A WNT protein therapeutic accelerates consolidation of a bone graft substitute in a pre-clinical sinus augmentation model.

AIM: Autologous bone grafts consolidate faster than bone graft substitutes (BGSs) but resorb over time, which compromises implant support. We hypothesized that differences in consolidation rates affected the mechanical properties of grafts and implant stability, and tested whether a pro-osteogenic protein, liposomal WNT3A (L-WNT3A), could accelerate graft consolidation. MATERIALS AND METHODS: A transgenic mouse model of sinus augmentation with immunohistochemistry, enzymatic assays, and histology were used to quantitatively evaluate the osteogenic properties of autografts and BGSs. Composite and finite element modelling compared changes in the mechanical properties of grafts during healing until consolidation, and secondary implant stability following remodelling activities. BGSs were combined with L-WNT3A and tested for its osteogenic potential. RESULTS: Compared with autografts, BGSs were bioinert and lacked osteoprogenitor cells. While in autografted sinuses, new bone arose evenly from all living autograft particles, new bone around BGSs solely initiated at the sinus floor, from the internal maxillary periosteum. WNT treatment of BGSs resulted in significantly higher expression levels of pro-osteogenic proteins (Osterix, Collagen I, alkaline phosphatase) and lower levels of bone-resorbing activity (tartrate-resistant acid phosphatase activity); together, these features culminated in faster new bone formation, comparable to that of an autograft. CONCLUSIONS: WNT-treated BGSs supported faster consolidation, and because BGSs typically resist resorption, their use may be superior to autografts for sinus augmentation.

Effects of masticatory loading on bone remodeling around teeth versus implants: Insights from a preclinical model.

OBJECTIVES: Teeth connect to bone via a periodontal ligament, whereas implants connect to bone directly. Consequently, masticatory loads are distributed differently to periodontal versus peri-implant bone. Our objective was to determine how masticatory loading of an implant versus a tooth affected peri-implant versus periodontal bone remodeling. Our hypothesis was that strains produced by functional loading of an implant would be elevated compared with the strains around teeth, and that this would stimulate a greater degree of bone turnover around implants versus in periodontal bone. MATERIALS AND METHODS: Sixty skeletally mature mice were divided into two groups. In the implant group, maxillary first molars (mxM1) were extracted, and after socket healing, titanium alloy implants were positioned subocclusally. After osseointegration, implants were exposed, resin crowns were placed, and masticatory loading was initiated. In the control group, the dentition was left intact. Responses of peri-implant and periodontal bone were measured using micro-CT, histology, bone remodeling assays, and quantitative histomorphometry while bone strains were estimated using finite element (FE) analyses. CONCLUSIONS: When a submerged osseointegrated implant is exposed to masticatory forces, peri-implant strains are elevated, and peri-implant bone undergoes significant remodeling that culminates in new bone accrual. The accumulation of new bone functions to reduce both peri-implant strains and bone remodeling activities, equivalent to those observed around the intact dentition.

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

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.

Are teeth superior to implants? A mapping review.

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.

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

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.

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

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.

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

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.

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

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.

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

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.Cite this article: Bone Joint Res. 2020;9(2):60-70.

Optimizing autologous bone contribution to implant osseointegration.

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.

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

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.

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

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-ß 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.

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

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.

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

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.

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

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.

A Thermal and Biological Analysis of Bone Drilling.

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.

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

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.

An osteopenic/osteoporotic phenotype delays alveolar bone repair.

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.

Linking suckling biomechanics to the development of the palate.

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.

Rescuing failed oral implants via Wnt activation.

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.