ensue. In controls, the remaining dentition was left intact but in the hyper-loaded (test) group, the remaining molars were extracted. 3D finite element analysis (FEA) calculated peri-implant strains resulting from normal and hyper-loading. Peri-implant tissues were analyzed at multiple time points using micro-computed tomography (µCT) imaging, histology, enzymatic assays of bone remodeling, and vital dye labeling to evaluate bone accrual.

Results: Compared to controls, hyper-loaded implants experienced a 3.6-fold increase in occlusal force, producing higher peri-implant strains. Bone formation and resorption were both significantly elevated around hyper-loaded implants, eventually culminating in a significant increase in peri-implant bone volume/total volume (BV/TV). In our mouse model, masticatory hyper-loading of an osseointegrated implant was associated with increased peri-implant strain, increased peri-implant bone remodeling, and a net gain in bone deposition.

Conclusion: Hyper-loading results in bone strain with catabolic and anabolic bone responses, leading to a net gain in bone deposition.
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http://dx.doi.org/10.1111/clr.13662DOI Listing
December 2020

Bone formation around unstable implants is enhanced by a WNT protein therapeutic in a preclinical in vivo model.

Clin Oral Implants Res 2020 Nov 14;31(11):1125-1137. Epub 2020 Sep 14.

Department of Plastic and Reconstructive Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA.

Objectives: Our objective was to test the hypothesis that local delivery of a WNT protein therapeutic would support osseointegration of an unstable implant placed into an oversized osteotomy and subjected to functional loading.

Materials And Methods: Using a split-mouth design in an ovariectomized (OVX) rat model, 50 titanium implants were placed in oversized osteotomies. Implants were subjected to functional loading. One-half of the implants were treated with a liposomal formulation of WNT3A protein (L-WNT3A); the other half received an identical liposomal formulation containing phosphate-buffered saline (PBS). Finite element modeling estimated peri-implant strains caused by functional loading. Histological, molecular, cellular, and quantitative micro-computed tomographic (µCT) imaging analyses were performed on samples from post-implant days (PID) 3, 7, and 14. Lateral implant stability was quantified at PID 7 and 14.

Results: Finite element analyses predicted levels of peri-implant strains incompatible with new bone formation. Micro-CT imaging, histological, and quantitative immunohistochemical (IHC) analyses confirmed that PBS-treated implants underwent fibrous encapsulation. In those cases where the peri-implant environment was treated with L-WNT3A, µCT imaging, histological, and quantitative IHC analyses demonstrated a significant increase in expression of proliferative (PCNA) and osteogenic (Runx2, Osterix) markers. One week after L-WNT3A treatment, new bone formation was evident, and two weeks later, L-WNT3A-treated gaps had a stiffer interface compared to PBS-treated gaps.

Conclusion: In a rat model, unstable implants undergo fibrous encapsulation. If the same unstable implants are treated with L-WNT3A at the time of placement, then it results in significantly more peri-implant bone and greater interfacial stiffness.
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http://dx.doi.org/10.1111/clr.13659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722236PMC
November 2020

Are teeth superior to implants? A mapping review.

J Prosthet Dent 2020 Aug 27. Epub 2020 Aug 27.

Professor, Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, Calif.

Statement Of Problem: There is a long-held assumption that teeth are superior to implants because the periodontal ligament (PDL) confers a preeminent defense against biologic and mechanical challenges. However, adequate analysis of the literature is lacking. As a result, differential treatment planning of tooth- and implant-supported restorations has been compromised.

Purpose: Given an abundance and diversity of research, the purpose of this mapping review was to identify basic scientific gaps in the knowledge of how teeth and implants respond to biologic and mechanical loads. The findings will offer enhanced evidence-based clinical decision-making when considering replacement of periodontally compromised teeth and the design of implant prostheses.

Material And Methods: The online databases PubMed, Science Direct, and Web of Science were searched. Published work from 1965 to 2020 was collected and independently analyzed by both authors for inclusion in this review.

Results: A total of 108 articles met the inclusion criteria of clinical, in vivo, and in vitro studies in the English language on the periradicular and peri-implant bone response to biologic and mechanical loads. The qualitative analysis found that the PDL's enhanced vascularity, stem cell ability, and resident cells that respond to inflammation allow for a more robust defense against biologic threats compared with implants. While the suspensory PDL acts to mediate moderate loads to the bone, higher compressive stress and strain within the PDL itself can initiate a biologic sequence of osteoclastic activity that can affect changes in the adjacent bone. Conversely, the peri-implant bone is more resistant to similar loads and the threshold for overload is higher because of the absence of a stress or strain sensitivity inherent in the PDL.

Conclusions: Based on this mapping review, teeth are superior to implants in their ability to resist biologic challenges, but implants are superior to teeth in managing higher compressive loads without prompting bone resorption.
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http://dx.doi.org/10.1016/j.prosdent.2020.07.002DOI Listing
August 2020

Effects of condensation and compressive strain on implant primary stability: A longitudinal, in vivo, multiscale study in mice.

Bone Joint Res 2020 Feb 16;9(2):60-70. Epub 2020 May 16.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, California, USA.

Aims: Surgeons and most engineers believe that bone compaction improves implant primary stability without causing undue damage to the bone itself. In this study, we developed a murine distal femoral implant model and tested this dogma.

Methods: Each mouse received two femoral implants, one placed into a site prepared by drilling and the other into the contralateral site prepared by drilling followed by stepwise condensation.

Results: Condensation significantly increased peri-implant bone density but it also produced higher strains at the interface between the bone and implant, which led to significantly more bone microdamage. Despite increased peri-implant bone density, condensation did not improve implant primary stability as measured by an in vivo lateral stability test. Ultimately, the condensed bone underwent resorption, which delayed the onset of new bone formation around the implant.

Conclusion: Collectively, these multiscale analyses demonstrate that condensation does not positively contribute to implant stability or to new peri-implant bone formation. 2020;9(2):60-70.
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http://dx.doi.org/10.1302/2046-3758.92.BJR-2019-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229305PMC
February 2020

Root resorption and ensuing cementum repair by Wnt/β-catenin dependent mechanism.

Am J Orthod Dentofacial Orthop 2020 Jul 4;158(1):16-27. Epub 2020 May 4.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, Calif. Electronic address:

Introduction: Physiological root resorption is a common occurrence in mammalian teeth, which suggests that there must be a corollary consisting of physiological cementum repair. The mechanism(s) responsible for this physiological repair process is unknown and was the focus of this study.

Methods: Using a rat model, we explored first the prevalence of physiological root resorption and then asked whether this prevalence changed as a result of an osteoporotic phenotype. The cellular mechanisms of resorption were characterized using a combination of finite element modeling coupled with in-vivo histologic, molecular, and cellular analyses in rats. A potential molecular mechanism for cementum repair was uncovered using a strain of transgenic mice in which Wnt-responsive cells could be labeled and followed over time.

Results: In rats, most resorption lacunae were concentrated on the distal surfaces of the roots. Rat molars undergo a physiological tooth drift distally, and using finite element modeling, we calculated the magnitude of the compressive strains that accumulated on these surfaces in response to mastication. Although the overall strain magnitudes were low, they were constant and coincided with the presence of resorption lacunae. Where resorption lacunae were present, progeny from a Wnt-responsive population of stem cells, embedded in the periodontal ligament, directly contributed to the repair of the lacunae.

Conclusions: Despite the fact that both are clastic conditions, an osteoporotic phenotype in rats was not associated with an increase in the prevalence of physiological root resorption. The location of the resorption lacunae corresponded to sites of low but constant compressive strains produced by physiological distal drift. At least 1 mechanism responsible for physiological cementum repair involved the contribution of Wnt-responsive stem or progenitor cells originating in the periodontal ligament. These data point toward a potential Wnt-based strategy to regenerate cementum in subjects with disease or damage.
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http://dx.doi.org/10.1016/j.ajodo.2019.06.021DOI Listing
July 2020

Optimizing autologous bone contribution to implant osseointegration.

J Periodontol 2020 12 28;91(12):1632-1644. Epub 2020 May 28.

Department of Plastic and Reconstructive Surgery, School of Medicine, Stanford University, Palo Alto, California, USA.

Background: Autologous bone can be harvested from the flutes of a conventional drill or from a bone scraper; here we compared whether autologous bone chips generated by a new slow-speed instrument were more osteogenic than the bone chips generated by conventional drills or bone scrapers. Additionally, we tested whether the osteogenic potential of bone chips could be further improved by exposure to a Wnt signaling (WNT) therapeutic.

Methods: Osteotomies were prepared in fresh rat maxillary first molar extraction sockets using a conventional drill or a new osseo-shaping instrument; titanium alloy implants were placed immediately thereafter. Using molecular/cellular and histologic analyses, the fates of the resulting bone chips were analyzed. To test whether increasing WNT signaling improved osteogenesis in an immediate post-extraction implant environment, a WNT therapeutic was introduced at the time of implant placement.

Results: Bone collected from a conventional drill exhibited extensive apoptosis; in contrast, bone generated by the new instrument remained in situ, which preserved their viability. Also preserved was the viability of the osteoprogenitor cells attached to the bone chips. Exogenous treatment with a WNT therapeutic increased the rate of osteogenesis around immediate post-extraction implants.

Conclusions: Compared with conventional drills or bone scrapers, a new cutting instrument enabled concomitant site preparation with autologous bone chip collection. Histology/histomorphometric analyses revealed that the bone chips generated by this new tool were more osteogenic and could be further enhanced by exposure to a WNT therapeutic. Even though gaps still existed in placebo controls and liposomal WNT3A (L-WNT3A) cases, the area of peri-implant bone was significantly greater in L-WNT3A treated sites.
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http://dx.doi.org/10.1002/JPER.19-0524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554098PMC
December 2020

A preclinical model links osseo-densification due to misfit and osseo-destruction due to stress/strain.

Clin Oral Implants Res 2019 Dec 11;30(12):1238-1249. Epub 2019 Oct 11.

Department of Plastic and Reconstructive Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA.

Objective: Primary stability is a prerequisite for implant osseointegration. Some degree of misfit between an implant and its osteotomy is required to ensure primary stability, and this is typically achieved by undersizing an implant osteotomy. In this preclinical study, we aimed at understanding the relationship between misfit, insertion torque, implant stability, and their cumulative short- and longer-term effects on peri-implant bone.

Materials And Methods: We placed implants in maxillary extraction sites of a rat; in the control group, these implants had minimal misfit while those in the test group had a high degree of misfit and therefore osseo-densified the peri-implant bone.

Results: Compared to controls, the misfit-induced stresses produced by osseo-densification led to micro-fractures in the peri-implant bone and an extensive zone of dying osteocytes. High interfacial pressures produced a pro-resorptive environment as shown by tartrate-resistant acid phosphatase activity and cathepsin K immunostaining (IHC). The lack of alkaline phosphatase activity and collagen I IHC supported the absence of new bone formation. Collectively, micro-computed tomography imaging, quantification of bone-implant contact (BIC), vimentin, and IL1-β IHCs demonstrated that implant failure occurred soon afterward, which presented as a crater-like lesion filled with fibrous, inflamed granulation tissue around the test implants.

Conclusion: By controlling every other risk indicator, we confirmed how excessive osseo-densification can lead directly to osseo-destruction.
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http://dx.doi.org/10.1111/clr.13537DOI Listing
December 2019

System for application of controlled forces on dental implants in rat maxillae: Influence of the number of load cycles on bone healing.

J Biomed Mater Res B Appl Biomater 2020 04 31;108(3):965-975. Epub 2019 Jul 31.

Laboratory for the Study of Calcified Tissues and Biomaterials, Faculty of Dental Medicine, Université de Montréal, Montreal, QC, Canada.

Experimental studies on the effect of micromotion on bone healing around implants are frequently conducted in long bones. In order to more closely reflect the anatomical and clinical environments around dental implants, and eventually be able to experimentally address load-management issues, we have developed a system that allows initial stabilization, protection from external forces, and controlled axial loading of implants. Screw-shaped implants were placed on the edentulous ridge in rat maxillae. Three loading regimens were applied to validate the system; case A no loading (unloaded implant) for 14 days, case B no loading in the first 7 days followed by 7 days of a single, daily loading session (60 cycles of an axial force of 1.5 N/cycle), and case C no loading in the first 7 days followed by 7 days of two such daily loading sessions. Finite element modeling of the peri-implant compressive and tensile strains plus histological and immunohistochemical analyses revealed that in case B any tissue damage resulting from the applied force (and related interfacial strains) did not per se disturb bone healing, however, in case C, the accumulation of damage resulting from the doubling of loading sessions severely disrupted the process. These proof-of-principle results validate the applicability of our system for controlled loading, and provide new evidence on the importance of the number of load cycles applied on healing of maxillary bone.
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http://dx.doi.org/10.1002/jbm.b.34449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078813PMC
April 2020

Relationship Between Primary/Mechanical and Secondary/Biological Implant Stability.

Int J Oral Maxillofac Implants 2019 Suppl;34:s7-s23

Purpose: This systematic review was prepared as part of the Academy of Osseointegration (AO) 2018 Summit, held August 8-10 in Oak Brook Hills, Illinois, to assess the relationship between the primary (mechanical) and secondary (biological) implant stability.

Materials And Methods: Electronic and manual searches were conducted by two independent examiners in order to address the following issues. Meta-regression analyses explored the relationship between primary stability, as measured by insertion torque (IT) and implant stability quotient (ISQ), and secondary stability, by means of survival and peri-implant marginal bone loss (MBL).

Results: Overall, 37 articles were included for quantitative assessment. Of these, 17 reported on implant stability using only resonance frequncy analysis (RFA), 11 used only IT data, 7 used a combination of RFA and IT, and 2 used only the Periotest. The following findings were reached: ·Relationship between primary and secondary implant stability: Strong positive statistically significant relationship (P < .001). ·Relationship between primary stability by means of ISQ and implant survival: No statistically significant relationship (P = .4). ·Relationship between IT and implant survival: No statistically significant relationship (P = .2). ·Relationship between primary stability by means of ISQ unit and MBL: No statistically significant relationship (P = .9). ·Relationship between IT and MBL: Positive statistically significant relationship (P = .02). ·Accuracy of methods and devices to assess implant stability: Insufficient data to address this issue.

Conclusion: Data suggest that primary/mechanical stability leads to more efficient achievement of secondary/biological stability, but the achievement of high primary stability might be detrimental for bone level stability. While current methods/devices for tracking implant stability over time can be clinically useful, a robust connection between existing stability metrics with implant survival remains inconclusive.
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http://dx.doi.org/10.11607/jomi.19suppl.g1DOI Listing
August 2019

Mechanical and Biological Advantages of a Tri-Oval Implant Design.

J Clin Med 2019 Mar 28;8(4). Epub 2019 Mar 28.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.

Of all geometric shapes, a tri-oval one may be the strongest because of its capacity to bear large loads with neither rotation nor deformation. Here, we modified the external shape of a dental implant from circular to tri-oval, aiming to create a combination of high strain and low strain peri-implant environment that would ensure both primary implant stability and rapid osseointegration, respectively. Using in vivo mouse models, we tested the effects of this geometric alteration on implant survival and osseointegration over time. The maxima regions of tri-oval implants provided superior primary stability without increasing insertion torque. The minima regions of tri-oval implants presented low compressive strain and significantly less osteocyte apoptosis, which led to minimal bone resorption compared to the round implants. The rate of new bone accrual was also faster around the tri-oval implants. We further subjected both round and tri-oval implants to occlusal loading immediately after placement. In contrast to the round implants that exhibited a significant dip in stability that eventually led to their failure, the tri-oval implants maintained their stability throughout the osseointegration period. Collectively, these multiscale biomechanical analyses demonstrated the superior in vivo performance of the tri-oval implant design.
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http://dx.doi.org/10.3390/jcm8040427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517945PMC
March 2019

A Novel Osteotomy Preparation Technique to Preserve Implant Site Viability and Enhance Osteogenesis.

J Clin Med 2019 Feb 1;8(2). Epub 2019 Feb 1.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.

The preservation of bone viability at an osteotomy site is a critical variable for subsequent implant osseointegration. Recent biomechanical studies evaluating the consequences of site preparation led us to rethink the design of bone-cutting drills, especially those intended for implant site preparation. We present here a novel drill design that is designed to efficiently cut bone at a very low rotational velocity, obviating the need for irrigation as a coolant. The low-speed cutting produces little heat and, consequently, osteocyte viability is maintained. The lack of irrigation, coupled with the unique design of the cutting flutes, channels into the osteotomy autologous bone chips and osseous coagulum that have inherent osteogenic potential. Collectively, these features result in robust, new bone formation at rates significantly faster than those observed with conventional drilling protocols. These preclinical data have practical implications for the clinical preparation of osteotomies and alveolar bone reconstructive surgeries.
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http://dx.doi.org/10.3390/jcm8020170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406409PMC
February 2019

A Thermal and Biological Analysis of Bone Drilling.

J Biomech Eng 2018 10;140(10)

Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, CA 94304 e-mail: .

With the introduction of high-speed cutting tools, clinicians have recognized the potential for thermal damage to the material being cut. Here, we developed a mathematical model of heat transfer caused by drilling bones of different densities and validated it with respect to experimentally measured temperatures in bone. We then coupled these computational results with a biological assessment of cell death following osteotomy site preparation. Parameters under clinical control, e.g., drill diameter, rotational speed, and irrigation, along with patient-specific variables such as bone density were evaluated in order to understand their contributions to thermal damage. Predictions from our models provide insights into temperatures and thresholds that cause osteocyte death and that can ultimately compromise stability of an implant.
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http://dx.doi.org/10.1115/1.4040312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059311PMC
October 2018

Bone healing response in cyclically loaded implants: Comparing zero, one, and two loading sessions per day.

J Mech Behav Biomed Mater 2018 09 31;85:152-161. Epub 2018 May 31.

Laboratory for the Study of Calcified Tissues and Biomaterials, Faculty of Dentistry, Université de Montréal, Montreal, QC, Canada. Electronic address:

When bone implants are loaded, they are inevitably subjected to displacement relative to bone. Such micromotion generates stress/strain states at the interface that can cause beneficial or detrimental sequels. The objective of this study is to better understand the mechanobiology of bone healing at the tissue-implant interface during repeated loading. Machined screw shaped Ti implants were placed in rat tibiae in a hole slightly bigger than the implant diameter. Implants were held stable by a specially-designed bone plate that permits controlled loading. Three loading regimens were applied, (a) zero loading, (b) one daily loading session of 60 cycles with an axial force of 1.5 N/cycle for 7 days, and (c) two such daily sessions with the same axial force also for 7 days. Finite element analysis was used to characterize the mechanobiological conditions produced by the loading sessions. After 7 days, the implants with surrounding interfacial tissue were harvested and processed for histological, histomorphometric and DNA microarray analyses. Histomorphometric analyses revealed that the group subjected to repeated loading sessions exhibited a significant decrease in bone-implant contact and increase in bone-implant distance, as compared to unloaded implants and those subjected to only one loading session. Gene expression profiles differed during osseointegration between all groups mainly with respect to inflammatory and unidentified gene categories. The results indicate that increasing the daily cyclic loading of implants induces deleterious changes in the bone healing response, most likely due to the accumulation of tissue damage and associated inflammatory reaction at the bone-implant interface.
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http://dx.doi.org/10.1016/j.jmbbm.2018.05.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035061PMC
September 2018

An osteopenic/osteoporotic phenotype delays alveolar bone repair.

Bone 2018 07 25;112:212-219. Epub 2018 Apr 25.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Aging is associated with a function decline in tissue homeostasis and tissue repair. Aging is also associated with an increased incidence in osteopenia and osteoporosis, but whether these low bone mass diseases are a risk factor for delayed bone healing still remains controversial. Addressing this question is of direct clinical relevance for dental patients, since most implants are performed in older patients who are at risk of developing low bone mass conditions. The objective of this study was to assess how an osteopenic/osteoporotic phenotype affected the rate of new alveolar bone formation. Using an ovariectomized (OVX) rat model, the rates of tooth extraction socket and osteotomy healing were compared with age-matched controls. Imaging, along with molecular, cellular, and histologic analyses, demonstrated that OVX produced an overt osteoporotic phenotype in long bones, but only a subtle phenotype in alveolar bone. Nonetheless, the OVX group demonstrated significantly slower alveolar bone healing in both the extraction socket, and in the osteotomy produced in a healed extraction site. Most notably, osteotomy site preparation created a dramatically wider zone of dying and dead osteocytes in the OVX group, which was coupled with more extensive bone remodeling and a delay in the differentiation of osteoblasts. Collectively, these analyses demonstrate that the emergence of an osteoporotic phenotype delays new alveolar bone formation.
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http://dx.doi.org/10.1016/j.bone.2018.04.019DOI Listing
July 2018

Linking suckling biomechanics to the development of the palate.

Sci Rep 2016 Feb 4;6:20419. Epub 2016 Feb 4.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford CA 94305.

Skulls are amongst the most informative documents of evolutionary history but a complex geometry, coupled with composite material properties and complicated biomechanics, have made it particularly challenging to identify mechanical principles guiding the skull's morphogenesis. Despite this challenge, multiple lines of evidence, for example the relationship between masticatory function and the evolution of jaw shape, nonetheless suggest that mechanobiology plays a major role in skull morphogenesis. To begin to tackle this persistent challenge, cellular, molecular and tissue-level analyses of the developing mouse palate were coupled with finite element modeling to demonstrate that patterns of strain created by mammalian-specific oral behaviors produce complementary patterns of chondrogenic gene expression in an initially homogeneous population of cranial neural crest cells. Neural crest cells change from an osteogenic to a chondrogenic fate, leading to the materialization of cartilaginous growth plate-like structures in the palatal midline. These growth plates contribute to lateral expansion of the head but are transient structures; when the strain patterns associated with suckling dissipate at weaning, the growth plates disappear and the palate ossifies. Thus, mechanical cues such as strain appear to co-regulate cell fate specification and ultimately, help drive large-scale morphogenetic changes in head shape.
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http://dx.doi.org/10.1038/srep20419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740798PMC
February 2016

Rescuing failed oral implants via Wnt activation.

J Clin Periodontol 2016 Feb 12;43(2):180-92. Epub 2016 Feb 12.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA, USA.

Aim: Implant osseointegration is not always guaranteed and once fibrous encapsulation occurs clinicians have few options other than implant removal. Our goal was to test whether a WNT protein therapeutic could rescue such failed implants.

Material And Methods: Titanium implants were placed in over-sized murine oral osteotomies. A lack of primary stability was verified by mechanical testing. Interfacial strains were estimated by finite element modelling and histology coupled with histomorphometry confirmed the lack of peri-implant bone. After fibrous encapsulation was established peri-implant injections of a liposomal formulation of WNT3A protein (L-WNT3A) or liposomal PBS (L-PBS) were then initiated. Quantitative assays were employed to analyse the effects of L-WNT3A treatment.

Results: Implants in gap-type interfaces exhibited high interfacial strains and no primary stability. After verification of implant failure, L-WNT3A or L-PBS injections were initiated. L-WNT3A induced a rapid, significant increase in Wnt responsiveness in the peri-implant environment, cell proliferation and osteogenic protein expression. The amount of peri-implant bone and bone in contact with the implant were significantly higher in L-WNT3A cases.

Conclusions: These data demonstrate L-WNT3A can induce peri-implant bone formation even in cases where fibrous encapsulation predominates.
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http://dx.doi.org/10.1111/jcpe.12503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973628PMC
February 2016

Biomechanical aspects of the optimal number of implants to carry a cross-arch full restoration.

Authors:
John B Brunski

Eur J Oral Implantol 2014 ;7 Suppl 2:S111-31

A proper definition of the 'optimal' number of implants to support a full arch prosthesis should go beyond solely a listing of the number of implants used in a treatment plan; it should be based upon a biomechanical analysis that takes into account several factors: the locations of the implants in the jaw; the quality and quantity of bone into which they are placed; the loads (forces and moments) that develop on the implants; the magnitudes of stress and strain that develop in the interfacial bone as well as in the implants and prosthesis; and the relationship of the stresses and strains to limits for the materials involved. Overall, determining an 'optimal' number of implants to use in a patient is a biomechanical design problem. This paper discusses some of the approaches that are already available to aid biomechanically focused clinical treatment planning. A number of examples are presented to illustrate how relatively simple biomechanical analyses - e.g. the Skalak model - as well as more complex analyses (e.g. finite element modelling) can be used to assess the pros and cons of various arrangements of implants to support fullarch prostheses. Some of the examples considered include the use of 4 rather than 6 implants to span the same arc-length in a jaw, and the pros and cons of using tilted implants as in the 'all-on-4' approach. In evaluating the accuracy of the various biomechanical analyses, it is clear that our current prediction methods are not always perfectly accurate in vivo, although they can provide a reasonably approximate analysis of a treatment plan in many situations. In the current era of cone beam computerised tomography (CT) scans of patients in the dental office, there is significant promise for finite element analyses (FEA) based on anatomically-accurate input data. However, at the same time it has to be recognised that effective use of FEA software requires a reasonable engineering background, especially insofar as interpretations of the clinical significance of stresses and strains in bone and prosthetic materials.
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September 2014

Molecular mechanisms underlying skeletal growth arrest by cutaneous scarring.

Bone 2014 Sep 14;66:223-31. Epub 2014 Jun 14.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford CA 94035, USA. Electronic address:

In pediatric surgeries, cutaneous scarring is frequently accompanied by an arrest in skeletal growth. The molecular mechanisms responsible for this effect are not understood. Here, we investigated the relationship between scar contracture and osteogenesis. An excisional cutaneous wound was made on the tail of neonatal mice. Finite element (FE) modeling of the wound site was used to predict the distribution and magnitude of contractile forces within soft and hard tissues. Morphogenesis of the bony vertebrae was monitored by micro-CT analyses, and vertebral growth plates were interrogated throughout the healing period using assays for cell proliferation, death, differentiation, as well as matrix deposition and remodeling. Wound contracture was grossly evident on post-injury day 7 and accompanying it was a significant shortening in the tail. FE modeling indicated high compressive strains localized to the dorsal portions of the vertebral growth plates and intervertebral disks. These predicted strain distributions corresponded to sites of increased cell death, a cessation in cell proliferation, and a loss in mineralization within the growth plates and IVD. Although cutaneous contracture resolved and skeletal growth rates returned to normal, vertebrae under the cutaneous wound remained significantly shorter than controls. Thus, localized contractile forces generated by scarring led to spatial alterations in cell proliferation, death, and differentiation that inhibited bone growth in a location-dependent manner. Resolution of cutaneous scarring was not accompanied by compensatory bone growth, which left the bony elements permanently truncated. Therefore, targeting early scar reduction is critical to preserving pediatric bone growth after surgery.
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http://dx.doi.org/10.1016/j.bone.2014.06.007DOI Listing
September 2014

Improving oral implant osseointegration in a murine model via Wnt signal amplification.

J Clin Periodontol 2014 Feb 8;41(2):172-80. Epub 2013 Dec 8.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA, USA; Department of Periodontology, Service of Odontology, Rothschild Hospital, AP-HP, Paris 7 - Denis, Diderot University, U.F.R. of Odontology, Paris, France.

Aim: To determine the key biological events occurring during implant failure and then we use this knowledge to develop new biology-based strategies that improve osseointegration.

Materials And Methods: Wild-type and Axin2(LacZ/LacZ) adult male mice underwent oral implant placement, with and without primary stability. Peri-implant tissues were evaluated using histology, alkaline phosphatase (ALP) activity, tartrate resistant acid phosphatase (TRAP) activity and TUNEL staining. In addition, mineralization sites, collagenous matrix organization and the expression of bone markers in the peri-implant tissues were assessed.

Results: Maxillary implants lacking primary stability show histological evidence of persistent fibrous encapsulation and mobility, which recapitulates the clinical problems of implant failure. Despite histological and molecular evidence of fibrous encapsulation, osteoblasts in the gap interface exhibit robust ALP activity. This mineralization activity is counteracted by osteoclast activity that resorbs any new bony matrix and consequently, the fibrous encapsulation remains. Using a genetic mouse model, we show that implants lacking primary stability undergo osseointegration, provided that Wnt signalling is amplified.

Conclusions: In a mouse model of oral implant failure caused by a lack of primary stability, we find evidence of active mineralization. This mineralization, however, is outpaced by robust bone resorption, which culminates in persistent fibrous encapsulation of the implant. Fibrous encapsulation can be prevented and osseointegration assured if Wnt signalling is elevated at the time of implant placement.
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http://dx.doi.org/10.1111/jcpe.12187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993043PMC
February 2014

Micromotion-induced strain fields influence early stages of repair at bone-implant interfaces.

Acta Biomater 2013 May 19;9(5):6663-74. Epub 2013 Jan 19.

Laboratory for the Study of Calcified Tissues and Biomaterials, Faculty of Dentistry, Université de Montréal, Montreal, Quebec, Canada.

Implant loading can create micromotion at the bone-implant interface. The interfacial strain associated with implant micromotion could contribute to regulating the tissue healing response. Excessive micromotion can lead to fibrous encapsulation and implant loosening. Our objective was to characterize the influence of interfacial strain on bone regeneration around implants in mouse tibiae. A micromotion system was used to create strain under conditions of (1) no initial contact between implant and bone and (2) direct bone-implant contact. Pin- and screw-shaped implants were subjected to displacements of 150 or 300 μm for 60 cycles per day for 7 days. Pin-shaped implants placed in five animals were subjected to three sessions of 150 μm displacement per day, with 60 cycles per session. Control implants in both types of interfaces were stabilized throughout the healing period. Experimental strain analyses, microtomography, image-based displacement mapping, and finite element simulations were used to characterize interfacial strain fields. Calcified tissue sections were prepared and Goldner trichrome stained to evaluate the tissue reactions in higher and lower strain regions. In stable implants bone formation occurred consistently around the implants. In implants subjected to micromotion bone regeneration was disrupted in areas of high strain concentrations (e.g. >30%), whereas lower strain values were permissive of bone formation. Increasing implant displacement or number of cycles per day also changed the strain distribution and disturbed bone healing. These results indicate that not only implant micromotion but also the associated interfacial strain field contributes to regulating the interfacial mechanobiology at healing bone-implant interfaces.
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http://dx.doi.org/10.1016/j.actbio.2013.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622828PMC
May 2013

Gene expression profiling and histomorphometric analyses of the early bone healing response around nanotextured implants.

Nanomedicine (Lond) 2013 Sep 3;8(9):1385-95. Epub 2013 Jan 3.

Laboratory for the Study of Calcified Tissues & Biomaterials, Department of Stomatology, Université de Montréal, PO Box 6128, Station Centre-Ville, Montreal, QC, H3C 3J7, Canada.

Unlabelled: While in vitro studies have shown that nanoscale surface modifications influence cell fate and activity, there is little information on how they modulate healing at the bone-implant interface.

Aim: This study aims to investigate the effect of nanotopography at early time intervals when critical events for implant integration occur.

Materials & Methods: Untreated and sulfuric acid/hydrogen peroxide-treated machined-surface titanium alloy implants were placed in rat tibiae. Samples were processed for DNA microarray analysis and histomorphometry.

Results: At both 3 and 5 days, the gene expression profile of the healing tissue around nanotextured implants differed from that around machined-surface implants or control empty holes, and were accompanied by an increase in bone-implant contact on day 5. While some standard pathways such as the immune response predominated, a number of unclassified genes were also implicated.

Conclusion: Nanotexture elicits an initial gene response that is more complex than suspected so far and favors healing at the bone-implant interface.
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http://dx.doi.org/10.2217/nnm.12.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676440PMC
September 2013

Nanoscale surface modifications of medically relevant metals: state-of-the art and perspectives.

Nanoscale 2011 Feb 26;3(2):335-53. Epub 2010 Oct 26.

Faculty of Engineering, Department of Mechanical Engineering, University of Ottawa, Ottawa, ON K1N 6N5, Canada.

Evidence that nanoscale surface properties stimulate and guide various molecular and biological processes at the implant/tissue interface is fostering a new trend in designing implantable metals. Cutting-edge expertise and techniques drawn from widely separated fields, such as nanotechnology, materials engineering and biology, have been advantageously exploited to nanoengineer surfaces in ways that control and direct these processes in predictable manners. In this review, we present and discuss the state-of-the-art of nanotechnology-based approaches currently adopted to modify the surface of metals used for orthopedic and dental applications, and also briefly consider their use in the cardiovascular field. The effects of nanoengineered surfaces on various in vitro molecular and cellular events are firstly discussed. This review also provides an overview of in vivo and clinical studies with nanostructured metallic implants, and addresses the potential influence of nanotopography on biomechanical events at interfaces. Ultimately, the objective of this work is to give the readership a comprehensive picture of the current advances, future developments and challenges in the application of the infinitesimally small to biomedical surface science. We believe that an integrated understanding of the in vitro and particularly of the in vivo behavior is mandatory for the proper exploitation of nanostructured implantable metals and, indeed, of all biomaterials.
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http://dx.doi.org/10.1039/c0nr00485eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105323PMC
February 2011

The acceleration of implant osseointegration by liposomal Wnt3a.

Biomaterials 2010 Dec 22;31(35):9173-81. Epub 2010 Sep 22.

Department of Periodontology, Service of Odontology, Hotel-Dieu Hospital, AP-HP, U.F.R. of Odontology, Paris 7 Denis Diderot University, Paris, France.

The strength of a Wnt-based strategy for tissue regeneration lies in the central role that Wnts play in healing. Tissue injury triggers local Wnt activation at the site of damage, and this Wnt signal is required for the repair and/or regeneration of almost all tissues including bone, neural tissues, myocardium, and epidermis. We developed a biologically based approach to create a transient elevation in Wnt signaling in peri-implant tissues, and in doing so, accelerated bone formation around the implant. Our subsequent molecular and cellular analyses provide mechanistic insights into the basis for this pro-osteogenic effect. Given the essential role of Wnt signaling in bone formation, this protein-based approach may have widespread application in implant osseointegration.
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http://dx.doi.org/10.1016/j.biomaterials.2010.08.045DOI Listing
December 2010

Effect of mechanical stimuli on skeletal regeneration around implants.

Bone 2007 Apr 18;40(4):919-30. Epub 2006 Dec 18.

Department of Plastic and Reconstructive Surgery, Stanford University, 257 Campus Drive, PSRL Building, Stanford, CA 94305, USA.

Due to the aging population and the increasing need for total joint replacements, osseointegration is of a great interest for various clinical disciplines. Our objective was to investigate the molecular and cellular foundation that underlies this process. Here, we used an in vivo mouse model to study the cellular and molecular response in three distinct areas of unloaded implants: the periosteum, the gap between implant and cortical bone, and the marrow space. Our analyses began with the early phases of healing, and continued until the implants were completely osseointegrated. We investigated aspects of osseointegration ranging from vascularization, cell proliferation, differentiation, and bone remodeling. In doing so, we gained an understanding of the healing mechanisms of different skeletal tissues during unloaded implant osseointegration. To continue our analysis, we used a micromotion device to apply a defined physical stimulus to the implants, and in doing so, we dramatically enhanced bone formation in the peri-implant tissue. By comparing strain measurements with cellular and molecular analyses, we developed an understanding of the correlation between strain magnitudes and fate decisions of cells shaping the skeletal regenerate.
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http://dx.doi.org/10.1016/j.bone.2006.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1987325PMC
April 2007

Quality of dental implants.

Int Dent J 2003 ;53(6 Suppl 2):409-43

Institute of Clinical Dentistry, University of Oslo, Blindern, Norway.

Background: Clinicians need quality research data to decide which dental implant should be selected for patient treatment. AIM(S)/OBJECTIVE(S): To present the scientific evidence for claims of relationship between characteristics of dental implants and clinical performance.

Study Design: Systematic search of promotional material and Internet sites to find claims of implant superiority related to specific characteristics of the implant, and of the dental research literature to find scientific support for the claims.

Main Outcome Measures: Critical appraisal of the research documentation to establish the scientific external and internal validity as a basis for the likelihood of reported treatment outcomes as a function of implant characteristics.

Results: More than 220 implant brands have been identified, produced by about 80 manufacturers. The implants are made from different materials, undergo different surface treatments and come in different shapes, lengths, widths and forms. The dentist can in theory choose among more than 2,000 implants in a given patient treatment situation. Implants made from titanium and titanium alloys appear to perform well clinically in properly surgically prepared bone, regardless of small variations of shapes and forms. Various surface treatments are currently being developed to improve the capacity of a more rapid anchorage of the implant into bone. A substantial number of claims made by different manufacturers on alleged superiority due to design characteristics are not based on sound and long-term clinical scientific research. Implants are, in some parts of the world, manufactured and sold with no demonstration of adherence to any international standards.

Conclusions: The scientific literature does not provide any clear directives to claims of alleged benefits of specific morphological characteristics of dental implants.
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http://dx.doi.org/10.1111/j.1875-595x.2003.tb00918.xDOI Listing
February 2004

Biomechanical aspects of oral/maxillofacial implants.

Authors:
John B Brunski

Int J Prosthodont 2003 ;16 Suppl:30-2; discussion 47-51

Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York, USA.

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January 2004

Comparison of load distribution for implant overdenture attachments.

Int J Oral Maxillofac Implants 2002 Sep-Oct;17(5):651-62

Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York, USA.

Purpose: The aim of this study was to compare the force and moment distributions that develop on different implant overdenture attachments when vertical compressive forces are applied to an implant-retained overdenture.

Materials And Methods: The following attachments were examined: Nobel Biocare bar and clip (NBC), Nobel Biocare standard ball (NSB), Nobel Biocare 2.25-mm-diameter ball (NB2), Zest Anchor Advanced Generation (ZAAG), Sterngold ERA white (SEW), Sterngold ERA orange (SEO), Compliant Keeper System with titanium shims (CK-Ti), Compliant Keeper System with black nitrile 2SR90 sleeve rings (CK-70), and Compliant Keeper System with clear silicone 2SR90 sleeve rings (CK-90). The attachments were tested using custom strain-gauged abutments and 2 Brånemark System implants placed in a test model. Each attachment type had one part embedded in a denture-like housing and the other part (the abutment) screwed into the implants. Compressive static loads of 100 N were applied (1) bilaterally, over the distal midline (DM); (2) unilaterally, over the right implant (RI); (3) unilaterally, over the left implant (LI); and (4) between implants in the mid-anterior region (MA). Both the force and bending moment on each implant were recorded for each loading location and attachment type. Results were analyzed using 2-way analysis of variance and the Duncan multiple-range test.

Results: Both loading location and attachment type were statistically significant factors (P < .05). In general, the force and moment on an implant were greater when the load was applied directly over the implant or at MA.

Discussion: While not significant at every loading location, the largest implant forces tended to occur with ZAAG attachments; the smallest were found with the SEW, the SEO, the NSB, the CK-70, and the CK-90. Typically, higher moments existed for NBC and ZAAG, while lower moments existed for SEW, SEO, NSB, CK-90, and CK-70.

Conclusion: For different loading locations, significant differences were found among the different overdenture attachment systems.
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January 2003