OsteoMacs and Their Role in Early Implant Failure and Osseointegration

Dental implants have transformed dentistry since their widespread adoption over the past 25 years, which has been due largely to their high survival rates and flexibility in rehabilitating oral function.¹ According to a recent study by iData Research, roughly 3 million dental implants are placed annually in the United States alone. Studies have reported the survival rate of implants as high as 95% or failure rates below 5%,^1-3 with implant failures typically classified as either early or late stage. Early failure is defined as occurring before or at the time of abutment connection, while late failure takes place after loading.³ The most common reason for early occurrences is failure at the implant surface during bone osseointegration, while late implant failure is caused by subsequent inadequate bone growth or infection due to systemic or local factors.^2-4 In a 10-year prospective cohort study it was estimated that early implant failures represent around 8% of total implant losses, while late-stage implant failures comprise about 12%.² In the early failure group of the study, the main reason for failure was lack of osseointegration (73.2%); the late failure group's main reasons for failure were peri-implantitis (32%), overloading (46.4%), and implant fracture (6.2%).²

The inflammatory immunological properties of macrophages have been documented extensively since the 19th century starting with studies of amoeboid movement and chemotaxis. However, it was not until the 1960s that different lineages of macrophages with distinct anti-inflammatory properties were documented.⁵ Currently, the dichotomy of macrophages is that they can polarize between an inflammatory role (M1 subtype) and pro-resolution/anti-inflammatory role (M2 subtype) (Figure 1). The ability to polarize to an entire spectrum of distinctly functioning macrophages regulating the immunological environment for different organ systems is increasingly gaining attention from clinicians and scientists. In particular, the proportion of M1 versus M2 macrophage has been documented to contribute to various pathologies in lung alveolus, arterial atheroma, wound healing, and bone homeostasis and has been the subject of intensive study over the past decade.⁶ There also exists a subset of macrophages, called osteal macrophages, or "OsteoMacs," that play a critical immune surveillance role in the osseointegration of dental implants and peri-implant bone homeostasis.^7,8

Based on a review of the literature by the authors, this article provides an overview of the current understanding of OsteoMacs and their role in early implant failure and osseointegration.

The Role of OsteoMacs in Osteogenesis

Initial bone volume growth immediately following implant placement as reported by Jennissen occurs primarily via contact and distance osteogenesis.⁹ The immunohistologic microenvironment around the implant surface modulates a sequence of events that involves acute inflammatory foreign body reaction, angiogenesis, and eventually osteogenesis. Jennissen observed macrophages of distinct cytology separate from osteoclasts and osteoblasts on an implant surface as early as the third to fifth day.⁹ These "osteal macrophages" (OsteoMacs) are increasingly being recognized as a critical player in bone hemostasis. Alexander et al reported in a mouse tibial injury model that the inflammatory osteal macrophage persisted throughout the entire healing process.¹⁰ Further in vivo depletion of osteal macrophage using a transgenic mouse model decreased the host's ability to deposit collagen type 1 and subsequent osteocyte mineralization. Chang et al reported in mice knockout in vitro studies up to a 23-fold decrease in mineralization potential when osteal macrophages were depleted.¹¹ Chehroudi et al reported osteal macrophages coating implant surfaces prior to osteoblast recruitment.¹²

Growing evidence suggests a critical regulatory function of osteal macrophages at the early-stage implant osteogenic environment, perhaps through their immune surveillance role (Figure 2). Although the exact mechanisms are unclear, osteal macrophages are hypothesized to promote osteogenesis through chondrocyte induction, releasing bioactive growth factors (eg, bone morphogenetic protein-2; 1,25 vitamin D3; transforming growth factor-ß, etc), and modulation of the local immune environment.¹³

OsteoMacs and Early Implant Failure

Although the intent of this article is not to examine osteal macrophages' pleiotropic properties, current evidence describes osteal macrophages as cells that exhibit a wide spectrum of functional plasticity and cellular cytology.^13,14 Primary stability during the early stage of implant osseointegration is enabled by the biological conditions of the neighboring bone of the osteotomy (biomechanical stability) and initial osteogenesis, while secondary stability largely depends on bone formation at the bone-implant interface achieved through distance and contact osteogenesis.^2,3 Therefore, the ability of the local peri-implant conditions to favor an osteogenic environment is key for primary stability or preventing early implant failure (Figure 2). Bone remodeling around an implant titanium oxide surface follows a distinct sequence of events starting with clot formation, protein adsorption, and macrophage infiltration.^15,16 These macrophages are the pioneer cells colonizing this new peri-implant bony environment and, therefore, may potentially play a lead role in defining the osteogenic conditions with their immunological properties. The ability of osteal macrophages to polarize between inflammatory and anti-inflammatory roles may be the controlling regulatory mechanism for controlling this microenvironment. Classically, M1 osteal macrophages release pro-inflammatory cytokines, including interleukin (IL)-1, IL-12, tumor necrosis factor-α, and matrix metalloproteinases. M2 osteal macrophages release wound healing cytokines, including transforming growth factor, vascular endothelial growth factor, platelet-derived growth factor, IL-4, and IL-10 (Figure 2).^14-18

Biomaterial Influence on OsteoMac Polarization

Implant surface properties have been designed to minimize foreign body reactions and promote an osteogenic environment. Rayahin and Gemeinhart have summarized various biomaterial strategies to modulate osteal macrophage phenotype.¹⁵ Such strategies are shown in Figure 3. Multi-nuclear giant cells are the hallmark of foreign body reactions as macrophages fuse with each other to increase their ability to engulf large foreign objects. Modulating implant surface size with biodegradable properties has shown to favor M2 osteal macrophage. Champion and Mitragotri reported a greater curvature that often exceeds the ability of macrophages to undergo cytoskeletal actin remodeling, therefore reducing M1 functionality.¹⁹ Classically, hydrophobic surfaces favor inflammatory M1 osteal macrophages as tissues associate exposed hydrophobic surfaces with unfavorability.^17,18 Alternatively, hydrophilic surfaces promote the M2 macrophage phenotype. Implant surface chemistry, ability to promote protein adsorption, and substrate stiffness are all important aspects that can influence osteal macrophage polarization (Figure 3).

In summary, biomaterials can potentially increase M2 osteal macrophage proportions through three mechanisms: (1) selective polarization of native OsteoMacs, (2) direct recruitment of native OsteoMacs with subsequent polarization, and (3) direct recruitment of existing embryonic M2 OsteoMacs.^15,18

Conclusion

Current basic cellular research efforts on implant failure emphasize osteoclasts, osteoblasts, and fibroblasts. Evidence in the past decade has increasingly focused on the role of osteal macrophages in modulating an osteogenic environment. Osteal macrophage polarization may play a pivotal role in driving the anabolic cytokines toward reducing undesirable inflammation and promoting wound healing. Osteal macrophage interaction with other cellular players to create favorable osteogenic conditions certainly warrants future research. Targeting osteal macrophages and modulating their polarization behavior through various biomaterial designs may be a potent therapeutical goal for reducing early implant failure.

About the Authors

Richard M. Yang, DDS
Oral and Maxillofacial Surgery Resident, Highland Hospital Alameda Health System, Oakland, California

Huzefa S. Talib, BDS, MFD RCSI, FFD RCSI (OSOM)
Clinical Associate Professor, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, New York; Diplomate, International Congress of Oral Implantologists

Richard J. Miron, DDS, MSc, PhD
Adjunct Faculty, Department of Periodontology, Nova Southeastern University, Fort Lauderdale, Florida; Adjunct Visiting Faculty, Department of Periodontology, University of Bern, Bern, Switzerland

Thomas G. Wiedemann, MD, PhD, DDS
Clinical Associate Professor, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, New York; Fellow, European Board of Oral and Maxillofacial Surgery; Diplomate, International Congress of Oral Implantologists