Highlights
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Atemporal osseointegration would improve patient’s function and quality of life.
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Accelerating/improving osseointegration demands combined and multiple engineering domains.
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Hierarchical designing shall provide an informed design rationale for development.
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Implant macrogeometry and surgical technique define the osseointegration pathway.
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Despite the several years after its introduction, osseointegration is yet unresolved.
Abstract
Objective
Osseointegration has been a proven concept in implant dentistry and orthopedics for decades. Substantial efforts for engineering implants for reduced treatment time frames have focused on micrometer and most recently on nanometer length scale alterations with negligible attention devoted to the effect of both macrometer design alterations and surgical instrumentation on osseointegration. This manuscript revisits osseointegration addressing the individual and combined role of alterations on the macrometer, micrometer, and nanometer length scales on the basis of cell culture, preclinical in vivo studies, and clinical evidence.
Methods
A critical appraisal of the literature was performed regarding the impact of dental implant designing on osseointegration. Results from studies with different methodological approaches and the commonly observed inconsistencies are discussed.
Results
It is a consensus that implant surface topographical and chemical alterations can hasten osseointegration. However, the tailored combination between multiple length scale design parameters that provides maximal host response is yet to be determined.
Significance
In spite of the overabundant literature on osseointegration, a proportional inconsistency in findings hitherto encountered warrants a call for appropriate multivariable study designing to ensure that adequate data collection will enable osseointegration maximization and/or optimization, which will possibly lead to the engineering of endosteal implant designs that can be immediately placed/loaded regardless of patient dependent conditions.
1
Introduction
Bone fusing to titanium was described in 1940 by Bothe et al , then by Leventhal more than 6 decades ago , who also showed that titanium failed to cause tissue reaction and that it would serve as an ideal metal for prostheses. After considerable time, the term osseointegration was created and it was then refined by a series of well-characterized scientific reports by Brånemark and colleagues . It has been defined as the formation of a direct interface between an implant and bone without soft tissue interposition at the optical microscopy level . This phenomenon has been the basis for multiple orthopedic and dental rehabilitation procedures, paving the way for quality of life improvement of a large number of patients .
The introduction of titanium and its alloys to implant dentistry has marked an era where the main driving force for advances in implant engineering has been centered at decreasing or eliminating the hiatus between surgical placement and functional loading due to improved host-to-implant response . Nonetheless, clinical and basic research on the field of implant dentistry resulted in a lack of sequential and hierarchical approach for implant designing that challenges biomedical engineers to retrospectively address the interaction of the main design parameters such as macrogeometry, microgeometry, nanogeometry, and surgical instrumentation in an objective fashion .
The implant design is one of the important parameters for the achievement of osseointegration, however, as of today, the optimal design for atemporal implant stability in bone is yet to be determined . Atemporal osseointegration became an academic and industrial goal since it would allow clinicians to rehabilitate patients in minimal treatment time frames .
This review manuscript revisits osseointegration in a structured format, first addressing how implant hardware design (bulk device design and related surgical instrumentation dimensions) features potentially influence bone healing pathway and the placement of other design parameters within implant hardware. Second, the effect of micrometer designing (a primary hardware ad-hoc ) on osseointegration is discussed in light of the current literature. Third, and due to its more recent body of literature, a section on the available evidence and utilization of nanotechnology (a secondary ad-hoc ) applied to implant surface engineering is presented based on their potential in further improving osseointegration when hierarchically applied onto the implant macrometer and micrometer design.
2
The effect of implant macrogeometric (hardware design) in bone healing pathway: implications for micrometer scale designing
It has been extensively reported that as time elapses following implantation of osteoconductive endosteal implants ( e.g. titanium-based alloys), intimate contact between bone and device will render the system biomechanical stability and load-bearing capability . Such observation has been supported by over ten thousand scientific reports that are based on a large number of different devices surgically placed in bone through a large variation in surgical instrumentation technique and sequence. Thus, even though through the course of over seven decades, osseointegration has gone from novelty to commodity in surgery, substantial attention is still devoted in understanding its principles and characteristics especially as a function of endosteal implant modification. While a plethora of studies concerns the effects of micrometer and more recently nanometer scale design parameter contribution to osseointegration, a significantly smaller body of work is available regarding how hardware design aspects affect osseointegration. For instance, far less explored in the literature is how osseointegration temporally occurs around endosteal implants substantially shift as a function of two major key implant design parameters: implant macrogeometry and its associated surgical instrumentation . While it is obvious that two different design parameters are under consideration, their contribution to the healing mode cannot be considered separately .
2.1
The interfacial remodeling (tight fit) healing pathway
The healing scenario described in this section is typically observed for tight fit screw type implants ( i.e. the majority of implant systems available in the market) as they are placed in the osteotomy in intimate contact between the implant and bone throughout the device’s threaded bulk. Such intimate interplay between device and osteotomy dimensions renders the system initial or primary stability where no biologic interplay yet exists . This mechanical interlocking is variably influenced by the implant geometry and surface micrometer level topography, as well as the implant osteotomy site dimensions, and regulate the distribution of strain applied to the hard tissue in proximity with the implant . Strain is directly related to bone-implant interfacial stress and frictional force, and is clinically expressed as insertion torque .
The theoretical background of the primary stability concept is that the bone is assumed to be an elastic material and that strain and implant stability will have a linear relation . However, in reality, the stability of the implant would decrease beyond the yield strain of the bone due to excessive microcrack formation and compression necrosis, which both phenomena trigger bone remodeling . Thus, high degrees of insertion torque must be questioned since elastic theory predicts that excessive strain not only leads to the decrease of biomechanical stability, but also incites negative biologic responses depending on the implant thread design that influence the compression . Such cell-mediated bone resorption and subsequent bone apposition most often occurring from the pristine bone wall toward the implant surface is responsible for what has under theoretical and experimental basis been coined as implant stability dip, where primary stability obtained through the mismatch between implant macrogeometry and surgical instrumentation dimensions is lost due to the cell-mediated interfacial remodeling to be regained through bone apposition .
This healing mode sequence concerns implant placement in sites that were surgically instrumented to dimensions that approximate the inner diameter of the implant threads ( Fig. 1 ). At early time points, an almost continuous bone-implant interface renders the system implant primary stability. At this stage, microcracks depicting that the yield strength of bone has been exceeded due to high stress levels are visualized along with initial remodeling taking place between the implant threads due to compression necrosis. As time elapses in vivo , an extensive remodeling region is evident presenting void spaces partially filled by newly formed bone . Thus, the scenario that has been histologically observed in multiple instances confirms the theoretical and experimental basis for the initial stability rendered by mechanical interlocking between implant and bone that at some point in time after placement under stable conditions decreased due to extensive bone resorption ( Fig. 1 ). Subsequently, the resorbed area will be altered by newly formed woven bone, which eventually reestablishes the contact to the implant interface (secondary stability), and will subsequently remodel multiple times toward a lamellar configuration that will support the metallic device throughout its lifetime ( Fig. 1 ).
2.2
Intramembranous-like healing pathway (healing chamber osseointegration)
The second osseointegration pathway concerns the opposite scenario of the tight fit screw type implant, where void spaces between the implant bulk and the surgically instrumented drilled site walls are formed . These void spaces left between bone and implant bulk, often referred as healing chambers, will be filled with blood clot immediately after placement and will not contribute to primary stability. These however, have been regarded as a key contributor to secondary stability .
The early healing biology and kinetics of bone formation in healing chambers has been discussed in detail by Berglundh et al. while the effect of healing chamber size and shape on bone formation has been explored elsewhere . Such healing chambers, filled with the blood clot, will evolve toward osteogenic tissue that subsequently ossifies through an intramembranous-like pathway . Noteworthy is that unlike the interfacial remodeling healing pathway, healing chamber configurations do not encompass the initial cleanup process due to microcracking and ostecompression . In this case, the blood filling the space between pristine bone and device will develop toward a connective tissue network that provides a seamless pathway for cell migration within the space once filled by the blood clot ( Fig. 2 ). Such healing configuration thus allows new bone formation throughout the healing chamber from all available surfaces (implant surface, instrumented bone surface) and within the chamber volume. Thus, intramembranous-like healing mode presents substantial deviation from the classic interfacial remodeling healing pathway observed in tight fit screw-type implant .
2.3
The hybrid healing pathway: bringing together interfacial remodeling and intramembranous-like bone healing modes
Recent investigations have employed either experimental implant designs with an outer thread design that provided stability while the inner thread and osteotomy dimensions allowed healing chambers or alterations in osteotomy dimensions in large thread pitch implant designs . The rationale for these alterations lie upon the fact that thread designing may allow for both high degrees of primary stability along with a surgical instrumentation outer diameter that is closer to the outer diameter of the implant allowing healing chamber formation. Since healing chambers allow rapid intramembranous-like rapid woven bone formation , such rapid bone growth may compensate for the implant stability loss due to compression regions where implant threads contacts bone for primary stability ( Fig. 3 ).
While promising developments have been made over the last five decades regarding implant hardware designing and how it dictates bone healing and long-term bone morphology around endosteal implants, it is widely recognized that other design features do in fact hasten osseointegration and can further increase the performance of implant hardware . For instance, lower length scale design parameters have been designed in an attempt to change the degree of intimacy between host biofluids and implant surface while also changing cell phenotype to hasten biological response . However, their early effects are directly related to their strategic hierarchical placement as a function of implant hardware design since healing mode and kinetics drastically shift as a function of the macrometer scale variables. It is thus intuitive that implant hardware should be strategically designed to allow adequate implant primary stability while maximizing interaction between the host biofluids and implant surface. For instance, the reduced length scale design features intended to improve the establishment and maintenance of continuous pathway for bone forming cell migration toward the implant surface will not be as efficient in accelerating osseointegration in regions where cell-mediated interfacial remodeling initially occurs after placement due to initial hardware design interaction with bone. Thus, implant hardware designs that allow healing chamber formation are more suited to deliver adequate conditions for improved micrometer and the nanometer length scale design features performance in hastening early osseointegration.
2
The effect of implant macrogeometric (hardware design) in bone healing pathway: implications for micrometer scale designing
It has been extensively reported that as time elapses following implantation of osteoconductive endosteal implants ( e.g. titanium-based alloys), intimate contact between bone and device will render the system biomechanical stability and load-bearing capability . Such observation has been supported by over ten thousand scientific reports that are based on a large number of different devices surgically placed in bone through a large variation in surgical instrumentation technique and sequence. Thus, even though through the course of over seven decades, osseointegration has gone from novelty to commodity in surgery, substantial attention is still devoted in understanding its principles and characteristics especially as a function of endosteal implant modification. While a plethora of studies concerns the effects of micrometer and more recently nanometer scale design parameter contribution to osseointegration, a significantly smaller body of work is available regarding how hardware design aspects affect osseointegration. For instance, far less explored in the literature is how osseointegration temporally occurs around endosteal implants substantially shift as a function of two major key implant design parameters: implant macrogeometry and its associated surgical instrumentation . While it is obvious that two different design parameters are under consideration, their contribution to the healing mode cannot be considered separately .
2.1
The interfacial remodeling (tight fit) healing pathway
The healing scenario described in this section is typically observed for tight fit screw type implants ( i.e. the majority of implant systems available in the market) as they are placed in the osteotomy in intimate contact between the implant and bone throughout the device’s threaded bulk. Such intimate interplay between device and osteotomy dimensions renders the system initial or primary stability where no biologic interplay yet exists . This mechanical interlocking is variably influenced by the implant geometry and surface micrometer level topography, as well as the implant osteotomy site dimensions, and regulate the distribution of strain applied to the hard tissue in proximity with the implant . Strain is directly related to bone-implant interfacial stress and frictional force, and is clinically expressed as insertion torque .
The theoretical background of the primary stability concept is that the bone is assumed to be an elastic material and that strain and implant stability will have a linear relation . However, in reality, the stability of the implant would decrease beyond the yield strain of the bone due to excessive microcrack formation and compression necrosis, which both phenomena trigger bone remodeling . Thus, high degrees of insertion torque must be questioned since elastic theory predicts that excessive strain not only leads to the decrease of biomechanical stability, but also incites negative biologic responses depending on the implant thread design that influence the compression . Such cell-mediated bone resorption and subsequent bone apposition most often occurring from the pristine bone wall toward the implant surface is responsible for what has under theoretical and experimental basis been coined as implant stability dip, where primary stability obtained through the mismatch between implant macrogeometry and surgical instrumentation dimensions is lost due to the cell-mediated interfacial remodeling to be regained through bone apposition .
This healing mode sequence concerns implant placement in sites that were surgically instrumented to dimensions that approximate the inner diameter of the implant threads ( Fig. 1 ). At early time points, an almost continuous bone-implant interface renders the system implant primary stability. At this stage, microcracks depicting that the yield strength of bone has been exceeded due to high stress levels are visualized along with initial remodeling taking place between the implant threads due to compression necrosis. As time elapses in vivo , an extensive remodeling region is evident presenting void spaces partially filled by newly formed bone . Thus, the scenario that has been histologically observed in multiple instances confirms the theoretical and experimental basis for the initial stability rendered by mechanical interlocking between implant and bone that at some point in time after placement under stable conditions decreased due to extensive bone resorption ( Fig. 1 ). Subsequently, the resorbed area will be altered by newly formed woven bone, which eventually reestablishes the contact to the implant interface (secondary stability), and will subsequently remodel multiple times toward a lamellar configuration that will support the metallic device throughout its lifetime ( Fig. 1 ).
2.2
Intramembranous-like healing pathway (healing chamber osseointegration)
The second osseointegration pathway concerns the opposite scenario of the tight fit screw type implant, where void spaces between the implant bulk and the surgically instrumented drilled site walls are formed . These void spaces left between bone and implant bulk, often referred as healing chambers, will be filled with blood clot immediately after placement and will not contribute to primary stability. These however, have been regarded as a key contributor to secondary stability .
The early healing biology and kinetics of bone formation in healing chambers has been discussed in detail by Berglundh et al. while the effect of healing chamber size and shape on bone formation has been explored elsewhere . Such healing chambers, filled with the blood clot, will evolve toward osteogenic tissue that subsequently ossifies through an intramembranous-like pathway . Noteworthy is that unlike the interfacial remodeling healing pathway, healing chamber configurations do not encompass the initial cleanup process due to microcracking and ostecompression . In this case, the blood filling the space between pristine bone and device will develop toward a connective tissue network that provides a seamless pathway for cell migration within the space once filled by the blood clot ( Fig. 2 ). Such healing configuration thus allows new bone formation throughout the healing chamber from all available surfaces (implant surface, instrumented bone surface) and within the chamber volume. Thus, intramembranous-like healing mode presents substantial deviation from the classic interfacial remodeling healing pathway observed in tight fit screw-type implant .
2.3
The hybrid healing pathway: bringing together interfacial remodeling and intramembranous-like bone healing modes
Recent investigations have employed either experimental implant designs with an outer thread design that provided stability while the inner thread and osteotomy dimensions allowed healing chambers or alterations in osteotomy dimensions in large thread pitch implant designs . The rationale for these alterations lie upon the fact that thread designing may allow for both high degrees of primary stability along with a surgical instrumentation outer diameter that is closer to the outer diameter of the implant allowing healing chamber formation. Since healing chambers allow rapid intramembranous-like rapid woven bone formation , such rapid bone growth may compensate for the implant stability loss due to compression regions where implant threads contacts bone for primary stability ( Fig. 3 ).
While promising developments have been made over the last five decades regarding implant hardware designing and how it dictates bone healing and long-term bone morphology around endosteal implants, it is widely recognized that other design features do in fact hasten osseointegration and can further increase the performance of implant hardware . For instance, lower length scale design parameters have been designed in an attempt to change the degree of intimacy between host biofluids and implant surface while also changing cell phenotype to hasten biological response . However, their early effects are directly related to their strategic hierarchical placement as a function of implant hardware design since healing mode and kinetics drastically shift as a function of the macrometer scale variables. It is thus intuitive that implant hardware should be strategically designed to allow adequate implant primary stability while maximizing interaction between the host biofluids and implant surface. For instance, the reduced length scale design features intended to improve the establishment and maintenance of continuous pathway for bone forming cell migration toward the implant surface will not be as efficient in accelerating osseointegration in regions where cell-mediated interfacial remodeling initially occurs after placement due to initial hardware design interaction with bone. Thus, implant hardware designs that allow healing chamber formation are more suited to deliver adequate conditions for improved micrometer and the nanometer length scale design features performance in hastening early osseointegration.
3
The effect of implant microgeometric designing in bone healing: a prelude to nanometer scale designing
One of the most researched areas, and one that has had significant impact on treatment strategies, is unquestionably the implant surface engineering. Over the years, surface topography modification has been attempted through various methodologies, and dramatic changes in osseointegration quality and quantity have been witnessed. The primitive surface finish of the osseointegrated implants proposed was that of turned implants manufactured by a machining process. These turned (machined) implants (better known as Brånemark-type implants) dominated the market until the mid-1990s and therefore, have the longest clinical documentation . From such long-term clinical evidences, it can be concluded that turned implants present a clinically acceptable prognosis, if the traditional healing protocol (2-stage approach with a healing period of 3 months in the mandible, and 6 months in the maxilla) is followed , with a baseline assumption that the implant sites were fully healed ridges with good bone quality.
Although successful from a long-term perspective, the indications for turned implants were limited to healthy subjects with sufficient bone, and the treatment period created discomfort for the patients. Thus, the central focus and motivation for further surface topography research have been to shorten the time to osseointegrate and to expand the clinical modalities. As a result, some implants with extremely rough surface topography were developed and have been circulated in the market for some years, based on the simple engineering concept that rougher surfaces would provide mechanically higher interlocking between surface and the bone.
One of the methods commonly used to roughen the implant surface was the titanium plasma spray (TPS) technique, which yielded a bumpy surface configuration with extremely high average (mean) height deviation ( R a of 4–5 μm) as compared to the turned Brånemark-type implants. In preclinical investigations, such extremely rough surface topography of the TPS surface presented improved osseointegration compared to the turned surfaces . Unfortunately, the clinical trials seemed to present little or rather negative outcomes with progressive marginal bone loss , resulting in TPS-roughened implant surfaces falling from favor among implant manufacturers.
From the mid-1990s to date, it has been experimentally demonstrated that osseointegration is improved and accelerated through various roughening procedures , such as sand blasting , acid etching , anodic oxidation , and even laser etching , and that there exists an optimal range in the micrometer scale . The so-called moderately microroughened implant surfaces have been proven to present improved osseointegration in experimental and in clinical studies . Today, implant surfaces with moderately textured microtopographies ( S a 1–2 μm) provide a basis for the majority of commercially available implants. Turned implants as a substrate are treated with the aforementioned procedures, strategically roughening them at the micrometer length scale to present improved bone response.
Owing to the improved osseointegration proven in experimental studies, it is now believed that the amount of time needed to establish implant–bone system biomechanical competence for functional load bearing can be significantly reduced . Based on this experimental evidence, alteration in the clinical loading protocol (from delayed to early or immediate) has been attempted, presenting long-term clinical success . It must be noted that the dramatic transition in clinical loading protocol results from the combined effect of numerous factors and, strictly speaking, cannot be attributed solely to the microroughened surface topography. Thus, although manufacturers commonly claim that a newly developed implant surface can reduce the time needed to osseointegrate, one must keep in mind that osseointegration is an outcome of the combination of different designs .
However, microtopography undoubtedly influences improved clinical success, especially in compromised situations such as poor-quality bone, or irradiated bone. It has been reported by Khang et al., in a multicenter study comparing the success of turned versus dual acid-etched surfaces in poor bone quality sites, that the clinical success was significantly higher for the moderately roughened implants than the turned implants . This is in accordance with the report from Pinholt stating that the survival of moderately roughened implants was significantly higher compared to that of turned implants in grafted maxillary bone sites . Even in post-tumor-resected irradiated sites, implant survival is dramatically higher for moderately roughened implant surfaces than for turned surfaces after 5 years in function , which indicates that treatment using moderately roughened implants significantly improved postoperative quality of life for patients who undergo massive oral and maxillofacial resection therapy.
In the space of a mere decade, implant surface modification has advanced to a new stage with the introduction of so-called nanolevel modification . The nanolevel modification of implant surfaces, normally impossible to detect unless adequate instrumentation is employed, is based on the knowledge that the application of nanostructures (less than 100 nm in size in at least one dimension) significantly upregulate the biologic responses, since elements such as growth factors, proteins, and cells interact at this level .
It has been reported that the nanostructured surface is bioactive , that is, it has the potential to cause a reaction in the living body, whereas it is well known that the titanium or the titania itself is a bioinert material, and thus has no such potential . Material bioactivity is one of the core concepts of the biologically inspired biomimetic engineering, which is a cross-link between material science and tissue engineering/regenerative medicine. The nanometer length scale modification has recently received significant attention in the interest of increased bioactivity.
4
The nanometer scale designing: current techniques and trends
While the macrometer and micrometer implant design parameters have been investigated over several decades, endosteal implant designing at the nanometer length scale is relatively new and its recent developments are hereafter presented in an objective fashion.
The nanometer scale was likely ‘born’ as early as when matter itself came into existence at the Big Bang. The universe as we see it is in the macrometer scale (1–1000 m); however, it can be drilled down to the invisible universe, to the micrometer scale (10 −3 m) and further down to the nanometer scale (10 −9 to 10 −6 m, i.e. 1–1000 nm), where the building blocks of the universe, the atom and the sub-atomic particles (protons, neutrons, and electrons) interact electromagnetically. At the time of its origin, the Earth’s matter in the nanometer scale comprised of inorganic particles of solidified core. Billions of years later, organic, biological molecules with various degrees of organization appeared, and started to interact with the inorganic components of the planet at various scales, resulting in complex inorganic–organic systems. The nanometer scale is quintessential to the function of these systems .
While it is obvious that the nanometer scale can be utilized for multiple engineering purposes, the reduced dimensions confer unique properties to the materials fabricated with nanotechnology (especially at 1–100 nm, which defines the grain size of such materials) and this has attracted significant interest in the research community. From a physical standpoint, nanoparticles are small enough to interact with DNA, which is approximately 2 nm in diameter .
The physical principles governing materials science in the macro- and micrometer scale have been exploited in the past, in the analysis of quantum mechanical relationships, which led to the development of novel fields, such as condensed matter physics (especially solid-state physics), statistical mechanics, and thermodynamics. Although these quantum mechanical relationships have been experimentally validated by material scientists, modern manufacturing techniques for precise atomic buildup at the nanometer scale, have shown that materials with a reduced scale in at least one of their 3 dimensions exhibit substantially different electronic configurations as compared to their larger-scale counterparts. This phenomenon, described as quantum confinement , depends on the number of dimensions with the reduced scale (typically <100 nm) in the xy , xz , and yz planes. In short, an alteration in electronic configuration based on the number of atoms contributing to the reduced-scale domains has facilitated substantial advances in the understanding of matter. This property has been well received by the material science community and is currently being developed for a variety of applications .
With regard to implant surfaces and nanomaterials, the possibilities are limitless, as nanoscale fabrication methods are becoming widely available. Nanotechnology-based manufacturing processes can alter the texture, length, scale and pattern of implant surfaces, while at the same time altering the chemical properties of the substrate by means of quantum confinement .
From a general perspective, recent research strongly suggests that alterations in surface topography can lead to changes in surface chemistry. Such phenomena may be intensified when features at the nanometer scale are considered. Not surprisingly, nanoscale features presenting both short- and long-range ordering have been shown to alter various aspects of cell behavior and are the subject of active research .
For instance, if one considers nanotopographical texturing of a surface, an exponential increase in surface area is expected along with alterations in surface electronic properties, due to the formation of nanoscale peaks, by virtue of 2-dimensional confinement. Thus, it is expected that the surface energy, resulting from nanotopographical texturing, will deviate from both smooth and microscale texturing. An increase in surface energy arises not only due to alterations in surface roughness, unevenness, and branching level (represented by the dispersed component contribution), but also due to alterations in surface chemistry, the presence of polar groups, electric charges, and free radicals (represented by the polar component contribution) when using the reduced scale rendered by nanotopography ( Fig. 4 ). The Owens–Wendt–Rabel–Kaelble approach is a common method for calculating the surface energy . In essence, droplets of purified water, ethylene glycol, and methylene iodide are separately used for the calculation of surface energy due to their wide range of intermolecular forces, non-toxicity, high surface tension, and known specific polarities . Surface energy is calculated as follows:
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