Orthopedic Biomaterials Research Articles

Regulation of extracellular bioactive cations in bone tissue microenvironment induces favorable osteoimmune conditions to accelerate in situ bone regeneration

The design of orthopedic biomaterials has gradually shifted from “immune-friendly” to “immunomodulatory,” in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration. Despite the well-known effects of bioactive metallic ions on osteogenesis, how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied. Herein, we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation (Mg2+) in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid (PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions. The results suggest that the Mg2+-controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory (IL-10) and pro-osteogenic (BMP-2 and TGF-β1) cytokines production. It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. The in vivo results further verify that a large amount of bony tissue, with comparable bone mineral density and mechanical properties, has been generated at an early post-surgical stage in rat intramedullary bone defect models. This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment.

Titanium for Orthopedic Applications: An Overview of Surface Modification to Improve Biocompatibility and Prevent Bacterial Biofilm Formation.

SummaryTitanium and its alloys have emerged as excellent candidates for use as orthopedic biomaterials. Nevertheless, there are often complications arising after implantation of orthopedic devices, most notably prosthetic joint infection and aseptic loosening. To ensure that implanted devices remain functional in situ, innovation in surface modification has attracted much attention in the effort to develop orthopedic materials with optimal characteristics at the biomaterial-tissue interface. This review will draw together metallurgy, surface engineering, biofilm microbiology, and biomaterial science. It will serve to appreciate why titanium and its alloys are frequently used orthopedic biomaterials and address some of the challenges facing these biomaterials currently, including the significant problem of device-associated infection. Finally, the authors shall consolidate and evaluate surface modification techniques employed to overcome some of these issues by offering a unique perspective as to the direction in which research is headed from a broad, interdisciplinary point of view.

Strontium regulates stem cell fate during osteogenic differentiation through asymmetric cell division

Strontium, a popular osteogenic component, has been incorporated into various types of orthopaedic biomaterials to enhance bone regeneration. Strontium performs dual effects in promoting bone formation and inhibiting bone resorption. Previous studies have focused on the effects of strontium ions (Sr2+) in regulating stem cell behavior to initiate regenerative capacity. However, its mechanisms for regulating the fate and homeostasis of stem cells have not been fully elucidated. In this study, the promotive effect of Sr2+ on the osteogenic differentiation of mesenchymal stem cells was confirmed both in vitro and in vivo. Interestingly, in response to Sr2+ treatment, stem cells performed asymmetric cell division to balance stemness maintenance and osteogenic differentiation. In initiating osteogenic differentiation, Sr2+ maintained more cells in the cell cycle by upregulating the population of S and G2/M phase cells, and this increase in the cell population contributed to enhanced osteogenic differentiation. The divided cells with different cell fates were observed, with one daughter cell maintained stemness, while the other committed to osteogenic lineage. Further investigation revealed that Sr2+ activated noncanonical Wnt signaling to regulate the expression and distribution of the Par complex, thus regulating cell division. As a result, the daughter cells committed to different cell fates due to the discriminately activation of osteogenic transcription factors caused by asymmetrically distributed Par3 and aPKC. The results of this study could facilitate the design of biomaterials for bone regeneration by providing a better understanding of cell fate determination regulated by strontium.

Tribological properties of High Density Polyethylene based composite: The effect of mollusc shell particles under dry condition

This article highlights the importance of the addition of Mollusc shell (MS) particles, as bio-filler, on the tribological behavior of high-density polyethylene (HDPE) matrix. The elaborated biocomposites are intended to be used as an orthopedic replacement biomaterial. Different mass content of MS (0, 5, 10, 15 and 20 wt. %) have been added to the HDPE matrix. FTIR analysis, crystallinity rate and Rockwell hardness of different bio-composites were performed. A reciprocating pin-on-disc tribometer was used to fulfil dry wear tests. FTIR analysis showed that the presence of MS particles improved the crystallinity of the HDPE phase. Adding to that, it was found that MS improved the hardness, friction coefficient and wear resistance of the HDPE polymer. In fact, by adding 5 wt. % of MS to the HDPE, good tribological properties were achieved. Scanning Electron Microscopy (SEM) was performed to investigate the wear morphology of biocomposites under dry condition. SEM images showed that the morphology of the worn surfaces had been improved by the addition of MS to the polymer. Finally, a wear scenario was proposed.

Surface treatment functionalization of sodium hydroxide onto 3D printed porous Ti6Al4V for improved biological activities and osteogenic potencies

In the design of multifunctional orthopedic biomaterials, enhanced biological activities, reinforced mechanical property, improved hydrophilicity and osteo-compatibility are the essential criteria. For achieving these goals, here a bioactive multifunctional Ti6Al4V implant with nanowire structured surface topography is designed and fabricated using 3D printing technique. Selective laser melting (SLM) is applied to fabricate scaffold materials with diamond cellular structures to meet the requirements of load-bearing function of bone tissue. With the alkali treatment of sodium hydroxide, osteogenic layer of Na2Ti6O13 is generated on the porous Ti6Al4V, on which apatite is easily deposited and immobilized. Clusters of Na2Ti6O13 exhibits excellent hydrophilicity and surface roughness with precise control of alkali treatment time. Additionally, the compressive strength of the modified porous Ti6Al4V (121.2 MPa-84.5 MPa) decreases due to the corrosion of sodium hydroxide, while it can satisfy the basic mechanical requirement of cortical bone. The results prove that the surface-modified 3D printed porous Ti6Al4V possesses balanced mechanical strength and osteogenic function, promising for potential application in complex multifunctional bone defects.

Selective Laser Melting of Ti6Al4V sub-millimetric cellular structures: Prediction of dimensional deviations and mechanical performance

Ti6Al4V sub-millimetric cellular structures arise as promising solutions concerning the progress of conventional orthopedic implants due to its ability to address a combination of mechanical, physical and topological properties. Such ability can improve the interaction between implant materials and surrounding bone leading to long-term successful orthopedic implants. Selective Laser Melting (SLM) capability to produce high quality Ti6Al4V porous implants is in great demand towards orthopedic biomaterials. In this study, Ti6Al4V cellular structures were designed, modeled, SLM produced and characterized targeting orthopedic implants. For that purpose, a set of tools is proposed to overcome SLM limited accuracy to produce porous biomaterials with desired dimensions and mechanical properties. Morphological analyses were performed to evaluate the dimensional deviations noticed between the model CAD and the SLM produced structures. Tensile tests were carried out to estimate the elastic modulus of the Ti6Al4V cellular structures. The present work proposes a design methodology showing the linear correlations found for the dimensions, the porosity and the elastic modulus when comparing the model CAD designs with Ti6Al4V structures by SLM.

Plasma surface modifications of orthopedic biomaterials by the adoption of bioinorganic cations: a review

A variety of bioinorganic ions have been reported to alter different cellular functions, including the transport of potassium (K+) and calcium (Ca2+) ions, while also modulating signal transduction, energy metabolism and cell proliferation due to the electro-potential change of the cell membrane. It was recently reported that the presence of such bivalent cations in the bone system is beneficial to bone growth and plays a key role in bone remodeling and skeletal development. In the present paper, the authors aim to report the potential mechanism of bone healing stimulated by bioinorganic ions and the relevant surface modification techniques for orthopedic biomaterials.

Strontium Regulates Stem Cells Fates During Osteogenic Differentiation Through an Asymmetric Cell Division

Strontium as a popular osteogenic component has been incorporated into various types of orthopaedic biomaterials to enhance bone regeneration. It performs dual effects in promoting bone formation and inhibiting bone resorption. Studies have focused on the effects of strontium in regulating stem cells behaviors to initiate regenerative capacity. However, the mechanism of strontium on regulating stem cells fates and homeostasis has not been fully elucidated. In this study, the promoted effect of strontium on osteogenic differentiation of mesenchymal stem cells was confirmed both in vitro and in vivo. Interestingly, in responding to strontium treatment, stem cells performed asymmetric cell division to balance stemness maintenance and osteogenic differentiation. Asymmetric distribution of Par complex in daughter stem cells induced different cell fates by discriminately activating of osteogenic transcription factors. Strontium activated noncanonical Wnt signaling to regulate Par complex distribution. Understanding the mechanism of strontium on regulating stem cell fate could facilitate biomaterials designing to initiate endogenous bone regenerative capacity.

Unexpected cytotoxicity of TiO2-coated magnesium alloys

Biodegradable Mg-based alloys have attracted increasing attention from orthopedic surgeons and biomaterials scientists since their Young’s modulus is close to that of bone. However, control of the degradation rate is still a challenge. Sputtered TiO2 coatings were deposited on Mg-Zn-Ca alloys aiming to reduce the initial strong reactivity of Mg with biological fluids. However, the degradation tests indicated that the coated samples induced a larger variation in the pH, greater H2 production and formation of degradation products in comparison to the bare alloys. Consequently, an enhanced cytotoxicity of the coated samples was observed.

Functionality-packed additively manufactured porous titanium implants.

The holy grail of orthopedic implant design is to ward off both aseptic and septic loosening for long enough that the implant outlives the patient. Questing this holy grail is feasible only if orthopedic biomaterials possess a long list of functionalities that enable them to discharge the onerous task of permanently replacing the native bone tissue. Here, we present a rationally designed and additive manufacturing (AM) topologically ordered porous metallic biomaterial that is made from Ti-6Al-4V using selective laser melting and packs most (if not all) of the required functionalities into a single implant. In addition to presenting a fully interconnected porous structure and form-freedom that enables realization of patient-specific implants, the biomaterials developed here were biofunctionalized using plasma electrolytic oxidation to locally release both osteogenic (i.e. strontium) and antibacterial (i.e. silver ions) agents. The same single-step biofunctionalization process also incorporated hydroxyapatite into the surface of the implants. Our measurements verified the continued release of both types of active agents up to 28 days. Assessment of the antibacterial activity in vitro and in an ex vivo murine model demonstrated extraordinarily high levels of bactericidal effects against a highly virulent and multidrug-resistant Staphylococcus aureus strain (i.e. USA300) with total eradication of both planktonic and adherent bacteria. This strong antibacterial behavior was combined with a significantly enhanced osteogenic behavior, as evidenced by significantly higher levels of alkaline phosphatase (ALP) activity compared with non-biofunctionalized implants. Finally, we discovered synergistic antibacterial behavior between strontium and silver ions, meaning that 4–32 folds lower concentrations of silver ions were required to achieve growth inhibition and total killing of bacteria. The functionality-packed biomaterial presented here demonstrates a unique combination of functionalities that make it an advanced prototype of future orthopedic biomaterials where implants will outlive patients.

Bio-inspired apatite particles limit skin penetration of drugs for dermatology applications

Most treatments of skin pathologies involve local administration of active agents. One issue can however be the partial transcutaneous diffusion of the drug to blood circulation, leading to undesirable effects. In this work, the original use of submicron mineral particles based on bio-inspired calcium phosphate apatite was explored for the first time as drug carriers for favoring topical delivery. The permeation of a model drug across synthetic and biological membranes was investigated in both static and dynamic conditions. Our data show that adsorption of the drug on the apatite particles surface drastically limits its permeation, with lower effective diffusion coefficients (Peff) and smaller total released amounts. The retention of the apatite colloidal particles on porcine ear skin explants surface was demonstrated by combining histological observations and Raman confocal microscopy. All results converge to show that association of the drug to apatite particles favors skin surface effects. These findings point to the relevance of mineral-based particles as drug carriers for local delivery to the skin, and open the way to novel applications of bio-inspired apatites in dermatology. Statement of SignificanceCalcium phosphates (CaP) are major biomaterials in orthopedics and dentistry. Their resemblance to bone mineral allows new applications beyond bone repair, e.g. in nanomedicine. In 2018, a 14-page detailed review (M. Epple, Acta Biomaterialia 77 (2018) 1–14) provided clear facts in favor of the non-toxicity of nanosized CaP as an answer to discussions from EU and US study groups, thus clarifying the path to novel applications of nano CaP. In the present paper, bio-inspired apatite nanoparticles are used for the first time as drug carriers for dermatology for drastically limiting drug transcutaneous permeation and retaining a topical effect. We demonstrate this proof of concept via permeation cell tests, histology, Raman microscopy and photoluminescence after application on porcine ear skin.

Radial Extracorporeal Shock Wave Therapy Against Cutibacterium acnes Implant-Associated Infections: An in Vitro Trial.

Background: Antibiotic management of low-virulent implant-associated infections induced by Cutibacterium acnes may be compromised by multi-drug resistance development, side effects, and increased cost. Therefore, we sought to assess the effects of shock wave therapy against the above pathogen using an in vitro model of infection. Methods: We used a total of 120 roughened titanium alloy disks, simulating orthopedic biomaterials, to assess the results of radial extracorporeal shock wave therapy (rESWT) against C. acnes (ATCC 11827) biofilms relative to untreated control. In particular, we considered 1.6 to 2.5 Bar with a frequency ranging from 8–11 Hz and 95 to 143 impulses per disk to investigate the antibacterial effect of rESWT against C. acnes planktonic (free-floating) and biofilm forms. Results: Planktonic bacteria load diminished by 54% compared to untreated control after a 1.8-bar setting with a frequency of 8 Hz and 95 impulses was applied (median absorbance (MA) for intervention vs. control groups was 0.9245 (IQR= 0.888 to 0.104) vs. 0.7705 (IQR = 0.712 to 0.864), respectively, p = 0.001). Likewise, a statistically significant reduction in the amount of biofilm relative to untreated control was documented when the above setting was considered (MA for treatment vs biofilm control groups was 0.244 (IQR= 0.215–0.282) and 0.298 (IQR = 0.247–0.307), respectively, p = 0.033). Conclusion: A 50% biofilm eradication was documented following application of low-pressure and low-frequency radial shock waves, so rESWT could be investigated as an adjuvant treatment to antibiotics, but it cannot be recommended as a standalone treatment against device-associated infections induced by C. ances.

Functional behavior of chitosan/gelatin/silica-gentamicin coatings by electrophoretic deposition on surgical grade stainless steel.

Metals are used in several orthopedic applications as fixation elements for the stabilization of fractures or as prostheses. One of the most common orthopedic biomaterials in many developing countries is surgical grade stainless steel (SS). However, its use as permanent implant in orthopedic surgery is conditioned due to its limited corrosion resistance in physiological media, lack of osseointegration, and absence of antibacterial effect. The aim of this work is to generate a degradable coating with antibacterial properties for stainless steel to be used in implants/medical devices. The coating is composed of a biopolymer/silica-gentamicin nanoparticles composite obtained by electrophoretic deposition (EPD) on surgical grade stainless steel plates. The coating surface was characterized by microscopic examination, and in vitro performance was evaluated after immersion in phosphate-buffered saline (PBS) solution, simulated body fluid (SBF), and cell culture medium, to analyze coating degradation, antibiotics release, cell attachment (ST-2 stromal cells), and antibacterial (Escherichia coli and Staphylococcus aureus) properties. EPD coatings were uniform and covered homogeneously the surface of the SS substrate. Also the distribution of silica-gentamicin nanoparticles was homogeneous on the coated area. The degradation of the chitosan-gelatin coatings was evident after 7days of immersion. The gentamicin release led to excellent antibacterial behavior at 24h, meanwhile the cell proliferation (at 7days culture) was not inhibited. The results show that the coating system exhibits promising behavior which could contribute to prevent hospital infections at early implantation times.

Development of durable microelectrodes for the detection of hydrogen peroxide and pH

AbstractCathodic electrical stimulation has been investigated as a way to treat implant‐associated infection of orthopaedic devices. One of the proposed mechanisms of these effects is the changes in chemical gradients adjacent to the implant generated by the cathodic reaction products. Of these reaction products, both alkaline pH and hydrogen peroxide have been implicated as antimicrobial agents. However, direct measurement of these chemical effects has yet to be fully characterized for orthopaedic biomaterials. Microelectrodes are powerful tools that can be used to measure localized chemical conditions. Most commercially available sensors are fabricated from pulled glass pipettes, which make them quite fragile. In order to more easily make measurements of the effects of electrical stimulation, more durable sensors are desired. Solid‐state electrodes were fabricated from platinum and iridium micro‐wires to make H2O2 and pH‐sensitive electrodes, respectively. Additionally, a similar method was used to fabricate electrodes that were housed within a stainless steel needle, which could be used to penetrate and measure in solid samples without damaging the sensor. The H2O2 microelectrode was found to have a sensitivity of 34.1 pA/µM and a R2 value of .996. The pH microelectrode was found to have a linear calibration from 2 to 12 with a sensitivity of 76.7 mV/pH and a R2 of .996. The needle‐based electrodes were found to be able to detect changes in both H2O2 and pH when tested in an agar gel model.

Ceramic resurfacing: the future and challenges

Ceramics have a history of use in total hip replacement (THR) including early use in hip resurfacing. Improvements in ceramics over the past two decades have resulted in the BIOLOX ® delta material which has a higher fracture resistance, low wear and excellent biocompatibility compared to other orthopaedic biomaterials. Cobalt Chromium Molybdenum (CoCrMo) metal alloy continues to be used in hip resurfacing but is generally limited to use of larger sizes in active males due to a legacy of concerns with metal ion release from discontinued devices and large diameter modular head trunnions. A novel hip resurfacing device (ReCerf ® , MatOrtho Ltd., UK) utilises BIOLOX ® delta, removing CoCrMo metal from the prosthesis. ReCerf ® is based on a clinically successful design from the same manufacturer (ADEPT ® , MatOrtho Ltd., UK) and although BIOLOX ® delta is a clinically proven material in THR, it requires significant testing to prove safety in the clinical environment. Increasing regulations particularly in Europe, has increased the time to market for new devices such as this and whilst the changes are being implemented to ensure the lowest risk for patients, they are also leaving patients unable to access new treatment routes. Ultimately, it is long term clinical outcomes that are required to determine whether the future of resurfacing is in using alternative materials such as ceramic and whether these compare favourably with the established, successful metal designs which have been in clinical use for over 20 years.

Biomaterials for orthopedics: anti-biofilm activity of a new bioactive glass coating on titanium implants

This study evaluated adhesion and biofilm formation by Candida albicans, Pseudomonas aeruginosa and Staphylococcus epidermidis on surfaces of titanium (Ti) and titanium coated with F18 Bioactive Glass (BGF18). Biofilms were grown and the areas coated with biofilm were determined after 2, 4 and 8 h. Microscopy techniques were applied in order to visualize the structure of the mature biofilm and the extracellular matrix. On the BGF18 specimens, there was less biofilm formation by C. albicans and S. epidermidis after incubation for 8 h. For P. aeruginosa biofilm, a reduction was observed after incubation for 4 h, and it remained reduced after 8 h on BGF18 specimens. All biofilm matrices seemed to be thicker on BGF18 surface than on titanium surfaces. BGF18 showed significant anti-biofilm activity in comparison with Ti in the initial periods of biofilm formation; however, there was extensive biofilm after incubation for 48 h.

Biomaterials for Adhesion in Orthopedic Applications: A Review

Abstract Adhesive biomaterials, historically, have had a wide range of applications in all medical fields. With the extensive variety of biomaterials with adhesion properties, the field of orthopedics benefits from using adhesives which can provide superior biocompatibility, resorbability, and low immunogenicity. The goal of this review is to serve as a reference of the types of adhesive biomaterials used clinically and their specific applicability in the field of orthopedics. The applications of adhesive biomaterials in orthopedics are as scaffolds, filler materials to treat bone defects and as carrier materials to deposit other bioactive materials to a site. First, we review the history and background of adhesive biomaterials and some of their general applications in orthopedics. Then we focus on the various types of adhesive biomaterials which include fibrin, collagen, polyurethane, epoxy resin, cyanoacrylates, polyesters and polymethylmethacrylate, all of which are excellent candidates for the field of orthopedics. We discuss their properties, current applications in all fields, and advantages and disadvantages found in some studies. Lastly, we indicate some future directions for adhesive biomaterials in orthopedics and highlight their advantages over conventional biomaterials in orthopedics.

Effect of insert material on forces on quadriceps, collateral ligament, and patellar tendon after rotating platform mobile-bearing total knee arthroplasty

There is a gradual increase in the number of patients for total knee arthroplasty (TKA), and TKA demonstrates reliable clinical outcomes. The orthopaedic biomaterials community continuously attempted over the past decades to improve the longevity of UHMWPE in TKA by using various improved technologies. Polyetheretherketone (PEEK) and carbon fiber reinforced-PEEK(CFR-PEEK) are suggested as potential tibial insert materials to replace UHMWPE in some applications. The aim of this study involves evaluating the biomechanical effects of UHMWPE and CFR-PEEK tibial materials on mobile-bearing TKA. The finite element (FE) model was obtained by conducting computed tomography and magnetic resonance imaging. The FE investigation included three types of loading conditions corresponding to the loads used in the experiments for FE model validation and model predictions under deep-knee bend loading conditions. We investigated forces on quadriceps, collateral ligament and patellar tendon with UHMWPE and CCFR-PEEK tibial insert materials under the deep-knee-bend condition. Quadriceps force decreased with flexion for CFR-PEEK when compared to that for UHMWPE. A similar trend was observed in terms of the patellar tendon force. An opposite trend was observed in the collateral ligament. Medial collateral ligament force in the CFR-PEEK exceeded that in the UHMWPE, and lateral collateral ligament force in the UHMWPE exceeded that in the CFR-PEEK. The CFR-PEEK represents an alternative insert material given its superior biomechanical effect after mobile-bearing total knee arthroplasty. However, a balance between the medial and lateral ligaments is considered as an important factor in the CFR-PEEK tibial insert due to its opposite biomechanical effect.

In vitro time-kill kinetics of dalbavancin against Staphylococcus spp. biofilms over prolonged exposure times

Staphylococcus aureus and Staphylococcus epidermidis are leading pathogens of biofilm-related infections and represent the most common cause of osteomyelitis and biomedical implants infections. Biofilm-related infections usually require long-term antibiotic treatment, often associated to surgical interventions. Dalbavancin is a newer lipoglycopeptide approved for the treatment of acute skin and skin-structure infections caused by Gram-positive pathogens. In addition, dalbavancin has recently been considered as a potential option for the treatment of staphylococcal osteomyelitis and orthopedic implant infections.In this study, time-kill kinetics of dalbavancin against S. aureus and S. epidermidis biofilms were determined over prolonged exposure times (up to 7 days), using both a standardized biofilm susceptibility model and biofilms grown onto relevant orthopedic biomaterials (i.e. titanium and cobalt-chrome disks). Dalbavancin (at concentrations achievable in bone and articular tissue) showed a potent activity against established staphylococcal biofilms in both tested models, and was overall superior to the comparator vancomycin.

Nanotechnology-based biomaterials for orthopaedic applications: Recent advances and future prospects.

Bioimplant engineering aims to mature biological alternatives to restore, retain, or modify damaged tissues and/or the functionality of organs. Remarkable advancements in modern material technology have helped the diversity of materials for orthopaedic implant application. As such, nanomaterials can simulate the surface properties of natural tissues, especially with respect to surface topography, surface chemistry, surface energy, and surface wettability. The novel properties of nanomaterials also encourage their use for improving the growth of different tissues. The present review lays the foundation for nanotechnology-driven biomaterials through revelation of fundamental design considerations to determine the performance of an orthopaedic implant in terms of success or failure, their antimicrobial/antibacterial activities, and response to cell adhesion, proliferation, and differentiation. In this context, the nano-functionalization of biomaterial surface has been widely investigated to improve cell adhesion, proliferation, differentiation, and migration for implants with high antimicrobial activity. The potential use of nanomaterials (in terms of nanostructured surface or functional nanocoating over implant surface) can resolve several issues (e.g., corrosion resistance and bacterial adhesion) pertaining to conventional metallic or non-metallic implants, especially for optimization of implant techniques. The future trends of orthopaedic biomaterials (e.g., porous structures, smart biomaterials, and 3D implants) are promising to achieve the desired properties and structure of an implant with stimuli-responsive behaviour. The major challenges in commercialization of nanotechnology-derived biomaterials are finally addressed to help overcome the limitations of pre-existing orthopaedic biomaterials in terms of key variables, e.g., quality, treatment cost, implant life, and pain relief.