Evaluation of Functional Dynamics During Osseointegration And

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Review Po-Chun Chang Evaluation of functional dynamics Niklaus P. Lang William V. Giannobile during osseointegration and regeneration associated with oral implants

Authors’ affiliations: Key words: bone–implant interactions, finite element analysis, growth factor Po-Chun Chang, William V. Giannobile, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Abstract Ann Arbor, MI, USA Objectives: The aim of this paper is to review current investigations on functional Po-Chun Chang, William V. Giannobile, assessments of osseointegration and assess correlations to the peri-implant structure. Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Material and methods: The literature was electronically searched for studies of promoting MI, USA dental implant osseointegration, functional assessments of implant stability, and finite Po-Chun Chang, Department of Preventive Dentistry, Division of Periodontology, Faculty of element (FE) analyses in the field of implant dentistry, and any references regarding Dentistry, National University of Singapore, biological events during osseointegration were also cited as background information. Singapore Niklaus P. Lang, Faculty of Dentistry, The Results: Osseointegration involves a cascade of protein and cell apposition, vascular University of Hong Kong, Hong Kong, China SAR invasion, de novo bone formation and maturation to achieve the primary and secondary William V. Giannobile, Michigan Center for Oral dental implant stability. This process may be accelerated by alteration of the implant surface Health Research, School of Dentistry, University of Michigan, Ann Arbor, MI, USA. roughness, developing a biomimetric interface, or local delivery of growth-promoting factors. The current available pre-clinical and clinical biomechanical assessments Correspondence to: William Giannobile demonstrated a variety of correlations to the peri-implant structural parameters, and University of Michigan functionally integrated peri-implant structure through FE optimization can offer strong School of Dentistry correlation to the interfacial biomechanics. Michigan Center for Oral Health Research 1011 N. University Ave. Conclusions: The progression of osseointegration may be accelerated by alteration of the Rm. 3305 Dental Bldg. implant interface as well as growth factor applications, and functional integration of peri- Ann Arbor, MI 48109, USA Tel.: þ 1 734 764 1562 implant structure may be feasible to predict the implant function during osseointegration. Fax: þ 1 734 763-5503 More research in this field is still needed. e-mail: [email protected]

Osseointegration, which histologically is Stiffness of the tissue–implant interface defined as ‘direct bone-to-implant contact’, and implant-supporting tissues are con- is believed to provide rigid fixation of a sidered as the main determinant factors in dental implant within the alveolar bone osseointegration (Ramp & Jeffcoat 2001). and may promote the long-term success While the structure and heterogeneity of of dental implants (Franchi et al. 2005; mineralization affects the stiffness of bone Joos et al. 2006). The processes of osseoin- (Hoffler et al. 2000), Johansson et al. (1998) tegration involve an initial interlocking demonstrated that biomechanical testing between alveolar bone and the implant may be a more suitable indicator to evalu- Date: body (primary implant stability), and later, ate the dynamic changes of osseointegra- Accepted 16 July 2009 biological fixation through continuous tion than any single structural parameter. To cite this article: bone apposition (contact osteogenesis) However, biomechanical testing, such as Chang P-C, Lang NP, Giannobile WV. Evaluation of functional dynamics during osseointegration and and remodeling toward the implant (sec- push-out and pull-out measurements, is regeneration associated with oral implants. ondary implant stability) (Berglundh et al. destructive and only available for pre- Clin. Oral Impl. Res. 21, 2010; 1–12. doi: 10.1111/j.1600-0501.2009.01826.x 2003). clinical use (Berzins et al. 1997). Therefore,

c 2009 John Wiley & Sons A/S 1 Chang et al Functional assessment of osseointegration the clinical value of non-destructive mea- itial cell attachment eventually establishes Albrektsson (2009), surface roughness can surements, such as resonance frequency on the implant surface (Kasemo & Gold be divided into four categories (Lang & analysis (RFA) or damping characteris- 1999). The interface area is first occupied Jepsen 2009): tics (Periotests technique, Siemens, Ben- by red blood cells, inflammatory cells, and Smooth surfaces: Sa value o0.5 mm sheim, Germany), are still limited due to degenerating cellular elements, then is gra- (e.g. polished abutment surface). the lower resolution and higher variability dually replaced with spindle-shaped or flat- Minimally rough surfaces: S value during examinations (Aparicio et al. 2006). tened cells, concurrent with initiation of a 0.5–o1 mm (e.g. turned implants). Thus, it is still of interest to develop osteolysis on the host bone surface until Moderately rough surfaces: S value 1– effective approaches to functionally assess day 3 (Futami et al. 2000). Osteoblasts a o2 mm (e.g. most commonly used osseointegration for the evaluation of peri- begin to attach and deposit collagen matrix types). implant wound healing and prognosis of at this stage (Meyer et al. 2004). Rough surfaces: S value 2 mm (e.g. implant therapy. Early bone formation is not evident until a plasma-sprayed surfaces). By reviewing the sequences of osseointe- days 5–7 (Berglundh et al. 2003; Colnot gration and current efforts on promoting et al. 2007) and is consistent with the se- Moderate roughness and roughness is osseointegration, this paper is concentrated quence of appositional matrix deposition associated with implant geometry, such on the scientific significance of pre-clinical and calcification from the lamina limitans as screw structure, and macroporous sur- biomechanical testing and has character- of host bone onto the implant surface face treatments. Previous studies demon- ized the state-of-the-art clinical functional (Marco et al. 2005). Most of the interfacial strated that this type of roughness allowed assessments as well as the model analysis. zone is occupied by provisional matrix rich for bone ongrowth and provided mechan- According to the development of modern in collagen fibrils and vasculature, and ical interlocking shortly after implant pla- medical imaging techniques and mechan- woven bone can be observed around the cement (Berglundh et al. 2003; Franchi ical modeling, the relationship between vascular areas by day 7 (Berglundh et al. et al. 2005). Higher bone–implant contact structural and biomechanical parameters 2003). Through continuous deposition, tra- (BIC) and removal torque force suggested were also described. becular bone fills the initial gap and ar- enhanced secondary stability compared ranges in a three-dimensional (3D) with smooth and minimally rough im- network at day 14 (Franchi et al. 2005). plants (Buser et al. 1991; Wennerberg et al. Timing of osseointegration The de novo formation of primary bone 1996). spongiosa offers not only a biological fixa- There are two main theories regarding While it has been demonstrated that ex- tion to ensure secondary implant stability the influence of implant surface microto- cessive mobility may cause fibrous tissue (Ferguson et al. 2006) but also a biological pography on peri-implant tissue formation formation and lead to failure of osseointe- scaffold for cell attachment and bone de- – (1) the surface energy and (2) the distor- gration (Huiskes et al. 1997; Lioubavina- position (Franchi et al. 2005). After 28 tional strain. The smaller grain size on the Hack et al. 2006), in order to limit the days, delineated bone marrow space and surface results in higher surface energy, micromotion and achieve primary stability thickened bone trabeculae with parallel- which is more favorable for cell adherence of the implant, a slightly undersized os- fibered and lamellar bone can be found (Kilpadi & Lemons 1994; Kim et al. 2008). teotomy is usually prepared for press-fit- within the interfacial area. After 8–12 Bowers et al. (1992) first demonstrated that ting of the implant. However, a 60 mm weeks, the interfacial area appears histolo- the moderate roughness with sandblasted gap between the implant and host bone has gically to be completely replaced by mature and acid-etching treatments significantly been noted under microscopic investiga- lamellar bone in direct contact with tita- promoted cell attachment. Anselme & tions (Futami et al. 2000; Colnot et al. nium (Berglundh et al. 2003). Bigerelle (2005) later investigated long- 2007), and depending on the extent of term osteoblast adherence and behavior injury to the host bone, this gap may later in vitro and demonstrated that a low am- extend to 100–500 mm (Eriksson et al. Implant surface alteration to plitude of the surface roughness induced 1984). Therefore, this gap is filled with accelerate osseointegration cell spreading more intimately than the blood and forms a water layer incorporated rougher one. Therefore, the microtopogra- with hydrated ions on the implant surfaces The chemical composition or charges of phy of the implant surface also influences immediately after implant placement (Park the implant interface on the implant sur- differentiation events by providing the dis- & Davies 2000; Berglundh et al. 2003). face were shown to affect initial cell attach- tortional signals. While osteoblastic cells The small proteins adsorbed on the surface ment (Kasemo & Gold 1999). This has show a cuboidal shape with polarized nu- are subsequently replaced by larger proteins aroused great interest on implant surface clei, the inactive bone-lining cells tended based on the ‘Vroman effect’. Although modification as a way to accelerate the rate to have a flattened morphology without different implant surface properties may of osseointegration (Junker et al. 2009; polarization (Kieswetter et al. 1996). Later affect the composition and conformational Wennerberg & Albrektsson 2009). studies further demonstrated that minor states of the binding proteins, the biological distortional strain and low compressive aggregates on the surface interact with the Surface roughness hydrostatic stress on mesenchymal stem cell extensions, cell membrane, mem- Depending on the scale of the features and cells were most likely for promoting osteo- brane-bound proteins or receptors, and in- based on the proposal of Wennerberg & genic differentiation, whereas excessive

2|Clin. Oral Impl. Res. 21, 2010 / 1–12 c 2009 John Wiley & Sons A/S Chang et al Functional assessment of osseointegration

Table 1. The modes of growth factor delivery for promoting dental implant osseointegration Growth factor Mechanisms Delivery mode References BMPs (-2 and -7) Osteogenic lineage differentiation Recombinant protein Barboza et al. (2004), Bianchi et al. (2004), Cochran et al. (1999), Nevins et al. (1996) Gene delivery Dunn et al. (2005) PDGF-BB Mitogenesis and chemotaxis of Recombinant protein Lee et al. (2000b), Nevins et al. (2005) mesenchymal and osteogenic cells populations Gene delivery Jin et al. (2004), Chang et al. (2009a) TGF-b Mitogenesis of osteoblasts Recombinant protein Ng et al. (2008), Xu et al. (2008) IGFs (-1 and -2) Collagen matrix production and stabilization, Recombinant protein Giustina et al. (2008) mitogenesis FGF-2 Mitogenesis and anti-apoptosis of Recombinant protein Kitamura et al. (2008), Marie (2003) osteoprogenitor cells PDGF-BB/IGF-1 Combinational effects of dual growth factors Recombinant protein Becker et al. (1992), Stefani et al. (2000) BMP-2/VEGF Combinational effects of dual growth factors Recombinant protein Huang et al. (2005), Patel et al. (2008) BMP-2/FGF-2 Combinational effects of dual growth factors Recombinant protein Lan et al. (2006) BMP-2/TGF-b Combinational effects of dual growth factors Recombinant protein Sumner et al. (2006) BMP, bone morphogenetic protein; PDGF, platelet-derived growth factor; TGF, transforming growth factor; IGF, insulin-like growth factor; FGF, ﬁbroblast growth factor; VEGF, vascular-endothelial growth factor.

distortional strain resulted in fibrogenesis with a titanium surface without coating, Growth factor delivery to as well as chondrogenesis, due to signifi- osteogenic cells attach, proliferate, and dif- accelerate osseointegration cant hydrostatic pressure (Andreykiv et al. ferentiate on the HA-coated surface (Knabe 2008). Based on the mesenchymal cell size et al. 2004), and result in superior initial The rate of osseointegration is dependent on of about 5–12 mm in length, surface micro- rates of osseointegration in vivo (Geurs the commitment, replication, and differen- topographic pits with a 4 mmdiameterand et al. 2002). However, the delamination tiation of osteoprogenitor cells, and on inter- 1.5 mm depth are thought to be optimal for of the coating and particle release from the facial tissue maturation (Brunski et al. 2000; cells to attach and subsequently differenti- implant surface causes long-term failure in Marie 2003). Since growth factors, such as ate on the implant surface (Hansson & some studies (Chang et al. 1999; Lee et al. bone morphogenetic protein (BMP) and pla- Norton 1999; Schwartz et al. 1999). 2000a). To prevent this, recent investiga- telet-derived growth factor (PDGF), enhance Based on the large proportion of grain tions have focused on depositing HA onto osteogenesis and were suggested to regener- boundaries increasing surface energy, sig- the implant surface through biomimetic ate the periodontal and dentoalveolar tissues nificant enhancement of cell attachment, approaches, such as electrodeposition or (Taba et al. 2005; Ramseier et al. 2006), se- proliferation, viability, spreading, and early immersion in SBF (Le Guehennec et al. veral of those biomolecules were also intro- osteogenic differentiation on these nano-/ 2007). duced to accelerate peri-implant wound ultrafine-grained structures has been Implant surfaces may be also coated with healing and osseointegration (Table 1). demonstrated in several investigations biomolecules, such as bio-adhesive motifs (Brett et al. 2004; Puckett et al. 2008; Misra or growth factors, to enhance osseointegra- BMPs et al. 2009). However, reproducible surface tion. The RGD sequence from fibronectin Belonging to the transforming growth fac- roughness on a nanoscale level is difficult is the most commonly used bio-adhesive tor-beta (TGF-b) superfamily, BMPs have to achieve, thus optimal surface nanotopo- motif, which binds adhesion receptors and been proven to drive the multipotent cells graphy for rapid osseointegration is still not promotes cell adhesion (Shakesheff et al. into an osteogenic lineage and promote achievable (Le Guehennec et al. 2007). 1998). RGD-functionalized, tissue-engi- extracellular matrix formation through neered constructs have shown improve- the Smad signaling pathway (Chen et al. ment during early bone ingrowth and 2004). Among all of the BMPs isoforms, Surface coating and biomimetic approaches matrix mineralization in vivo (Alsberg BMP-2, and BMP-7 are the most com- Another category of implant surface mod- et al. 2001; Lu¨ tolf et al. 2003). However, monly investigated. BMP can induce ecto- ification is to coat the implant with layers RGD immobilization on titanium implant pic and periosteal bone formation in vivo of bioactive materials. One approach is to surfaces has not improved BIC nor osteo- (Hak et al. 2006; Chang et al. 2007). coat the titanium surface of implants with blast differentiation (Schliephake et al. Within the dental field, BMP has been calcium phosphates, mainly composed of 2002; Tosatti et al. 2004), presumably shown to promote tooth extraction socket hydroxyapatite (HA), by plasma-spraying. due to neglecting the conformation-depen- healing, peri-implant wound healing, and Calcium phosphates are released to the dent effects and absence of crucial modula- sinus floor and alveolar ridge augmentation peri-implant area after implantation and tory domains from the native fibronectin, in pre-clinical studies (Nevins et al. 1996; precipitated biological apatites, which thus diminishing the RGD signals through Cochran et al. 1999; Fiorellini et al. 2005; serve as matrices for subsequent osteogenic non-specific adsorption of plasma protein Nakashima & Reddi 2003; Barboza et al. cell attachment and growth (Le Guehennec and interactions with inflammatory com- 2004; Dunn et al. 2005). Some investiga- et al. 2007; Junker et al. 2009). Compared ponents (Garcia & Reyes 2005). tions have also reported that BMP exhibits

c 2009 John Wiley & Sons A/S 3|Clin. Oral Impl. Res. 21, 2010 / 1–12 Chang et al Functional assessment of osseointegration superior short- but not long-term effects generation around the press-fit titanium talk most likely exists among them (Marie over controls (Matin et al. 2001; Jones et al. implants (Lynch et al. 1991; Becker et al. 2003; Singhatanadgit et al. 2006). Thus, 2006; Jovanovic et al. 2007). In clinical 1992). Recently Chang et al. (2009a) de- combination of growth factors is a viable trials, BMP tended to accelerate extraction monstrated the PDGF protein or gene de- approach to amplify osteogenesis. The first socket and alveolar ridge augmentation livery was capable of accelerating oral approach was proposed based on the syner- compared with collagen vehicle alone implant osseointegration in vivo as well gistic effects on wound healing using a within the period of 4–6 months (Howell as improving biomechanical properties. combination of PDGF-BB and IGF-1 et al. 1997; Bianchi et al. 2004). However, On the other hand, the possible inhibi- (Lynch et al. 1989a). This combination no significant difference could be found tory effects to osteogenesis have also been exhibited greater alveolar bone and cemen- between BMP application and bone grafting documented. Kono et al. (2007) reported tum regeneration than single growth factor in the treatment of sinus floor and alveolar that PDGF treatment negatively regulates application (Lynch et al. 1989b; Gianno- ridge augmentation (Jung et al. 2003; osteogenic differentiation, and Tokunaga bile et al. 1996), and promoted initial Boyne et al. 2005). et al. (2008) demonstrated that specifically dental implant osseointegration in later the PDGF receptor beta had a determinable investigations (Lynch et al. 1991; Becker PDGFs effect on mesenchymal cell differentiation. et al. 1992; Stefani et al. 2000). The com- PDGF is a potent mitogen and chemotactic Therefore, the bidirectional effect on osteo- bination of angiogenic (i.e., VEGF) and factor for cells of mesenchymal origin, genesis is associated with the expression osteogenic growth factors (i.e., BMP) pro- including periodontal ligament (PDL) cells, profile of PDGF, with pulse PDGF applica- moted bone regeneration (Huang et al. and osteoblasts (Oates et al. 1993). PDGF tion stimulating osteogenesis while contin- 2005; Patel et al. 2008), and dual delivery can also regulate the expression of vascular uous PDGF exposure elicits an inhibitory of BMP/TGF-b or BMP/FGF also enhanced endothelial growth factor (VEGF) to pro- effect (Hsieh & Graves 1998). osseointegration in vivo (Lan et al. 2006; mote angiogenesis and is reported as an Sumner et al. 2006). However, application essential hormone in the healing process Other growth factors and combinations should be controlled by sequential release of soft tissue and bone (Hollinger et al. Besides BMP and PDGF, there are several profile of the growth factors in order to 2008). PDGF exists as a dimeric form growth factors being investigated for accel- maximize the beneficial effects of combi- (-AA, -AB, -BB, -CC, and -DD) and signals erating osteogenesis, such as TGF-b,IGF, natorial delivery (Kempen et al. 2009). through binding to tyrosine kinase recep- and fibroblast growth factor (FGF) (An- tors, termed PDGF receptors alpha and beta drades et al. 1999; Mukherjee & Rotwein (Seifert et al. 1989), with PDGF-BB the 2009). TGF-b has been proposed as an Pre-clinical biomechanical most widely used isoform of PDGF based osteoinductive factor based on its ability assessments for on its capability to bind to all known to promote proliferation of osteoblasts osseointegration PDGF receptor isotypes (Hollinger et al. (Macdonald et al. 2007). However, studies 2008). also demonstrate that TGF-b enhances Tensional test The interfacial tensile strength was origin- PDGF plays an indirect role in osteogen- chondrogenesis rather than osteogenesis ally measured by detaching the implant esis by recruiting and expanding the osteo- in MSCs (Ng et al. 2008; Xu et al. 2008). plate from the supporting bone (Kitsugi genic cell populations, and subsequent IGF-1 and IGF-2 regulate the bone forma- et al. 1996) (Table 2). Bra˚nemark later mod- differentiation of those cells is achieved tion process through increasing type I col- ified this technique by applying the lateral by BMPs (Chaudhary & Hruska 2001; lagen synthesis, decreasing collagen load to the cylindrical fixture (Bra˚nemark Cho et al. 2002). In vivo investigations degradation, modestly enhancing mitogen- et al. 1998) (Fig. 1a). However, they also also indicate that applying PDGF to de- esis, and stabilizing a-catenin, a key reg- addressed the difficulties of translating the nuded tooth root surfaces increase prolif- ulator in Wnt pathway of osteogenic test results to any area-independent me- eration of PDL cells, osteoblasts, and differentiation (Giustina et al. 2008). chanical properties. perivascular cells, and accelerate alveolar FGF-2 promotes mitogenesis and reduces bone regeneration (Wang et al. 1994; Park apoptosis of osteoprogenitor cells, which et al. 1995; Giannobile et al. 1996). A increases the population of functional os- Push-out/pull-out test multicenter clinical trial validated PDGF- teoblasts, but induces apoptosis in more The ‘push-out’ or ‘pull-out’ test is the BB is capable of promoting periodontal differentiated osteoblasts, thus limiting the most commonly used approach to investi- defect regeneration (Nevins et al. 2005). early increase of mature cells in the osteo- gate the healing capabilities at the bone– Furthermore, a significant amount of in blast pool (Marie 2003). A recent clinical implant interface (Brunski et al. 2000; vivo bone regeneration was also noted in investigation demonstrated that FGF-2 sig- Kempen et al. 2009). In the typical push- a ‘pure’ orthopedic environment such as nificantly increased the alveolar bone out or pull-out test, a cylinder-type im- the calvarial or femoral critical-sized os- height after 36 weeks in patients with plant is placed transcortically or intrame- teomtomy using a combination of calcium periodontitis suggesting that FGF-2 could dullarly in bone structures and then phosphate graft and PDGF (Nash et al. be a potential stimulator for bone regenera- removed by applying a force parallel to the 1994; Lee et al. 2000b). Combination of tion (Kitamura et al. 2008). interface (Fig. 1b–c). The maximum load PDGF and insulin-like growth factor-1 The process of osteogenesis is regulated capability (or failure load) is defined as the (IGF-1) had shown to stimulate bone re- through several growth factors, and cross- maximum force on the force–displacement

4|Clin. Oral Impl. Res. 21, 2010 / 1–12 c 2009 John Wiley & Sons A/S Chang et al Functional assessment of osseointegration

Table 2. Current biomechanical assessments for dental implant osseointegration Methodology Destructive Clinical use Property investigated Parameters References Tensional test Yes No Lateral resistance Maximal lateral load Bra˚ nemark et al. (1998), Kitsugi et al. (1996) Push-out/pull-out Yes No Interfacial shear Maximal force Berzins et al. (1997), Brunski et al. (2000) Interfacial stiffness Removal torque Yes No Interfacial shear Loosening torque Johansson et al. (1998), Meredith et al. (1997) Torque load Cutting resistance/ No Yes Interfacial shear Peak insertional torque Friberg et al. (1995), O’Sullivan et al. (2000) Insertional torque Torque load Periotest No Yes Damping Periostest value (PTV) Aparicio et al. (2006), Schulte & Lukas (1993) Resonance No Yes Vibration/damping Implant stability Friberg et al. (1999), Meredith et al. (1997), frequency analysis quotient (ISQ) Turkyilmaz et al. (2009)

torque and then pulling the implant out. In this investigation, the removal torque was related to the interfacial bonding capability, and the pull-out strength was related to the shear properties from the implant-supporting structure.

Clinical biomechanical assessments for osseointegration

Cutting resistance/insertional torque The cutting resistance refers to the energy required in cutting of a unit volume of bone (Friberg et al. 1995) while the insertional torque occurs during the fixture tightening procedure (Ueda et al. 1991). Both of these measurements consider the lateral com- pression force and friction at the interface during implant insertion and are mainly influenced by the tolerance of the fixture thread design (O’Sullivan et al. 2000). Fig. 1. Biomechanical assessments for oral implant osseointegration (a) tensional test, (b) push-out test, (c) Many researchers also used the peak inser- pull-out test, (d) insertional/removal torque test, (e) Periotest, and (e) resonance frequency analysis (RFA). tional torque value, which is generated during the last fixture-tightening step, as an indicator of primary implant stability (Table 2). A positive correlation between plot, and the interfacial stiffness is visua- Removal torque insertional and removal torque is evident lized as the slope of a tangent approxi- The removal torque refers to the torsional however, any relationship between the mately at the linear region of the force– force necessary for unscrewing the fixture cutting resistance and the peak insertional displacement curve before breakpoint (Fig. 1d) and was first investigated by torque is still unclear (Molly 2006). (Brunski et al. 2000; Lu¨ tolf et al. 2003) Johansson et al. (1998). The removal tor- (Table 2). Therefore, the general loading que value was recorded using a torque s capacity of the interface (or interfacial shear manometer calibrated in Newton-centi- Periotest strength) can be measured by dividing the meters (N cm). This technique primarily Significant deformation of the bone–im- maximum force by the area of implant in focuses on interfacial shear properties (Ta- plant unit is not measurable for most contact with the host bone (Berzins et al. ble 2). However, the results may be af- clinical situations. To overcome this lim- 1997). However, the push-out and pull-out fected by implant geometry and topography itation, damping characteristics, or the dy- tests are only applicable for non-threaded (Meredith et al. 1997; Yeo et al. 2008). namic tissue recovery processes after cylinder type implants, whereas most of loading, have been recommended for clinically available fixtures are of threaded non-invasive assessment of osseointegra- Combination of push-out/pull-out and s design, and their interfacial failures are removal torque tion (Aparicio et al. 2006). A Periotest solely dependent on shear stress without This combinational trial was introduced by (Siemens) was originally designed to assess any consideration for either tensile or com- Bra˚nemark et al. (1998) by applying tor- the damping characteristics of the PDL by pressive stresses (Brunski et al. 2000). sional force until reaching the maximum calculating the contact time between the

c 2009 John Wiley & Sons A/S 5|Clin. Oral Impl. Res. 21, 2010 / 1–12 Chang et al Functional assessment of osseointegration test subject and the percussion rod (Fig. 1e) of bone–implant interface (Brunski 1992; ship between the amount of bone within and are reported as Periotest value (PTV) Bischof et al. 2004), a number of studies the threaded area and the removal torque (Schulte & Lukas 1993) (Table 2). have been initiated to provide insights of value was not made clear from these ap- s The main limitation of the Periotest is a correlation between peri-implant structure proaches (Wennerberg et al. 1996). Because lack of sensitivity in evaluating osseointe- and implant stability (Tables 3 and 4). of the inability to perform biomechanical gration, whereby the range of PTV in testing and structural analysis on the same osseointegrated implants falls to a narrow specimens due to, at that time, a lack of Correlations between primary implant zone ( 5to þ 5) within a wide scale ( 8 stability and peri-implant structures reliable clinical biomechanical assessments to þ 50) (Olive & Aparicio 1990). This Considering that intrinsic properties of the or more definitive imaging techniques, could be accounted for by physical diffe- peri-implant bone may affect the stiffness careful review of those results appears to rences between periodontium and the of bone–implant interface (Brunski et al. be necessary. bone–implant interface, because bone is 2000; Bischof et al. 2004), a number of Measuring specimens during and after much stiffer and does not allow for signi- studies have undertaken to provide insight implant removal, Bra˚nemark et al. (1998) ficant deformation as compared with the into the correlation between peri-implant demonstrated that the total bone thickness soft tissue of the periodontium (Mere- structure and implant stability (Tables 3 (TBT) 50 mm from the interface and BIC dith et al. 1997). Moreover, results may and 4). area were significantly correlated to the also be influenced by the position and maximal and breakpoint torque, and the direction of the percussion rod (Schulte & TBT also strongly correlated to the subse- Correlations between primary implant Lukas 1992). stability and peri-implant structures quent pull-out force. The correlation be- The relationship between the primary im- tween insertional torque value and cortical RFA plant stability and peri-implant structures bone thickness was recently reported (Mo- RFA was first introduced by Meredith et al. was first reported by Niimi et al. (1997). toyoshi et al. 2007). However, the oppo- (1997). An L-shaped transducer connected These authors applied torque to implants site result was found from a study on dog to the implant was utilized to provide a within the fibulae, iliac crest, and scapula of mandibles, where the pull-out force was high-frequency mechanical vibration and human cadavers and found that the removal correlated to primary implant stability, but record the frequency and amplitude of the torque value was significantly correlated to this correlation became non-significant in signal received (Fig. 1f). The resonance cortical bone thickness but was not asso- the latter healing stages (Salmoria et al. frequency was thus defined as the peak of ciated with the trabecular bone area based 2008). the frequency–amplitude plot and con- on histological sections. This same correla- Using non-destructive biomechanical as- s verted to a value representing stiffness of tion was also observed in a later investiga- sessments (i.e., Periotest , RFA) on dog the bone–implant interface. Currently, Os- tion using implant pull out methods from mandibles, a high correlation was found s stell (Integration Diagnostic AB, Gote- dog mandibulae (Salmoria et al. 2008). between the mechanical impedance from s borg, Sweden), a commercialized product Primary implant stability may also be the Periotest and BIC as well as bone utilizing the concept of RFA, has translated correlated to the bone mineral density density from histology and radiography at the resonance frequency ranging from 3000 (BMD) by analyzing and interpreting 3D 3 months post-implantation (Ramp & Jeff- to 8500 Hz as the implant stability quoti- computed tomography (CT) images coat 2001). Significant correlations be- ent (ISQ) of 0–100 (Atsumi et al. 2007) (Homolka et al. 2002; Turkyilmaz et al. tween PTV and BIC based on histology (Table 2). 2009), and is strongly correlated with in- were also found (Sykaras et al. 2004). While moderate to strong correlation is creasing implant diameter. Akça et al. However, using a different treatment mod- found between cutting resonance and ISQ (2006) also found significant correlation ality such as the pull-out test, the PTV was value upon implant placement (Friberg between the trabecular bone structure and not sensitive to the osseous wound repair et al. 1999), and because of the non-inva- the insertional torque value. However, (Sykaras et al. 2004). Significant, but weak sive nature of the measurement, RFA has most of these investigations also revealed correlations between ISQ values and BIC been widely used for clinically assessing that the insertional torque value tended were shown in some reports (Itoh et al. osseointegration, as well as for prognostic to be more sensitive to the peri-implant 2003; Scarano et al. 2006), whereas others evaluation (Meredith et al. 1997; Aparicio structure than the ISQ value (Table 3). failed to demonstrate such correlations et al. 2006; Oates et al. 2009). However, (Schliephake et al. 2002). Moreover, recent investigations utilizing the latter aspect still has to be questioned Correlations between secondary implant (Aparicio et al. 2006). stability and peri-implant structures micro-CT technology also demonstrated a An early pre-clinical study demonstrated a variety of moderate to strong correlations similar tendency of change in removal between the structural parameters (i.e., Relevance of the peri-implant torque value and BIC over a period of BIC, bone volume, trabecular bone thick- structure to interfacial time (Johansson et al. 1998), demonstrat- ness, trabecular number, and connectivity biomechanics ing that results could be influenced by density) and pull-out results, and different implant topography or metal biocompat- treatment strategies resulted in similar a Considering that intrinsic properties of the ibility (Johansson et al. 1998; Wennerberg correlation between the biomechanical and peri-implant bone may affect the stiffness & Albrektsson 2009). However, a relation- structural properties (Gabet et al. 2006).

6|Clin. Oral Impl. Res. 21, 2010 / 1–12 c 2009 John Wiley & Sons A/S Chang et al Functional assessment of osseointegration

Table 3. Correlation between biomechanical testing and peri-implant structures (primary stability) Methodology Model Structure assessment Structural parameters Correlation Reference (s) PO Canine Histology CBT r ¼ 0.44n Salmoria et al. (2008) IT Human cadaver CT (3D) BMD r ¼ 0.690n Turkyilmaz et al. (2009) RFA Human cadaver CT (3D) BMD r ¼ 0.557n Turkyilmaz et al. (2009) IT Human cadaver Micro-CT (3D) Tb.Th r ¼ 0.825n Akc¸a et al. (2006) Tb.N r ¼ 0.718n Tb.Sp r ¼0.795n RFA Human cadaver Micro-CT (3D) Tb.Th NS for any parameter Akc¸a et al. (2006) Tb.N Tb.Sp IT Human cadaver CT (3D) BMD r2 ¼ 0.81n Homolka et al. (2002) IT Human CT (3D) BMD r ¼ 0.1–0.83n Turkyilmaz et al. (2007) RFA Human CT (3D) BMD r ¼ 0.34–0.91n Turkyilmaz et al. (2007) IT Human cadaver CT (3D) BMD r ¼ 0.86n Beer et al. (2003) n IT Human CT (3D) BMD (IDo4 mm) r ¼ 0.33–0.59 Turkyilmaz et al. (2006) BMD (ID44 mm) r ¼ 0.05–0.29 n RT Human cadaver Calipers CBT Po0.05 Niimi et al. (1997) TBT NS

n Po0.05. IT, insertional torque; PO, pull-out; PS, push-out; RFA, resonance frequency analysis; CT, computed tomography; CBT, cortical bone thickness; BIC, bone– implant contact; BVD, bone-volume density; BMD, bone mineral density; BV/TV, bone volume/total volume; ID, implant diameter; TBT, total bone thickness; Tb.Th, trabecular thickness; Tb.N, trabecular number; Tb.Sp, trabecular separation; Conn.D, connectivity density; NS, no signiﬁcant difference (P40.05).

Table 4. Correlation between biomechanical testing and peri-implant structures (secondary stability) Methodology Model Structure assessment Structural parameters Correlation Reference (s) IT Human CT (2D) CBT r ¼ 0.320n Motoyoshi et al. (2007) PO Canine Histology CBT NS Salmoria et al. (2008) RFA Human Histology BIC P ¼ 0.016 Scarano et al. (2006) RFA Canine Histology BIC r ¼ 0.128, P ¼ 0.264 Schliephake et al. (2002) BVD r ¼ 0.206, P ¼ 0.072 Periotest Canine Radiography BIC r ¼ 0.38n Sykaras et al. (2004) Periotest Canine Histology and radiography BIC (His) r2 ¼ 0.72n Ramp & Jeffcoat (2001) BIC (Rad) r2 ¼ 0.88n BVD (His) r2 ¼ 0.8n RFA Porcine Histology BIC r ¼ 0.221n Ito et al. (2008) RT Rodent Histology BIC r ¼ 0.78–0.84n Bra˚ nemark et al. (1997) TBT r ¼ 0.68–0.76n PO Rodent Histology TBT r ¼ 0.87n Bra˚ nemark et al. (1997) PO Rodent Micro-CT (3D) BIC r2 ¼ 0.52 (FL)n 0.24 (IS)n Gabet et al. (2006) BV/TV r2 ¼ 0.72 (FL)n 0.43 (IS)n Tb.Th r2 ¼ 0.6 (FL)n 0.31 (IS)n Tb.N r2 ¼ 0.47 (FL)n 0.32 (IS)n Conn.D r2 ¼ 0.37 (FL)n 0.28 (IS)n PS Rodent Micro-CT (3D) and FE optimization BV r ¼ 0.67 (OA)n 0.34 (OS)n P.C. Chang et al., 2009b, BMC r ¼ 0.7 (OA)n 0.71 (OS)n unpublished data BMD r ¼ 0.61 (OA)n 0.62 (OS)n FBAM r ¼ 0.96 (OA)n 0.84 (OS)n FCAM r ¼ 0.74 (OA)n 0.95 (OS)n

n Po0.05. nnHighest correlation coefﬁcient for each parameter. IT, insertional torque; PO, pull-out; PS, push-out; RFA, resonance frequency analysis; CT, computed tomography; CBT, cortical bone thickness; BIC, bone– implant contact; BV, bone volume; BVD, bone-volume density; BMC, bone mineral content; BMD, bone mineral density; BV/TV, bone volume/total volume; FBAM, functional bone apparent modulus; FCAM, functional composite tissue apparent modulus; ID, implant diameter; FL, failure load; IS, interfacial stiffness; OS, implant placing in osteotomy hole with osseous defect situation (0.6 1 mm circumferential); OA, implant placing in osteotomy-alone without any surrounding defect situation; TBT, total bone thickness; Tb.Th, trabecular thickness; Tb.N, trabecular number; Tb.Sp, trabecular separation; Conn.D, connectivity density; NS, no signiﬁcant difference (P40.05).

Model analysis for of implant density over the past two dec- ical iteration, the functional performance of osseointegration ades (Geng et al. 2001). The FE model was dental implant systems could be expressed built based on the pre-determined geome- as speciﬁc values or gradient distribution of Finite element (FE) analysis try of tissue and implant, material proper- stress and strain in the model (Van Staden FE analysis had been extensively used as a ties, and boundary conditions. Through et al. 2006). Thus, FE analysis has been tool of functional assessments in the ﬁeld applying the loading situation and numer- utilized to investigate the functional

c 2009 John Wiley & Sons A/S 7|Clin. Oral Impl. Res. 21, 2010 / 1–12 Chang et al Functional assessment of osseointegration influence the implant geometry (Himmlova Functional apparent moduli bone apparent modulus represented the et al. 2004), material properties of implant Homogenization of the mechanical proper- effective modulus of bone architecture, (Yang & Xiang 2007), quality of implant- ties to calculate the effective stiffness of and functional composite tissue modulus supporting tissue (Sevimay et al. 2005; bone was first introduced by Hollister et al. for effective modulus of whole tissue with- Petrie & Williams 2007), fixture–prosthe- (1994). They acquired three-dimensional in the wound (P.C. Chang et al., 2009b, sis connection (Akça et al. 2003), and the trabecular bone architecture from micro- unpublished data). Compared with indivi- loading condition (Mellal et al. 2004; Na- CT imaging and investigated the stress and dual structural parameters, the results in- tali et al. 2006). strain distribution of the elements under dicated that the bone repair in early stage The bone–implant interface was consid- simulated loading conditions to calculate was to provide significant resistance to ered as the boundary condition, and usually the effective Young’s modulus of the bulk support the dental implant rather than fill assigned as the pre-determined situation in specimen. The effective modulus revealed the wound space or maturation. A much FE model. Thus, the interfacial biomecha- significant agreement with experimental stronger correlation to interfacial biome- nics have not been directly assessed from FE results. Utilizing the concept of homogeni- chanics than all the other structural para- analysis (Van Staden et al. 2006). Therefore, zation, later investigations by heteroge- meters was also noted (Table 4). in most of the FE models, the assignment of neous micro-elastic property assignments material properties was based on the theo- demonstrated that the non-uniform mineral Conclusions retical value or references, and a simplified density and trabecular architecture could model following reasonable assumptions influence the effective tissue modulus (van Although several approaches are available was usually suggested to reduce the com- der Linden et al. 2001; Morgan et al. 2004; to assess implant stability (at the implant plexity of iteration and assure the numerical Renders et al. 2008). or surrounding host bone regions), limita- convergence. The numerical artifacts may According to the unavailability of functions still exist to date, and no definite link somewhat influence the accuracy of evalua- tionally evaluating peri-implant tissue, our between the function and peri-implant tions (Ladd & Kinney 1998). Thus, the group utilized the homogenization theory structure can be established. Functional results from FE analyses should be carefully to calculate the effective stiffness of peri- apparent modulus through FE optimization interpreted, and the experimental validation implant tissue under loading from dental is feasible to evaluate peri-implant osseous should be performed if possible. implant (Fig. 2), whereas the functional wound repair as well as interfacial biomechanics. Hence, integration of peri-implant structure may be necessary to predict the interfacial properties. However, further confirmation through pre-clinical and clinical models is still needed for investigating the mechanism involved in osseointegration and bone regeneration associated with oral implants.

Acknowledgements: Funding: This study was supported by the AO Foundation Research Advisory Council and NIH/NIDCR DE 13397.

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