Biphasic constitutive laws for biological interface evolution

 A model of tissue differentiation at the bone–implant interface is proposed. The basic hypothesis of the model is that the mechanical environment determines the tissue differentiation. The stimulus chosen is related to the bone–implant micromotions. Equations governing the evolution of the interfacial tissue are proposed and combined with a finite element code to determine the evolution of the fibrous tissue around prostheses. The model is applied to the case of an idealized hip prosthesis. Received: 28 May 2002 / Accepted: 10 November 2002     

Efficient computational method for assessing the effects of implant positioning in cementless total hip replacements

The present work describes a statistical investigation into the effects of implant positioning on the initial stability of a cementless total hip replacement (THR). Mesh morphing was combined with design of computer experiments to automatically construct Finite Element (FE) meshes for a range of pre-defined femur-implant configurations and to predict implant micromotions under joint contact and muscle loading. Computed micromotions, in turn, are postprocessed using a Bayesian approach to: (a) compute the main effects of implant orientation angles, (b) predict the sensitivities of the considered implant performance metrics with respect to implant ante-retroversion, varus-valgus and antero-posterior orientation angles and (c) identify implant positions that maximise and minimise each metric. It is found that the percentage of implant area with micromotion greater than 50 μm, average and maximum micromotions are all more sensitive to antero-posterior orientation than ante-retroversion and varus-valgus orientation. Sensitivities, combined with the main effect results, suggest that bone is less likely to grow if the implant is increasingly moved from the neutral position towards the anterior part of the femur, where the highest micromotions occur. The computed implant best position leads to a percentage of implant area with micromotion greater than 50 μm of 1.14 when using this metric compared to 14.6 and 5.95 in the worst and neutrally positioned implant cases. In contrast, when the implant average/maximum micromotion is used to assess the THR performance, the implant best position corresponds to average/maximum micromotion of 9 μm/59 μm, compared to 20 μm/114 μm and 13 μm/71 μm in the worst and neutral positions, respectively. The proposed computational framework can be extended further to study the effects of uncertainty and variability in anatomy, bone mechanical properties, loading or bone-implant interface contact conditions.     

A nonlinear homogenized finite element analysis of the primary stability of the bone–implant interface

Stability of an implant is defined by its ability to undergo physiological loading–unloading cycles without showing excessive tissue damage and micromotions at the interface. Distinction is usually made between the immediate primary stability and the long-term, secondary stability resulting from the biological healing process. The aim of this research is to numerically investigate the effect of initial implantation press-fit, bone yielding, densification and friction at the interface on the primary stability of a simple bone–implant system subjected to loading–unloading cycles. In order to achieve this goal, human trabecular bone was modeled as a continuous, elasto-plastic tissue with damage and densification, which material constants depend on bone volume fraction and fabric. Implantation press-fit related damage in the bone was simulated by expanding the drilled hole to the outer contour of the implant. The bone–implant interface was then modeled with unilateral contact with friction. The implant was modeled as a rigid body and was subjected to increasing off-axis loading cycles. This modeling approach is able to capture the experimentally observed primary stability in terms of initial stiffness, ultimate force and progression of damage. In addition, it is able to quantify the micromotions around the implant relevant for bone healing and osseointegration. In conclusion, the computationally efficient modeling approach used in this study provides a realistic structural response of the bone–implant interface and represents a powerful tool to explore implant design, implantation press-fit and the resulting risk of implant failure under physiological loading.     

The bending rod prosthesis: an experimental approach to metaphyseal hip arthroplasty]

The aim of our study was to develop a femoral component for total hip arthroplasty that would exclusively anchor in the metaphysis of the femoral neck. To forego trochanteric fixation, the load needs to be transferred to the metaphysis at as many points as possible. A computer simulation model suggested that an implant with a central cylinder and 16 rods aligned along a thread would be the preferable solution. To evaluate primary implantation stability, 14 fresh frozen cadaver femora were used. A special instrument set was developed to allow for centered implantation of the prosthesis without the need to dissect the greater trochanter. For our tests, we used two prototype implants: one made from titanium and the other from a CoCrMo alloy. For the measurement of micromotions at the medial proximal femur, sinusoid dynamic loading with a force between 300 N and 1700 N and a frequency of 1 Hz was employed. In a neutral position of 16 degrees adduction and 9 degrees antetorsion, the average micromotions measured were 119 microm. Despite these convincing in vitro results with regards to primary stability, circular cut-out of the implant, followed by aseptic osteonecrosis, loosening might still occur in a clinical situation. Animal experiments are therefore required to further evaluate this new implant design.     

Influence of the stiffness of bone defect implants on the mechanical conditions at the interface--a finite element analysis with contact

The study focused on the influence of the implant material stiffness on stress distribution and micromotion at the interface of bone defect implants. We hypothesized that a low-stiffness implant with a modulus closer to that of the surrounding trabecular bone would yield a more homogeneous stress distribution and less micromotion at the interface with the bony bed. To prove this hypothesis we generated a three-dimensional, non-linear, anisotropic finite element (FE) model. The FE model corresponded to a previously developed animal model in sheep. A prismatic implant filled a standardized defect in the load-bearing area of the trabecular bone beneath the tibial plateau. The interface was described by face-to-face contact elements, which allow press fits, friction, sliding, and gapping. We assumed a physiological load condition and calculated contact pressures, shear stresses, and shear movements at the interface for two implants of different stiffness (titanium: E=110GPa; composite: E=2.2GPa). The FE model showed that the stress distribution was more homogeneous for the low-stiffness implant. The maximum pressure for the composite implant (2.1 MPa) was lower than for the titanium implant (5.6 MPa). Contrary to our hypothesis, we found more micromotion for the composite (up to 6 microm) than for the titanium implant (up to 4.5 microm). However, for both implants peak stresses and micromotion were in a range that predicts adequate conditions for the osseointegration. This was confirmed by the histological results from the animal studies.     

Treatment of midfacial defects using prostheses supported by ITI dental implants

The purpose of this study was to evaluate retrospectively the use of ITI dental implants used for anchoring facial prostheses in the restorative treatment of midface defects. The authors analyzed the clinical data of 26 patients with orbital defects (n = 11), orbitonasal defects (n = 4), orbitonasomaxillary defects (n = 3), and nasal defects (n = 8). Data included age, sex, primary disease, implant position, implant length, implant failure, prosthetic attachment, radiation therapy, and peri-implant skin reactions. Follow-up was at 1, 3, 6, and 12 months and then on a yearly basis. The authors noted the status of healing and complications, if any. In total, 62 implants were placed as follows: 27 (43.5 percent) for orbital prostheses, 12 (19.4 percent) for orbitonasal prostheses, 14 (22.6 percent) for orbitonasomaxillary prostheses, and nine (14.5 percent) for nasal prostheses. Thirty-eight implants (61.3 percent) were placed in previously irradiated areas in 18 patients (69.2 percent). Mild skin reactions together with mild accumulation of sebaceous crusting around implants were recorded in 14.2 percent of the skin observations. No patient experienced severe inflammation requiring administration of systemic antibiotics or surgical revision. Implant success was 100 percent in both irradiated and nonirradiated patients. In conclusion, ITI dental implants result in a high rate of success in retaining midface prostheses and offer good stability and aesthetic satisfaction.     

A finite element model for evaluation of tibial prosthesis-bone interface in total knee replacement

A numerical model based on the finite element method was developed for the load transfer analysis at the tibial bone-implant interfaces in total knee replacement. A transverse isotropic material model, based on a quadratic elastic potential and on Hill's quadratic yield criterion, was next developed for bone constitutive laws. The bone-cement and bone-prosthesis interfaces were both assumed to be discontinuous. A dry friction model based on Coulomb's criterion was adopted for the interfaces friction. The model was shown to be able to give compressive and shear stresses distributions and distractive and relative shear micromotions at these interfaces. A preliminary application was conducted for cemented metal tray total condylar (MTTC) and for cemented and uncemented porous coated anatomic (PCA) tibial plateaus. The PCA plateaus were found to be more deformable and had greater global displacements than the MTTC one. Debonding of the bone-peg interface was observed for the uncemented PCA. Correspondingly, the stress peaks at the interface beneath the tray were lower for the PCA than for the MTTC. Shear micromotions appeared under the tray for both the two prostheses. We observed that bone anisotropy and interface discontinuity affected the results sensibly.     

Stress transfer properties of different commercial dental implants: a finite element study

Dental implantology has high success rates, and a suitable estimation of how stresses are transferred to the surrounding bone sheds insight into the correct design of implant features. In this study, we estimate stress transfer properties of four commercial implants (GMI, Lifecore, Intri and Avinent) that differ significantly in macroscopic geometry. Detailed three-dimensional finite element models were adopted to analyse the behaviour of the bone-implant system depending on the geometry of the implant (two different diameters) and the bone-implant interface condition. Occlusal static forces were applied and their effects on the bone, implant and bone-implant interface were evaluated. Large diameters avoided overload-induced bone resorption. Higher stresses were obtained with a debonded bone-implant interface. Relative micromotions at the bone-implant interface were within the limits required to achieve a good osseointegration. We anticipate that the methodology proposed may be a useful tool for a quantitative and qualitative comparison between different commercial dental implants.     

Craniofacial distraction with a modular internal distraction system: evolution of design and surgical techniques.

The present report summarizes the evolution of design for a modular internal distraction system that is applicable throughout the craniofacial region. Eleven patients (5 boys, 6 girls), whose ages ranged from 4 months to 10 years at the time of distraction, constitute the basis for this study. The clinical indications for distraction were exorbitism with corneal exposure (n = 1), obstructive sleep apnea (n = 4), tracheostomy decannulation (n = 1), severe maxillary hypoplasia with class III malocclusion (n = 3), severe vertical and sagittal maxillary deficiency with anophthalmia (n = 1), and relapse following frontoorbital advancement in a case of rare craniofacial clefting (n = 1). Twenty-two distraction devices were used in these 11 patients. Two initial prototypes were tested (prototype 1 = 8 devices; prototype 2 = 2 devices) until the modular internal distraction system (MIDS, Howmedica-Leibinger, Inc.) was developed (n = 12 devices). The craniofacial osteotomies used were Le Fort III (n = 4), monobloc (n = 3), mandibular (n = 3), Le Fort I (n = 2), and cranial (n = 1). The distraction distances ranged from 11 to 28 mm. One patient undergoing mandibular distraction developed transient swelling in the left mandibular region, which responded to antibiotics. There were no other complications. Depending on the age of the patient and the length of distraction, the distraction gap was allowed to consolidate from 6 weeks to 3 months. The devices were then removed on either an outpatient or a 23-hour-stay basis. The modular internal distraction system permits widespread application of easily customizable, buried distraction devices throughout the craniofacial region.     

Bone remodelling around a cementless glenoid component

Post-operative change in the mechanical loading of bone may trigger its (mechanically induced) adaptation and hamper the mechanical stability of prostheses. This is especially important in cementless components, where the final fixation is achieved by the bone itself. The aim of this study is, first, to gain insight into the bone remodelling process around a cementless glenoid component, and second, to compare the possible bone adaptation when the implant is assumed to be fully bonded (best case scenario) or completely loose (worst case scenario). 3D finite element models of a scapula with and without a cementless glenoid component were created. 3D geometry of the scapula, material properties, and several physiological loading conditions were acquired from or estimated for a specific cadaver. Update of the bone density after implantation was done according to a node-based bone remodelling scheme. Strain energy density for different loading conditions was evaluated, weighted according to their frequencies in activities of daily life and used as a mechanical stimulus for bone adaptation. The average bone density in the glenoid increased after implantation. However, local bone resorption was significant in some regions next to the bone-implant interface, regardless of the interface condition (bonded or loose). The amount of bone resorption was determined by the condition imposed to the interface, being slightly larger when the interface was loose. An ideal screw, e.g. in which material fatigue was not considered, was enough to keep the interface micromotions small and constant during the entire bone adaptation simulation.     

Topological optimization in hip prosthesis design

With particular interest on total hip arthroplasty (THA), optimization of orthopedic prostheses is employed in this work to minimize the probability of implant failure or maximize prosthesis reliability. This goal is often identified with the reduction of stress concentrations at the interface between bone and these devices. However, aseptic loosening of the implant is mainly influenced by bone resorption phenomena revealed in some regions of the femur when a prosthesis is introduced. As a consequence, bone resorption appears due to stress shielding, that is to say the decrease of the stress level in the implanted femur caused by the significant load carrying of the prosthesis due to its higher stiffness. A maximum stiffness topological optimization-based (TO) strategy is utilized for non-linear static finite element (FE) analyses of the femur–implant assembly, with the goal of reducing stress shielding in the femur and to furnish guidelines for re-designing hip prostheses. This is accomplished by employing an extreme accuracy for both the three-dimensional reconstruction of the femur geometry and the material properties maps assigned as explicit functions of the local densities.     

A finite element comparison between the mechanical behaviour of rigid and resilient oral implants with respect to immediate loading

In this paper, a qualitative comparison between two types of dental implants with respect to their behaviour under immediate loading is presented. This analysis has been carried out using the finite element method. Since micromotions (and not the load) are responsible of the appearance of a fibrous interface avoiding osseointegration, the relative displacement between the bone surface and the implant has been the main variable analyzed at different loading states and for the two implant types here considered. The implants analyzed differ in their mechanical behavior: rigid or resilient. Their main difference lies in the joining between the different pieces that make up the dental system. While in the rigid implant all the pieces are screwed, in the resilient implant a relative displacement between the pieces is allowed, with the additional introduction of a silicone gasket that acts like the periodontal ligament. Both implants were considered with a similar geometry and under two different loading scenarios, one equivalent to the force of chewing applied to a molar and another which corresponds to a premolar. For the resilient implant, a hyperelastic behaviour for the silicone and contact conditions between the different mobile parts of the implant are considered. The displacements of the emerging-body in both designs are also compared with the values obtained by several authors. However, the results show that both implants fulfill the constraint of the immediate loading protocol. The micromotions of the resilient implant are lower to those of the rigid one, favouring therefore a good osseointegration process while keeping the stresses in the implant under admissible maximum values.     

TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction of type 1 interferons

Toll-like receptor (TLR) 3 and 4 mediate the expression of many genes, including NF-kappaB- and interferon-regulatory factor (IRF)-3/interferon (IFN)-inducible genes, in macrophages and dendritic cells (DCs) in response to their ligand stimuli, polyI:C and lipopolysaccharide (LPS). Toll-IL-1 receptor homology domain (TIR)-containing adapter molecule 1 (TICAM-1) facilitates expression of IFN-inducible genes via TLR3. Although MyD88 and Mal/TIRAP adapters function downstream of TLR4, they barely induce IFN-beta. In addition, DC maturation as well as IFN-beta induction are largely independent of MyD88 and Mal/TIRAP. TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. In LPS-mediated TLR4 activation, a complex of TICAM-1 and an additional TLR4-binding adapter serves as the adapter. We named this TLR4-TICAM-1-bridging adapter TICAM-2. Our results reveal the details of MyD88-independent pathways which separately recruit the distinct adapters downstream of TLR3 and TLR4 and variations of the TLR output are in part regulated by the two additional adapters in DCs.     

Conversion of the FokI endonuclease to a universal restriction enzyme: cleavage of phage M13mp7 DNA at predetermined sites

Endonuclease FokI belongs to class IIS of restriction enzymes, for which the DNA cut points lie outside the enzyme-recognition sites. This permitted conferring new cleavage specificities by combining FokI with tailored oligodeoxynucleotide adapters. Such adapters carry a single-stranded (ss) target-recognition domain, complementary to the selected ss target DNA, and a double-stranded (ds) enzyme-recognition site. Neither enzyme nor adapter alone has endonucleolytic activity toward phage M13mp7 ss DNA, whereas the enzymeadapter complex cleaves this ss target DNA at the particular sites foreordained by the sequence of the ss domain of the adapter. Two kinds of adapters (32 and 34 nucleotides long), with opposing orientations of the asymmetric FokI recognition site, were constructed and shown to direct specific cleavage under a variety of conditions. In addition to FokI, other class IIS enzymes, HphI, MboII and BbvI, which alone do not cleave ss DNA, are suitable for construction of tailored enzyme-adapter complexes with predictable cleavage specificities.

This report provides a preliminary experimental confirmation for the proposal of Szybalski [Gene 40 (1985) 169-173] for the design of adapter-enzyme complexes with novel and predictable specificities. Theoretically, using this approach any sequence could be precisely cleaved at a predetermined point.     

Importin beta-depending nuclear import pathways: role of the adapter proteins in the docking and releasing steps

Nuclear imports of uridine-rich small nuclear ribonucleoprotein (U1 snRNP) and proteins with classical nuclear localization signal (cNLS-protein) are mediated by importin beta. However, due to the presence of different import signals, the adapter protein of the imported molecules and importin beta is different for each pathway. Although the adapter for cNLS-protein is importin alpha, the adapter for U1 snRNP is snurportin1 (SPN1). Herein, we show that the use of distinct adapters by importin beta results in differences at the docking and releasing step for these two import pathways. Nuclear pore complex (NPC) docking of U1 snRNP but not of cNLS-protein was inhibited by an anti-CAN/Nup214 antibody. Thus, the initial NPC-binding site is different for each pathway. Pull-down assays between immobilized SPN1 and two truncated forms of importin beta documented that SPN1 and importin alpha have different binding sites on importin beta. Importin beta fragment 1-618, which binds to SPN1 but not to importin alpha, was able to support the nuclear import of U1 snRNPs. After the translocation through the NPC, both import complexes associated with the nuclear side of the NPC. However, we found that the nature of the importin beta-binding domain of the adapters influences the release of the cargo into the nucleoplasm.     

High-tech hip implant for wireless temperature measurements in vivo

When walking long distances, hip prostheses heat up due to friction. The influence of articulating materials and lubricating properties of synovia on the final temperatures, as well as any potential biological consequences, are unknown. Such knowledge is essential for optimizing implant materials, identifying patients who are possibly at risk of implant loosening, and proving the concepts of current joint simulators. An instrumented hip implant with telemetric data transfer was developed to measure the implant temperatures in vivo. A clinical study with 100 patients is planned to measure the implant temperatures for different combinations of head and cup materials during walking. This study will answer the question of whether patients with synovia with poor lubricating properties may be at risk for thermally induced bone necrosis and subsequent implant failure. The study will also deliver the different friction properties of various implant materials and prove the significance of wear simulator tests. A clinically successful titanium hip endoprosthesis was modified to house the electronics inside its hollow neck. The electronics are powered by an external induction coil fixed around the joint. A temperature sensor inside the implant triggers a timer circuit, which produces an inductive pulse train with temperature-dependent intervals. This signal is detected by a giant magnetoresistive sensor fixed near the external energy coil. The implant temperature is measured with an accuracy of 0.1°C in a range between 20°C and 58°C and at a sampling rate of 2-10 Hz. This rate could be considerably increased for measuring other data, such as implant strain or vibration. The employed technique of transmitting data from inside of a closed titanium implant by low frequency magnetic pulses eliminates the need to use an electrical feedthrough and an antenna outside of the implant. It enables the design of mechanically safe and simple instrumented implants.     

Modulation of bone ingrowth of rabbit femur titanium implants by in vivo axial micromechanical loading.

Titanium implants commonly used in orthopedics and dentistry integrate into host bone by a complex and coordinated process. Despite increasingly well illustrated molecular healing processes, mechanical modulation of implant bone ingrowth is poorly understood. The objective of the present study was to determine whether micromechanical forces applied axially to titanium implants modulate bone ingrowth surrounding intraosseous titanium implants. We hypothesized that small doses of micromechanical forces delivered daily to the bone-implant interface enhance implant bone ingrowth. Small titanium implants were placed transcortically in the lateral aspect of the proximal femur in 15 New Zealand White rabbits under general anesthesia and allowed to integrate with the surrounding bone for 6 wk. Micromechanical forces at 200 mN and 1 Hz were delivered axially to the right femur implants for 10 min/day over 12 consecutive days, whereas the left femur implants served as controls. The average bone volume 1 mm from mechanically loaded implants (n = 15) was 73 +/- 12%, which was significantly greater than the average bone volume (52 +/- 21%) of the contralateral controls (n = 15) (P < 0.01). The average number of osteoblast-like cells per endocortical bone surface was 55 +/- 8 cells/mm(2) for mechanically loaded implants, which was significantly greater than the contralateral controls (35 +/- 6 cells/mm(2)) (P < 0.01). Dynamic histomorphometry showed a significant increase in mineral apposition rate and bone-formation rate of mechanically stressed implants (3.8 +/- 1.2 microm/day and 2.4 +/- 1.0 microm(3).microm(-2).day(-1), respectively) than contralateral controls (2.2 +/- 0.92 microm/day and 1.2 +/- 0.60 microm(3).microm(-2).day(-1), respectively; P < 0.01). Collectively, these data suggest that micromechanical forces delivered axially on intraosseous titanium implants may have anabolic effects on implant bone ingrowth.     

蛋白质多肽文库构建中限制性显示技术的接头设计

为了探讨限制性显示(RD)技术在构建蛋白质多肽文库中灵活的接头设计,分别根据原核表达载体pET22b以及酵母表达载体pNMT-TOPO设计了三套接头,三套接头依次增加一个碱基以保证与之连接的片段总有可能表达正确的开放阅读框.然后以HIV-1 B亚型代表株U26942全基因质粒DNA为对象,利用RD技术分别建立了相应的蛋白质多肽文库.从每个库中各随机挑选12个克隆进行测序分析并进行蛋白质表达预测.结果从原核表达文库中获得了一个可以表达HIV Pol多肽的克隆,SDS-聚丙烯酰胺凝胶电泳(SDS-PAGE)结果显示该克隆在细菌BL21(DE3)中有较高的表达,蛋白质印迹为阳性,与理论预测相符.这些结果提示,RD技术是一种建立基因组随机多肽文库的新方法,该方法灵活的接头设计可以满足不同的表达载体需求.     

TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta

Lipopolysaccharide (LPS) is an agonist for Toll-like receptor (TLR) 4 and expresses many genes including NF-kappaB- and interferon regulatory factor (IRF)-3/IFN-inducible genes in macrophages and dendritic cells (DCs). TICAM-1/TRIF was identified as an adapter that facilitates activation of IRF-3 followed by expression of interferon (IFN)-beta genes in TLR3 signaling, but TICAM-1 does not directly bind TLR4. Although MyD88 and Mal/TIRAP adapters functions downstream of TLR4, DC maturation and IFN-beta induction are independent of MyD88 and Mal/TIRAP. In this investigation, we report the identification of a novel adapter, TICAM-2, that physically bridges TLR4 and TICAM-1 and functionally transmits LPS-TLR4 signaling to TICAM-1, which in turn activates IRF-3. In its structural features, TICAM-2 resembled Mal/TIRAP, an adapter that links TLR2/4 and MyD88. However, TICAM-2 per se exhibited minimal ability to activate NF-kappaB and the IFN-beta promoter. Hence, in LPS signaling TLR4 recruits two types of adapters, TIRAP and TICAM-2, to its cytoplasmic domain that are indirectly connected to two effective adapters, MyD88 and TICAM-1, respectively. We conclude that for LPS-TLR4-mediated activation of IFN-beta, the adapter complex of TICAM-2 and TICAM-1 plays a crucial role. This results in the construction of MyD88-dependent and -independent pathways separately downstream of the two distinct adapters.     

A paradigm for the development and evaluation of novel implant topologies for bone fixation: Implant design and fabrication

The future development of bio-integrated devices will improve the functionality of robotic prosthetic limbs. A critical step in the advancement of bio-integrated prostheses will be establishing long-term, secure fixation to the remnant bone. To overcome limitations associated with contemporary bone-anchored prosthetic limbs, we established a paradigm for developing and fabricating novel orthopedic implants undergoing specified loading. A topology optimization scheme was utilized to generate optimal implant macrostructures that minimize deformations near the bone-implant interface. Variations in implant characteristics and interfacial connectivity were investigated to examine how these variables influence the layout of the optimized implant. For enhanced tissue integration, the optimally designed macroscopic geometry of a titanium (Ti)-alloy implant was further modified by introducing optimized microstructures. The complex geometries of selected implants were successfully fabricated using selective laser sintering (SLS) technology. Fabrication accuracy was assessed by comparing volumes and cross-sectional areas of fabricated implants to CAD data. The error of fabricated volume to CAD design volume was less than 8% and differences in cross sectional areas between SEM images of fabricated implants and corresponding cross sections from CAD design were on average less than 9%. We have demonstrated that this computational design method, combined with solid freeform fabrication techniques, provides a versatile way to develop novel orthopedic implants.