Bio

Bio


John B. Brunski is currently Senior Research Engineer in the Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, CA. From 1977 to December 2009, he was Professor in the Department of Biomedical Engineering at Rensselaer Polytechnic Institute in Troy, NY. He received his B.S. degree at the University of Pennsylvania, his M.S. degree at Stanford University, and his Ph.D. at the University of Pennsylvania, all in Metallurgy and Materials Science. Dr. Brunski’s 1977 Ph.D. thesis identified factors responsible for development of fibrous tissue vs. bone at the oral implant interface, and it was the first doctorate degree to be granted for dental implant research at an engineering school in the US.

Dr. Brunski’s research has largely focused on bioengineering aspects of dental and orthopaedic implant design, bone-implant interactions, and the biomechanics of bone healing. Dr. Brunski is one of the Principal Investigators of an ongoing R01 research grant from NIH to Stanford University and the University of Montreal entitled “Mechanobiology at healing bone-implant interfaces.” Dr. Brunski has authored over 30 textbook chapters on oral implants, bone, and related topics, plus 125 papers and extended abstracts. He has also delivered over 160 public presentations on these and related topics at national and international meetings, including many keynote lectures. Over his career, Dr. Brunski has been the Principal Investigator or co-investigator on over 20 research grants.

For more than 10 years Dr. Brunski was a Consultant to the Dental Devices Panel of the FDA. From 2009-2012 he was a member of the Musculoskeletal Tissue Engineering (MTE) Study Section of the NIH. Dr. Brunski has also professionally consulted for over 20 legal firms and corporations on topics ranging from patent infringement to product design and product liability. Dr. Brunski serves as Section Editor for Biomechanics and Biomaterials for the International Journal of Oral and Maxillofacial Implants. He has also served on the editorial boards of Clinical Oral Implant Research, J Dent Research, J Biomechanics, and other journals, and has served as a reviewer for many other journals including Bone, J Orthopaedic Research, and J Biomechanical Engineering.

Dr. Brunski has received a number of awards for innovation and excellence in teaching and engineering education, including being a member of a 10-person Rensselaer team that won the first Boeing Outstanding Educator Award in 1995. Also, he was part of a Rensselaer faculty team that won the Premier Award for Excellence in Engineering Education Courseware, Dec. 2000, sponsored by NEEDS and John Wiley and Sons, as well as the 2001 American Society of Mechanical Engineers (ASME) Curriculum Innovation Award.

For his research, Dr. Brunski received the Isaiah Lew Memorial Research Award from the American Academy of Implant Dentistry Research Foundation in 2001, being only the third engineer to receive this award. In 2006, Dr. Brunski was appointed as the first William R. Laney Visiting Professor at the Division of Prosthodontics at the Mayo Foundation in Rochester, NY, and also received the Jerome M. and Dorothy Schweitzer Research Award from the Greater New York Academy of Prosthodontics, New York City, NY. In 2007 Dr. Brunski was the recipient of the Anders Tjellström Award from the Craniofacial Osseointegration and Maxillofacial Prosthetics Rehabilitation Unit, Edmonton, Alberta, Canada. In 2008 he received the Astra Tech Scientific Award for Applied Research in Osseointegration.

Current Role at Stanford


Senior Research Engineer, Division of Plastic & Reconstructive Surgery, Dept. of Surgery

Honors & Awards


  • Isaiah Lew Memorial Research Award, American Academy of Implant Dentistry Research Foundation (2001)
  • William R. Laney Visiting Professor Award, Mayo Clinic Foundation in Rochester, MN (2006)
  • Jerome M. and Dorothy Schweitzer Research Award, Greater New York Academy of Prosthodontics, New York City, NY (2006)
  • Anders Tjellström Award, Craniofacial Osseointegration and Maxillofacial Prosthetics Rehabilitation Unit, Alberta, Canada (2007)
  • Astra Tech Scientific Award for Applied Research in Osseointegration, Astra Tech Implant Corporation (2008)

Education & Certifications


  • B.S., University of Pennsylvania, Metallurgy & Materials Science (1970)
  • M.S., Stanford University, Materials Science and Engineering (1972)
  • Ph.D., University of Pennsylvania, Metallurgy and Materials Science (1977)

Projects


  • Mechanobiology at Healing Bone-Implant Interfaces, Stanford University

    This project investigated the role of implant micromotion and the associated interfacial strain fields on bone-implant healing.

    This was an NIH project involving J. Brunski, Jill Helms and Antonio Nanci, Co-PIs, thru April 2013.

    Location

    CA

Professional

Work Experience


  • Professor Emeritus, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy NY, Rensselaer Polytechnic Institute (12/31/2009 - Present)

    Assistant Prof 1977-1983
    Assoc Prof 1983-1992
    Professor 1992-2009
    Emeritus Prof 2009-present

    Location

    Troy, NY

Professional Affiliations and Activities


  • member, Orthopaedic Research Society (1988 - Present)
  • member, Academy of Osseointegration (1990 - Present)

Publications

All Publications


  • A preclinical model links osseo-densification due to misfit and osseo-destruction due to stress/strain. Clinical oral implants research Coyac, B. R., Leahy, B., Salvi, G., Hoffmann, W., Brunski, J. B., Helms, J. A. 2019

    Abstract

    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 TRAP activity and Cathepsin K immunostaining. The lack of ALP activity and Collagen I IHC supported the absence of new bone formation. Collectively, CT imaging, quantification of Bone Implant Contact (BIC), Vimentin and IL1-beta IHCs demonstrated that implant failure occurred soon afterwards, 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.

    View details for DOI 10.1111/clr.13537

    View details for PubMedID 31520494

  • System for application of controlled forces on dental implants in rat maxillae: Influence of the number of load cycles on bone healing. Journal of biomedical materials research. Part B, Applied biomaterials de Barros E Lima Bueno, R., Dias, A. P., Ponce, K. J., Brunski, J. B., Nanci, A. 2019

    Abstract

    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 14days, case B no loading in the first 7 days followed by 7 days of a single, daily loading session (60cycles 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.

    View details for DOI 10.1002/jbm.b.34449

    View details for PubMedID 31368244

  • Mechanical and Biological Advantages of a Tri-Oval Implant Design. Journal of clinical medicine Yin, X., Li, J., Hoffmann, W., Gasser, A., Brunski, J. B., Helms, J. A. 2019; 8 (4)

    Abstract

    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.

    View details for DOI 10.3390/jcm8040427

    View details for PubMedID 30925746

  • Relationship Between Primary/Mechanical and Secondary/Biological Implant Stability INTERNATIONAL JOURNAL OF ORAL & MAXILLOFACIAL IMPLANTS Monje, A., Ravida, A., Wang, H., Helms, J. A., Brunski, J. B. 2019; 34: S7-+

    Abstract

    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.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).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.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.

    View details for DOI 10.11607/jomi.19suppl.g1

    View details for Web of Science ID 000476794800002

    View details for PubMedID 31116830

  • A Novel Osteotomy Preparation Technique to Preserve Implant Site Viability and Enhance Osteogenesis. Journal of clinical medicine Chen, C. H., Coyac, B. R., Arioka, M., Leahy, B., Tulu, U. S., Aghvami, M., Holst, S., Hoffmann, W., Quarry, A., Bahat, O., Salmon, B., Brunski, J. B., Helms, J. A. 2019; 8 (2)

    Abstract

    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.

    View details for PubMedID 30717291

  • A Thermal and Biological Analysis of Bone Drilling. Journal of biomechanical engineering Aghvami, M., Brunski, J. B., Serdar Tulu, U., Chen, C., Helms, J. A. 2018; 140 (10)

    Abstract

    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.

    View details for PubMedID 30029243

  • Bone healing response in cyclically loaded implants: Comparing zero, one, and two loading sessions per day JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS Bueno, R., Dias, A., Ponce, K. J., Wazen, R., Brunski, J. B., Nanci, A. 2018; 85: 152–61

    Abstract

    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.

    View details for PubMedID 29894930

    View details for PubMedCentralID PMC6035061

  • An osteopenic/osteoporotic phenotype delays alveolar bone repair. Bone Chen, C., Wang, L., Serdar Tulu, U., Arioka, M., Moghim, M. M., Salmon, B., Chen, C., Hoffmann, W., Gilgenbach, J., Brunski, J. B., Helms, J. A. 2018; 112: 212–19

    Abstract

    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.

    View details for PubMedID 29704698

  • Effects of Condensation on Peri-implant Bone Density and Remodeling JOURNAL OF DENTAL RESEARCH Wang, L., Wu, Y., Perez, K. C., Hyman, S., Brunski, J. B., Tulu, U., Bao, C., Salmon, B., Helms, J. A. 2017; 96 (4): 406-413
  • Relationships among Bone Quality, Implant Osseointegration, and Wnt Signaling. Journal of dental research Li, J., Yin, X., Huang, L., Mouraret, S., Brunski, J. B., Cordova, L., Salmon, B., Helms, J. A. 2017: 22034517700131-?

    Abstract

    A variety of clinical classification schemes have been proposed as a means to identify sites in the oral cavity where implant osseointegration is likely to be successful. Most schemes are based on structural characteristics of the bone, for example, the relative proportion of densely compact, homogenous (type I) bone versus more trabeculated, cancellous (type III) bone. None of these schemes, however, consider potential biological characteristics of the bone. Here, we employed multiscale analyses to identify and characterize type I and type III bones in murine jaws. We then combined these analytical tools with in vivo models of osteotomy healing and implant osseointegration to determine if one type of bone healed faster and supported osseointegration better than another. Collectively, these studies revealed a strong positive correlation between bone remodeling rates, mitotic activity, and osteotomy site healing in type III bone and high endogenous Wnt signaling. This positive correlation was strengthened by observations showing that the osteoid matrix that is responsible for implant osseointegration originates from Wnt-responsive cells and their progeny. The potential application of this knowledge to clinical practice is discussed, along with a theory unifying the role that biology and mechanics play in implant osseointegration.

    View details for DOI 10.1177/0022034517700131

    View details for PubMedID 28571512

  • Effects of Condensation on Peri-implant Bone Density and Remodeling. Journal of dental research Wang, L., Wu, Y., Perez, K. C., Hyman, S., Brunski, J. B., Tulu, U., Bao, C., Salmon, B., Helms, J. A. 2016: 22034516683932-?

    Abstract

    Bone condensation is thought to densify interfacial bone and thus improve implant primary stability, but scant data substantiate either claim. We developed a murine oral implant model to test these hypotheses. Osteotomies were created in healed maxillary extraction sites 1) by drilling or 2) by drilling followed by stepwise condensation with tapered osteotomes. Condensation increased interfacial bone density, as measured by a significant change in bone volume/total volume and trabecular spacing, but it simultaneously damaged the bone. On postimplant day 1, the condensed bone interface exhibited microfractures and osteoclast activity. Finite element modeling, mechanical testing, and immunohistochemical analyses at multiple time points throughout the osseointegration period demonstrated that condensation caused very high interfacial strains, marginal bone resorption, and no improvement in implant stability. Collectively, these multiscale analyses demonstrate that condensation does not positively contribute to implant stability.

    View details for DOI 10.1177/0022034516683932

    View details for PubMedID 28048963

    View details for PubMedCentralID PMC5384489

  • Axin2-expressing cells execute regeneration after skeletal injury SCIENTIFIC REPORTS Ransom, R. C., Hunter, D. J., Hyman, S., Singh, G., RANSOM, S. C., Shen, E. Z., Perez, K. C., Gillette, M., Li, J., Liu, B., Brunski, J. B., Helms, J. A. 2016; 6

    Abstract

    The mammalian skeleton performs a diverse range of vital functions, requiring mechanisms of regeneration that restore functional skeletal cell populations after injury. We hypothesized that the Wnt pathway specifies distinct functional subsets of skeletal cell types, and that lineage tracing of Wnt-responding cells (WRCs) using the Axin2 gene in mice identifies a population of long-lived skeletal cells on the periosteum of long bone. Ablation of these WRCs disrupts healing after injury, and three-dimensional finite element modeling of the regenerate delineates their essential role in functional bone regeneration. These progenitor cells in the periosteum are activated upon injury and give rise to both cartilage and bone. Indeed, our findings suggest that WRCs may serve as a therapeutic target in the setting of impaired skeletal regeneration.

    View details for DOI 10.1038/srep36524

    View details for Web of Science ID 000388150800001

    View details for PubMedID 27853243

    View details for PubMedCentralID PMC5113299

  • Mechanoresponsive Properties of the Periodontal Ligament JOURNAL OF DENTAL RESEARCH Huang, L., Liu, B., Cha, J. Y., Yuan, G., Kelly, M., Singh, G., Hyman, S., Brunski, J. B., Li, J., Helms, J. A. 2016; 95 (4): 467-475
  • Rescuing failed oral implants via Wnt activation. Journal of clinical periodontology Yin, X., Li, J., Chen, T., Mouraret, S., Dhamdhere, G., Brunski, J. B., Zou, S., Helms, J. A. 2016; 43 (2): 180-192

    Abstract

    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.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.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.These data demonstrate L-WNT3A can induce peri-implant bone formation even in cases where fibrous encapsulation predominates.

    View details for DOI 10.1111/jcpe.12503

    View details for PubMedID 26718012

  • Linking suckling biomechanics to the development of the palate. Scientific reports Li, J., Johnson, C. A., Smith, A. A., Hunter, D. J., Singh, G., Brunski, J. B., Helms, J. A. 2016; 6: 20419-?

    Abstract

    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.

    View details for DOI 10.1038/srep20419

    View details for PubMedID 26842915

    View details for PubMedCentralID PMC4740798

  • Disrupting the intrinsic growth potential of a suture contributes to midfacial hypoplasia. Bone Li, J., Johnson, C. A., Smith, A. A., Salmon, B., Shi, B., Brunski, J., Helms, J. A. 2015; 81: 186-195

    Abstract

    Children with unoperated cleft palates have nearly normal growth of their faces whereas patients who have had early surgical repair often exhibit midfacial hypoplasia. Surgical repair is responsible for the underlying bone growth arrest but the mechanisms responsible for these surgical sequelae are poorly understood. We simulated the effect of cleft palate repair by raising a mucoperiosteal flap in the murine palate. Three-dimensional micro-CT reconstructions of the palate along with histomorphometric measurements, finite element (FE) modeling, immunohistochemical analyses, and quantitative RT-PCR were employed to follow the skeletal healing process. Inflammatory bone resorption was observed during the first few days after denudation, which destroyed the midpalatal suture complex. FE modeling was used to predict and map the distribution of strains and their associated stresses in the area of denudation and the magnitude and location of hydrostatic and distortional strains corresponded to sites of skeletal tissue destruction. Once re-epithelialization was complete and wound contracture subsided, the midpalatal suture complex reformed. Despite this, growth at the midpalatal suture was reduced, which led to palatal constriction and a narrowing of the dental arch. Thus the simple act of raising a flap, here mimicked by denuding the mucoperiosteum, was sufficient to cause significant destruction to the midpalatal suture complex. Although the bone and cartilage growth plates were re-established, mediolateral skeletal growth was nonetheless compromised and the injured palate never reached its full growth potential. These data strongly suggest that disruption of suture complexes, which have intrinsic growth potential, should be avoided during surgical correction of congenital anomalies.

    View details for DOI 10.1016/j.bone.2014.04.020

    View details for PubMedID 24780877

  • Multiscale Analyses of the Bone-implant Interface. Journal of dental research Cha, J. Y., Pereira, M. D., Smith, A. A., Houschyar, K. S., Yin, X., Mouraret, S., Brunski, J. B., Helms, J. A. 2015; 94 (3): 482-490

    Abstract

    Implants placed with high insertion torque (IT) typically exhibit primary stability, which enables early loading. Whether high IT has a negative impact on peri-implant bone health, however, remains to be determined. The purpose of this study was to ascertain how peri-implant bone responds to strains and stresses created when implants are placed with low and high IT. Titanium micro-implants were inserted into murine femurs with low and high IT using torque values that were scaled to approximate those used to place clinically sized implants. Torque created in peri-implant tissues a distribution and magnitude of strains, which were calculated through finite element modeling. Stiffness tests quantified primary and secondary implant stability. At multiple time points, molecular, cellular, and histomorphometric analyses were performed to quantitatively determine the effect of high and low strains on apoptosis, mineralization, resorption, and collagen matrix deposition in peri-implant bone. Preparation of an osteotomy results in a narrow zone of dead and dying osteocytes in peri-implant bone that is not significantly enlarged in response to implants placed with low IT. Placing implants with high IT more than doubles this zone of dead and dying osteocytes. As a result, peri-implant bone develops micro-fractures, bone resorption is increased, and bone formation is decreased. Using high IT to place an implant creates high interfacial stress and strain that are associated with damage to peri-implant bone and therefore should be avoided to best preserve the viability of this tissue.

    View details for DOI 10.1177/0022034514566029

    View details for PubMedID 25628271

  • Molecular mechanisms underlying skeletal growth arrest by cutaneous scarring. Bone Li, J., Johnson, C. A., Smith, A. A., Shi, B., Brunski, J. B., Helms, J. A. 2014; 66: 223-231

    Abstract

    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.

    View details for DOI 10.1016/j.bone.2014.06.007

    View details for PubMedID 24933346

  • Molecular mechanisms underlying skeletal growth arrest by cutaneous scarring. Bone Li, J., Johnson, C. A., Smith, A. A., Shi, B., Brunski, J. B., Helms, J. A. 2014; 66: 223-231

    Abstract

    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.

    View details for DOI 10.1016/j.bone.2014.06.007

    View details for PubMedID 24933346

  • Biomechanical aspects of the optimal number of implants to carry a cross-arch full restorationl EUROPEAN JOURNAL OF ORAL IMPLANTOLOGY Brunski, J. B. 2014; 7: S111-S131
  • Improving oral implant osseointegration in a murine model via Wnt signal amplification. Journal of clinical periodontology Mouraret, S., Hunter, D. J., Bardet, C., Popelut, A., Brunski, J. B., Chaussain, C., Bouchard, P., Helms, J. A. 2014; 41 (2): 172-180

    Abstract

    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.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.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.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.

    View details for DOI 10.1111/jcpe.12187

    View details for PubMedID 24164629

  • A pre-clinical murine model of oral implant osseointegration. Bone Mouraret, S., Hunter, D. J., Bardet, C., Brunski, J. B., Bouchard, P., Helms, J. A. 2014; 58: 177-184

    Abstract

    Many of our assumptions concerning oral implant osseointegration are extrapolated from experimental models studying skeletal tissue repair in long bones. This disconnect between clinical practice and experimental research hampers our understanding of bone formation around oral implants and how this process can be improved. We postulated that oral implant osseointegration would be fundamentally equivalent to implant osseointegration elsewhere in the body. Mice underwent implant placement in the edentulous ridge anterior to the first molar and peri-implant tissues were evaluated at various timepoints after surgery. Our hypothesis was disproven; oral implant osseointegration is substantially different from osseointegration in long bones. For example, in the maxilla peri-implant pre-osteoblasts are derived from cranial neural crest whereas in the tibia peri-implant osteoblasts are derived from mesoderm. In the maxilla, new osteoid arises from periostea of the maxillary bone but in the tibia the new osteoid arises from the marrow space. Cellular and molecular analyses indicate that osteoblast activity and mineralization proceeds from the surfaces of the native bone and osteoclastic activity is responsible for extensive remodeling of the new peri-implant bone. In addition to histologic features of implant osseointegration, molecular and cellular assays conducted in a murine model provide new insights into the sequelae of implant placement and the process by which bone is generated around implants.

    View details for DOI 10.1016/j.bone.2013.07.021

    View details for PubMedID 23886841

  • A pre-clinical murine model of oral implant osseointegration BONE Mouraret, S., Hunter, D. J., Bardet, C., Brunski, J. B., Bouchard, P., Helms, J. A. 2014; 58: 177-184

    View details for DOI 10.1016/j.bone.2013.07.021

    View details for Web of Science ID 000328304000023

    View details for PubMedID 23886841

  • Effects of Biomechanical Properties of the Bone-Implant Interface on Dental Implant Stability: From In Silico Approaches to the Patient's Mouth ANNUAL REVIEW OF BIOMEDICAL ENGINEERING, VOL 16 Haiat, G., Wang, H., Brunski, J. 2014; 16: 187-213

    Abstract

    Dental implants have become a routinely used technique in dentistry for replacing teeth. However, risks of failure are still experienced and remain difficult to anticipate. Multiscale phenomena occurring around the implant interface determine the implant outcome. The aim of this review is to provide an understanding of the biomechanical behavior of the interface between a dental implant and the region of bone adjacent to it (the bone-implant interface) as a function of the interface's environment. First, we describe the determinants of implant stability in relation to the different multiscale simulation approaches used to model the evolution of the bone-implant interface. Then, we review the various aspects of osseointegration in relation to implant stability. Next, we describe the different approaches used in the literature to measure implant stability in vitro and in vivo. Last, we review various factors affecting the evolution of the bone-implant interface properties.

    View details for DOI 10.1146/annurev-bioeng-071813-104854

    View details for Web of Science ID 000348433000008

    View details for PubMedID 24905878

  • Gene expression profiling and histomorphometric analyses of the early bone healing response around nanotextured implants NANOMEDICINE Wazen, R. M., Kuroda, S., Nishio, C., Sellin, K., Brunski, J. B., Nanci, A. 2013; 8 (9): 1385-1395

    Abstract

    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.This study aims to investigate the effect of nanotopography at early time intervals when critical events for implant integration occur.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.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.Nanotexture elicits an initial gene response that is more complex than suspected so far and favors healing at the bone-implant interface.

    View details for DOI 10.2217/NNM.12.167

    View details for Web of Science ID 000330528600011

    View details for PubMedID 23286527

  • Micromotion-induced strain fields influence early stages of repair at bone-implant interfaces. Acta biomaterialia Wazen, R. M., Currey, J. A., Guo, H., Brunski, J. B., Helms, J. A., Nanci, A. 2013; 9 (5): 6663-6674

    Abstract

    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.

    View details for DOI 10.1016/j.actbio.2013.01.014

    View details for PubMedID 23337705

  • Primary cilia act as mechanosensors during bone healing around an implant MEDICAL ENGINEERING & PHYSICS Leucht, P., Monica, S. D., Temiyasathit, S., Lenton, K., Manu, A., Longaker, M. T., Jacobs, C. R., Spilkere, R. L., Guo, H., Brunski, J. B., Helms, J. A. 2013; 35 (3): 392-402

    Abstract

    The primary cilium is an organelle that senses cues in a cell's local environment. Some of these cues constitute molecular signals; here, we investigate the extent to which primary cilia can also sense mechanical stimuli. We used a conditional approach to delete Kif3a in pre-osteoblasts and then employed a motion device that generated a spatial distribution of strain around an intra-osseous implant positioned in the mouse tibia. We correlated interfacial strain fields with cell behaviors ranging from proliferation through all stages of osteogenic differentiation. We found that peri-implant cells in the Col1Cre;Kif3a(fl/fl) mice were unable to proliferate in response to a mechanical stimulus, failed to deposit and then orient collagen fibers to the strain fields caused by implant displacement, and failed to differentiate into bone-forming osteoblasts. Collectively, these data demonstrate that the lack of a functioning primary cilium blunts the normal response of a cell to a defined mechanical stimulus. The ability to manipulate the genetic background of peri-implant cells within the context of a whole, living tissue provides a rare opportunity to explore mechanotransduction from a multi-scale perspective.

    View details for DOI 10.1016/j.medengphy.2012.06.005

    View details for Web of Science ID 000315931400013

    View details for PubMedID 22784673

    View details for PubMedCentralID PMC3517784

  • Nanoscale surface modifications of medically relevant metals: state-of-the art and perspectives NANOSCALE Variola, F., Brunski, J. B., Orsini, G., de Oliveira, P. T., Wazen, R., Nanci, A. 2011; 3 (2): 335-353

    Abstract

    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.

    View details for DOI 10.1039/c0nr00485e

    View details for Web of Science ID 000287363500001

    View details for PubMedID 20976359

  • The acceleration of implant osseointegration by liposomal Wnt3a BIOMATERIALS Popelut, A., Rooker, S. M., Leucht, P., Medio, M., Brunski, J. B., Helms, J. A. 2010; 31 (35): 9173-9181

    Abstract

    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.

    View details for DOI 10.1016/j.biomaterials.2010.08.045

    View details for Web of Science ID 000284393300004

    View details for PubMedID 20864159

  • Molecular analysis of healing at a bone-implant interface JOURNAL OF DENTAL RESEARCH Colnot, C., Romero, D. M., Huang, S., Rahman, J., Currey, J. A., Nanci, A., Brunski, J. B., Helms, J. A. 2007; 86 (9): 862-867

    Abstract

    While bone healing occurs around implants, the extent to which this differs from healing at sites without implants remains unknown. We tested the hypothesis that an implant surface may affect the early stages of healing. In a new mouse model, we made cellular and molecular evaluations of healing at bone-implant interfaces vs. empty cortical defects. We assessed healing around Ti-6Al-4V, poly(L-lactide-co-D,L,-lactide), and 303 stainless steel implants with surface characteristics comparable with those of commercial implants. Our qualitative cellular and molecular evaluations showed that osteoblast differentiation and new bone deposition began sooner around the implants, suggesting that the implant surface and microenvironment around implants favored osteogenesis. The general stages of healing in this mouse model resembled those in larger animal models, and supported the use of this new model as a test bed for studying cellular and molecular responses to biomaterial and biomechanical conditions.

    View details for Web of Science ID 000249013200011

    View details for PubMedID 17720856

  • FAK-Mediated Mechanotransduction in Skeletal Regeneration PLOS ONE Leucht, P., Kim, J., Currey, J. A., Brunski, J., Helms, J. A. 2007; 2 (4)

    Abstract

    The majority of cells are equipped to detect and decipher physical stimuli, and then react to these stimuli in a cell type-specific manner. Ultimately, these cellular behaviors are synchronized to produce a tissue response, but how this is achieved remains enigmatic. Here, we investigated the genetic basis for mechanotransduction using the bone marrow as a model system. We found that physical stimuli produced a pattern of principal strain that precisely corresponded to the site-specific expression of sox9 and runx2, two transcription factors required for the commitment of stem cells to a skeletogenic lineage, and the arrangement and orientation of newly deposited type I collagen fibrils. To gain insights into the genetic basis for skeletal mechanotransduction we conditionally inactivated focal adhesion kinase (FAK), an intracellular component of the integrin signaling pathway. By doing so we abolished the mechanically induced osteogenic response and thus identified a critical genetic component of the molecular machinery required for mechanotransduction. Our data provide a new framework in which to consider how physical forces and molecular signals are synchronized during the program of skeletal regeneration.

    View details for DOI 10.1371/journal.pone.0000390

    View details for Web of Science ID 000207445600004

    View details for PubMedID 17460757

    View details for PubMedCentralID PMC1849965

  • Effect of mechanical stimuli on skeletal regeneration around implants BONE Leucht, P., Kim, J., Wazen, R., Currey, J. A., Nanci, A., Brunski, J. B., Heims, J. A. 2007; 40 (4): 919-930

    Abstract

    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.

    View details for DOI 10.1016/j.bone.2006.10.027

    View details for Web of Science ID 000245419800015

    View details for PubMedID 17175211

    View details for PubMedCentralID PMC1987325