Tibial Implants Research Articles

New Ti-6Al-2Nb-2Ta-1Mo alloy as implant biomaterial: In vitro corrosion and in vivo osseointegration evaluations

Over the last decade, new titanium alloys are developed in different areas of implantology. The aim of this study was to characterize a new Ti-Al-Nb-Ta-Mo based alloy, with high potential for being used as a biomedical implant. The evaluation of Ti-6Al-2Nb-2Ta-1Mo was performed both in vitro (by monitoring its corrosion resistance in Hank's Balanced Salt Solution, HBSS) and in vivo (by evaluating the osseointegration following rabbit tibia implantation), by comparison with titanium and Ti-6Al-7Nb alloy. Electrochemical impedance spectroscopy (EIS) data showed high impedance values for all titanium samples after 1 week immersion times in HBSS at 37 °C. According to EIS analysis, the corrosion resistance of the Ti-6Al-2Nb-2Ta-1Mo alloy immersed in HBSS was higher compared to the standard cp-Ti or with the Ti-6Al-7Nb alloy. In addition, a higher degree of osseointegration was achieved by the Ti-6Al-2Nb-2Ta-1Mo alloy, thus probing that a higher resistance to electrochemical corrosion provided enhanced protection to the implant surface against biodegradation, thus positively affecting the qualitative and quantitative evolution of bone tissue repair.

Exploring the mechanism behind improved osteointegration of phosphorylated titanium implants with hierarchically structured topography

Titanium (Ti) and its alloys have been frequently used in dental and orthopedic implants, but the undesired oxide layer easily formed on the surface tends to be the cause of implant failure for Ti-based implants. To address this problem, we herein prepared a phosphorylated Ti coating (TiP-Ti) with a micro/nano hierarchically structured topography on commercially pure Ti implants by a hydrothermal method to improve its osteointegration capacity. The surface morphology, chemical composition, and biological activity were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), contact-angle measurement, and protein adsorption assay. Osteointegration of TiP-Ti implants in rat tibia was investigated by biomechanical testing, micro-CT and histological analyses. We further explored the proposed mechanism which improves osteointegration of TiP-Ti implants by proliferation, adhesion, and differentiation assays of rat bone marrow mesenchymal stem cells (BMSCs). Our results demonstrated that the improved osteointegration mainly benefited from the better spread and adhesion of BMSCs on the micro/nano hierarchically structured TiP-Ti surfaces compared to hydroxyapatite coated Ti (HA-Ti), the positive control, and untreated Ti (untreated-Ti), the negative control. In conclusion, TiP-Ti surface is a promising candidate implant surface design to accelerate the osteointegration of Ti-based implants in biomedical applications.

Micro- and Nanohemispherical 3D Imprints Modulate the Osteogenic Differentiation and Mineralization Tendency of Bone Cells.

Surface topography has been reported to play a key role in modulating cell behaviors, yet the mechanism through which it modulates these behaviors is not fully understood, especially in the case of three-dimensional (3D) topographies. In this study, a series of novel hemispherical 3D imprints ranging from the nanoscale to the microscale were prepared on titanium (Ti) surfaces using a customized interfacial lithography method. Mouse embryo osteoblast precursor cells (MC3T3-E1) were selected to investigate the solitary effect of specific hemispherical 3D imprints on cellular behaviors. The results indicated that varied hemispherical 3D imprints can affect the formation of filopodia and the arrangement of the cytoskeleton in different ways. Specifically, they can alter the spreading morphologies of cells and lead to deformation of the nucleus, which eventually affects cell proliferation and osteogenic differentiation. Cells cultured on different hemispherical 3D imprints exhibited promoted proliferation and osteogenic differentiation to different degrees; for example, cells cultured on 90 and 500 nm hemispherical imprints formed abundant filopodia and exhibited the highest alkaline phosphatase activity and osteogenic gene expression, respectively. Four-week tibia implantation also confirmed that 90 nm hemispherical imprints improved the osteogenic ability in vivo compared with an unpatterned Ti substrate. In addition to promoted proliferation, colonization of more cells on the surface of implants and induction of rapid osteogenic differentiation can occur. Our work provides a rational way to balance cell proliferation and differentiation, which can accelerate bone integration of an implant and host tissue.

Aseptic Ligatures Induce Marginal Peri-Implant Bone Loss-An 8-Week Trial in Rabbits.

The clinical value of ligature-induced experimental peri-implantitis studies has been questioned due to the artificial nature of the model. Despite repeated claims that ligatures of silk, cotton and other materials may not induce bone resorption by themselves; a recent review showed that the tissue reaction toward them has not been investigated. Hence, the current study aimed to explore the hard and soft tissue reactions toward commonly used ligature materials. A total of 60 dental implants were inserted into the femur (n = 20) and tibia (n = 40) of 10 rabbits. The femoral implants were ligated with sterile 3-0 braided silk in one leg and sterile cotton retraction chord in the other leg. The tibial implants were ligated with silk or left as non-ligated controls. All wounds were closed in layers. After a healing time of 8 weeks, femoral (silk versus cotton) and proximal tibial (silk versus non-ligated control) implants were investigated histologically. Distal tibial (silk versus non-ligated control) implants were investigated with real time polymerase chain reaction (qPCR). The distance from the implant-top to first bone contact point was longer for silk ligated implants compared to non-ligated controls (p = 0.007), but did not vary between cotton and silk. The ligatures triggered an immunological reaction with cell infiltrates in close contact with the ligature materials, adjacent soft tissue encapsulation and bone resorption. qPCR further demonstrated an upregulated immune response toward the silk ligatures compared to non-ligated controls. Silk and cotton ligatures provoke foreign body reactions of soft tissue encapsulation type and bone resorption around implants in the absence of plaque.

Correlation of Anthropometric Measurements of Proximal Tibia in Iranian Knees with Size of Current Tibial Implants.

The results of clinical studies have reported that Asian knee anatomical aspects are smaller than those of the Caucasian population. The purpose of this study was to investigate the morphometry of the proximal tibia in the standard resected surface of total knee arthroplasty (TKA). In this descriptive study, the anthropometric data of the proximal tibia were measured in 132 knees (80 males and 52 females) using magnetic resonance imaging in 2015. The collected data included anteroposterior (AP) length, mediolateral (ML) width, medial AP, lateral AP, and aspect ratio (ML/AP). The medial and lateral AP distance to bone center was calculated for symmetry analysis. The morphometric data were also compared with the same dimensions of four current tibial implants. The mean age of the subjects was 38.26±11.45 year (age range: 20-60 years). The mean AP length and mean ML width in the resected surface of the bone, as well as the mean aspect ratio (ML/AP) of tibial bone in all the subjects, were 46.53±4.05 mm, 73.36±6.86 mm, and 1.58±0.11, respectively. The mean values of medial and lateral AP distance up to bone center were 13.40±6.17 and 17.09±6.83 mm, respectively, indicating asymmetric proximal tibia in the study population. The measurements of anatomic shapes and dimensions of the proximal tibia revealed that women have smaller dimensions than their male counterparts. Prostheses with smaller AP size tended to be undersized and larger AP size had a tendency towards overhang in the mediolateral dimension. The data and obtained results of this study can be used as guidance on designing tibial implant components suitable for TKA in the Iranian population.

Effects of a hydroxyapatite coating on the stability of endosseous implants in rabbit tibiae.

A dental implant surface which would promote rapid and strong osseointegration is a key factor of success in modern implantology. To achieve this goal, different implant surface modifications are developed. A hydroxyapatite (HA) coating changing a bioinert titanium surface into bioactive is one of them. The objective of the study was to investigate the effects on bone osseointegration in rabbits resulting from the application of a HA coating deposited on titanium endosseous implants using a modified electrochemical method. Titanium implants with HA coatings and controls with Al2O3 grit-blasted surfaces were embedded into rabbit tibiae. The chemical composition, roughness and morphology of the implants were determined. Implant stability tests were performed, and the Periotest® value (PTV) and the implant stability quotient (ISQ) value for Osstell Mentor were recorded in order to evaluate the osseointegration. The surface characterization of the implants revealed a microstructure with an arithmetical mean height (Sa) in the range of 0.71-1.04 μm. The HA coating was free of contamination, whereas the controls were enriched with corundum. After healing, a statistically significant increase in the mean ISQ and a decrease in the mean PTV for the HA-coated implants was observed. In the case of the control implants, only PTV decreased significantly with time. The present study found that implant surface properties affected implant stability as determined by Osstell and Periotest measurements. The HA coating reported herein was found to have chemical and physical properties which appear to improve osseointegration compared to grit-blasted implants.

Non-Destructive Testing of Ceramic Knee Implants Using Micro-Computed Tomography

BackgroundBecause of the accumulated numbers and the increasing rate of knee replacement surgeries larger numbers of revision cases are likely. Although the success rate of knee arthroplasties is high, complications like the loosening of the implant necessitate subsequent treatments. Therefore, new concepts such as metal-free ceramic implants are necessary, for example, using zirconium dioxide (ZrO2). Several studies showed that the strength of ceramic ZrO2 implants is equivalent to cobalt-chromium components. MethodsNon-destructive testing remains challenging due to the high density (6 g/cm³) of ZrO2. In this feasibility study, we investigated 8 tibial and 8 femoral implants respectively using an industrial X-ray micro-computed tomography (XCT) system at a voxel size of 100 μm. We established a non-destructive testing protocol for ceramic knee implants optimizing scanning parameters and sample orientation using CT simulations. Finally, we used an iterative artifact reduction procedure for beam hardening correction. ResultsThe results show that corrected image data enable the non-destructive inspection of high-density components. In this sample, none of the investigated components show any internal defects like pores or cracks. In general, XCT is a major imaging method that is able to provide a 3-dimensional representation of higher dense objects that allows the inspection of metal or ceramic knee implants. Even though we established an optimized scanning routine for tibial and femoral ceramic components, it is not possible to completely eliminate scanning artifacts of XCT. ConclusionAltogether, after visual inspection, none of the beam-hardening corrected XCT data sets for femoral and tibial implants showed any defects, that is, no inclusions, cracks, or pores were detected. XCT test is therefore an essential addition to the fatigue testing since it is the only non-destroying testing method.

In vivo and in vitro bioactivity of a “precursor of apatite” treatment on polyetheretherketone

We recently developed a surface treatment, “precursor of apatite” (PrA), for polyetheretherketone (PrA-PEEK) via a simple, low-temperature process aiming to achieve stronger and faster adhesion to bone. The treatment involves three steps: H2SO4 immersion, exposure to O2 plasma discharge, and alkaline simulated body fluid (alkaline SBF) treatment. This method produces homogeneous fine particles of amorphous calcium phosphate on the PEEK, and we confirmed that PrA-PEEK had excellent apatite formation ability in an SBF immersion test. In the present study using PEEK implants in rabbit tibia, mechanical tests, and histological and radiological analyses revealed that PrA provided the PEEK substrate with excellent bone-bonding properties and osteo-conductivity at early stages (4 and 8 weeks), extending to 16 weeks. In vitro study using MC3T3-E1 cells revealed via XTT assay that PrA on the PEEK substrate resulted in no cytotoxicity, though PrA treatment seemed to suppress gene expression of integrin β-1 and Alp after 7-day incubation as shown by real-time PCR. On the whole, PrA treatment succeeded in giving in vivo bone-bonding properties to the PEEK substrate, and the treatment is a safe and promising method that can be applied in clinical settings. There was an inconsistency between in vivo and in vitro bioactivity, and this discrepancy indicated that apatite formation does not always need activation of osteoblasts at very early stage and that optimal conditions at cell and organism level may be different. Statement of SignificancePolyetheretherketone (PEEK) is an attractive engineering polymer used for spine and dental surgery. To further improve clinical outcome of PEEK-based materials, we developed “Precursor of apatite” (PrA) treatment on the PEEK surface to confer bone-bonding properties. The advantages of this treatment are that it does not require high-temperature processing or special chemicals, and it is inexpensive. The present study clarified excellent in vivo bone-bonding property of PrA treatment. In addition, the results revealed important insights indicating that optimal conditions, especially wettability and crystallinity in calcium phosphate, differ at cell and organism levels. Moreover, our results indicated that prediction of in vivo bioactivity should be done in combination with multiple in vitro tests.

Targeted Interleukin‐27 Gene Therapy Development for Disrupting Key Malignant Crosstalk between Metastatic Prostate Cancer and Bone

Prostate cancer (PCa) bone metastases have been reported in up to 90% of patients with advanced disease. Prostate cancer cells ‘hijack’ bone homeostasis by disrupting the crosstalk between critical cells within the tumor/bone microenvironment (osteoblasts, osteoclasts, and immune cells), and utilizing this effector‐rich environment for cancer cell survival and growth. Crosstalk pathways primarily involve Interleukins (IL‐6 and IL‐11) and transforming growth factor β (TGFβ). Therefore, a key therapeutic objective in malignant skeletal disease management is to eliminate tumors while restoring bone homeostasis. Current treatments are limited to palliative radiotherapy, chemotherapy, or anti‐RANK treatments, all of which have considerable side effects such as osteonecrosis of the jaw or enhanced tumor invasion. An emerging approach to treating skeletal malignancies, osteoimmunology, investigates new multifunctional immune‐stimulatory agents that can simultaneously combat tumor growth, and promote bone regeneration. IL‐27 is an immunomodulatory cytokine with a great potential as a multifunctional cancer therapeutic. Its regulatory roles include antitumor immune responses (promoting Th1 differentiation), inhibition of tumor growth, and direct modification of tumor/bone crosstalk to support bone regeneration. Thus, we hypothesize that a tumor‐targeted IL‐27 gene therapy approach would facilitate the accumulation of IL‐27 in the bone/tumor microenvironment and enhance its therapeutic efficacy. To test this hypothesis, we created a tumor‐targeted IL‐27 gene by incorporating a novel peptide (LSLITRL); an IL‐6 receptor antagonist known to inhibit angiogenesis and tumor growth; or a scrambled control peptide at the C‐terminus. To detect the expression, secretion, and tumor recognition specificity, IL‐27 constructs were fused to a NanoLuciferase expressing vector. We have also assessed the potential for tumor‐targeted IL‐27 expression in disrupting malignant characteristics of PCa in vitro in terms of viability and invasiveness following transfection. Future studies will examine the expression and therapeutic efficacy of tumor‐targeted IL‐27 in vivo in a TRAMP‐C2 tibial implantation model.Support or Funding InformationNIH‐NCI R01CA196947‐S1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Use of Stems for Morbid Obesity in Total Knee Arthroplasty.

Morbidly obese patients undergoing total knee arthroplasty have worse functional outcomes and implant survival, and increased revision rates compared with nonobese patients. In addition to increased medical comorbidities and difficult exposure, increased stress on the tibial implant and altered kinematics of knee motion contribute to aseptic loosening and medial collapse. Increased implant fixation, including use of a stemmed tibial implant, may be a way to help avoid these complications. While there is limited data on tibial stems in the morbidly obese patients specifically, cemented stemmed tibial implants should be strongly considered in these patients, especially if bone quality is poor. The initial increased cost of a stemmed implant can be justified in this high-risk patient population to minimize the risk of costly revisions related to compromised tibia component fixation.

Does the condylar lift-off method or the separation method better detect loss of contact between tibial and femoral implants based on analysis of single-plane radiographs following total knee arthroplasty?

BackgroundLoss of contact between the femoral and tibial implants following total knee arthroplasty (TKA) has been related to accelerated polyethylene wear and other complications. Two methods have been used to detect loss of contact in single-plane fluoroscopy, the condylar lift-off method and the separation method. The objectives were to assess the ability of each method to detect loss of contact. MethodsTKA was performed on ten cadaveric knee specimens. Tibial force was measured in each compartment as specimens were flexed from 0° to 90° while internal-external and varus-valgus moments were applied. Single-plane radiographs taken simultaneously with tibial force were analyzed for loss of contact using the two methods. Receiver operating characteristic (ROC) and optimum threshold distances were determined. ResultsFor the lift-off method and the separation method, the areas under the ROC curves were 0.89 vs 0.60 for the lateral compartment only and 0.81 vs 0.70 for the medial compartment only, respectively. For the lift-off method, the optimum threshold distances were 0.7 mm in the lateral compartment only and 0.1 mm in the medial compartment only but the false positive rate for the medial compartment only almost doubled. For both compartments jointly, the areas under the ROC curves decreased to 0.70 and 0.59 for the lift-off and separation methods, respectively. ConclusionWhen detecting loss of contact using single-plane fluoroscopy, the lift-off method is useful for the lateral compartment only but not for the medial compartment only and not for both compartments jointly. The separation method is not useful.

The effects of saline soaking on the removal torque of titanium implants in rabbit tibia after 10 days

The effects of saline soaking on the removal torque of titanium implants in rabbit tibia after 10 days

Synergistic effect of surface phosphorylation and micro-roughness on enhanced osseointegration ability of poly(ether ether ketone) in the rabbit tibia

This study was aimed to investigate the osseointegration ability of poly(ether ether ketone) (PEEK) implants with modified surface roughness and/or surface chemistry. The roughened surface was prepared by a sandblast method, and the phosphate groups on the substrates were modified by a two-step chemical reaction. The in vitro osteogenic activity of rat mesenchymal stem cells (MSCs) on the developed substrates was assessed by measuring cell proliferation, alkaline phosphatase activity, osteocalcin expression, and bone-like nodule formation. Surface roughening alone did not improve MSC responses. However, phosphorylation of smooth substrates increased cell responses, which were further elevated in combination with surface roughening. Moreover, in a rabbit tibia implantation model, this combined surface modification significantly enhanced the bone-to-implant contact ratio and corresponding bone-to-implant bonding strength at 4 and 8 weeks post-implantation, whereas modification of surface roughness or surface chemistry alone did not. This study demonstrates that combination of surface roughness and chemical modification on PEEK significantly promotes cell responses and osseointegration ability in a synergistic manner both in vitro and in vivo. Therefore, this is a simple and promising technique for improving the poor osseointegration ability of PEEK-based orthopedic/dental implants.

Contact of Rough Surfaces in Ankle Implants Under Combined Normal and Twist Loading

The medical application of implant replacements to remedy the pain in joints has necessitated a comprehensive study of wear due to contact of implant surfaces. Excessive wear can lead to toxicity and other implant associated medical issues such as patient discomfort and decreased mobility. Since implant wear is the result of contact between surfaces of tibia and talus implant, it is important to establish a model that can address implant surface contact mechanics with roughness effects. In this research, a statistical contact model is developed for the interaction of tibia and talus including normal and lateral contact in which surface roughness effects are included. The model accounts for the elastic–plastic interaction of the implant surface with roughness. For this purpose, tibia and talus implants are considered as macroscopic surfaces containing micron-scale roughness. Approximate equations are obtained that relate the contact force to the mean surface separation explicitly. Closed-form equations are obtained for hysteretic energy loss in implant using the approximate equations. Such a function can serve as a very useful tool for implant designers and manufacturers. Natural frequencies of both adduction-abduction and planter-dorsiflexion rotations are obtained using nonlinear vibration analyses.

In vivo tissue response and antibacterial efficacy of minocycline delivery system based on polymethylmethacrylate bone cement.

This study aims the in vivo biological characterization of an innovative minocycline delivery system, based on polymethylmethacrylate bone cement. Bone cements containing 1% or 2.5% (w/w) minocycline were formulated and evaluated through solid-state characterization. Biological evaluation was conducted in vivo, within a rat model, following the subcutaneous and bone tissue implantation, and tissue implantation associated with Staphylococcus aureus is challenging. The assessment of the tissue/biomaterial interaction was conducted by histologic, histomorphometric and microtomographic techniques. Minocycline addition to the composition of the polymethylmethacrylate bone cement did not modify significantly the cement properties. Drug release profile was marked by an initial burst release followed by a low-dosage sustained release. Following the subcutaneous tissue implantation, a reduced immune-inflammatory reaction was verified, with diminished cell recruitment and a thinner fibro-connective capsule formation. Minocycline-releasing cements were found to enhance the bone-to-implant contact and bone tissue formation, following the tibial implantation. Lastly, an effective antibacterial activity was mediated by the implanted cement following the tissue challenging with S. aureus. Kinetic minocycline release profile, attained with the developed polymethylmethacrylate system, modulated adequately the in vivo biological response, lessening the immune-inflammatory activation and enhancing bone tissue formation. Also, an effective in vivo antibacterial activity was established. These findings highlight the adequacy and putative application of the developed system for orthopedic applications.

A 9-Year Outcome Study Comparing Cancellous Titanium-Coated Cementless to Cemented Tibial Components of a Single Knee Arthroplasty Design

BackgroundThe cemented Advance Medial-Pivot total knee arthroplasty (TKA) was designed to reflect contemporary knee kinematics data and has shown satisfactory long-term outcomes. MethodsWe retrospectively evaluated prospectively collected data from 2 groups of patients. Group A consisted of 54 patients (54 TKAs), 18 men and 36 women, and mean age at surgery was 63.2 ± 5.2 years; group B consisted of 54 patients (54 TKAs), 17 men and 37 women, and mean age at surgery was 63.8 ± 5.1 years. Patients of both groups were matched for age, gender, side, body mass index, and length of follow-up. The cementless components of this design were implanted in group A and the cemented in group B. Implant failure, complication rates, clinical (both subjective and objective) and radiological outcomes were assessed in all patients of both groups. ResultsAll patients of both groups were available for final follow-up evaluation at a mean of 8.6 ± 0.4 years. Survival analysis at 9 years showed a cumulative success rate of 100% in both groups with all end points. In neither group were implant-related, surgeon-related, or patient-related failures observed. When both groups were compared, in all time intervals, no differences were recorded on Knee Society system, Western Ontario and McMaster University Osteoarthritis Index, Short Form-12, and Oxford Knee Scores. On radiological examination, for both groups, all parameters evaluated were satisfactory. ConclusionThis study presents satisfactory midterm clinical and radiological outcomes with the use of both versions of this design. Moreover, no implant-related failures were observed with the use of cancellous titanium-coated tibial implants.

Promoting Osseointegration of Ti Implants through Micro/Nanoscaled Hierarchical Ti Phosphate/Ti Oxide Hybrid Coating.

In this study, micro/nanoscaled hierarchical hybrid coatings containing titanium (Ti) phosphate and Ti oxide have been fabricated with the aim of promoting osseointegration of Ti-based implants. Three representative surface coatings, namely, micro/nanograss Ti (P-G-Ti), micro/nanoclump Ti, (P-C-Ti), and micro/nanorod Ti (P-R-Ti), have been produced. In-depth investigations into the coating surface morphology, topography, chemical composition, and the surface/cell interaction have been carried out using scanning electron microscopy, transmission electron microscope, X-ray photoelectron spectroscopy, X-ray diffraction, contact-angle measurement, and protein adsorption assay. In addition, in vitro performance of the coating (cell proliferation, adhesion, and differentiation) has been evaluated using rat bone marrow stromal cells (BMSCs), and in vivo assessments have been carried out based on a rat tibia implantation model. All the hybrid coating modified implants demonstrated enhanced protein adsorption and BMSC viability, adhesion and differentiation, with P-G-Ti showing the best bioactivity among all samples. Subsequent i n vivo osseointegration tests confirmed that P-G-Ti has induced a much stronger interfacial bonding with the host tissue, indicated by the 2-fold increase in the ultimate shear strength and over 6-fold increase in the maximum push-out force compared to unmodified Ti implants. The state-of-the-art coating technology proposed for Ti-based implants in this study holds great potential in advancing medical devices for next-generation healthcare technology.

Abstract LB-260: Development and validation of propeptide therapeutics for treating bone metastatic prostate cancer

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Most prostate cancer related fatalities are not due to tumors at origination sites, but rather due to prostate cancer metastasis throughout the body. Although the relative 5-year survival rate for localized prostate cancer nears 100%, unfortunately, upon metastasis the 5-year survival rate drops to 29.8%. Bone metastases disrupt tissue homeostasis and weaken the skeleton, resulting in an increased risk of severe bone pain and fracture. This is due to increased formation of immature unmineralized bone by osteoblasts, and increased osteolysis by osteoclasts, which induce high levels of bone resorption. Thus, a primary therapeutic objective for malignant bone disease is to eliminate tumors while promoting bone homeostasis. Current therapies are very limited and include palliative radiotherapy, and biphosphate or anti-RANK treatments, which target osteoclasts and decrease the rate of bone resorption. However, these treatments only delay, but do not prevent, skeletal related injuries. Our laboratory has recently developed a strategy aimed at disrupting malignant cytokines signals using inhibitory peptides targeting IL-6 receptors. I here present a novel strategy to express these peptides in vivo following gene delivery as targeted and multifunctional “propeptides.” These propeptides target bone metastases via EGFR antagonist (tumor-homing peptide) and contain dual therapeutic domains consistent of IL-6Ra antagonistic peptides and a pro-osteogenesis peptide, osteostatin. The propeptides are activated by metalloproteases (MMP2/9), which are overexpressed in metastatic prostate tumors and associated bone lesions. We can detect expression of the propeptides following C2C12 muscle cell transfection via real time quantitative PCR and are currently optimizing biochemical strategies for detecting propeptide products via western blot. We hypothesize that optimized secretion and targeting of the therapeutic propeptides will be effective in eliminating prostate tumor metastases, and restoring bone homeostasis. Future studies will examine the expression of propeptide in vivo following gene delivery to muscle and efficacy of propeptides in treating bone metastatic prostate tumors in a TRAMP-C2Ras tibial implantation model. Citation Format: Janelle W. Salameh, Charles S. Umbaugh, Marxa L. Figueiredo. Development and validation of propeptide therapeutics for treating bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-260.

Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression.

Lappaconitine is a representative C18-diterpenoid alkaloid extracted from Aconitum sinomontanum Nakai and has been prescribed as a pain relief medicine in China for more than 30years. This study evaluated its antihypersensitivity activity in the rat models of neuropathic and cancer pains and explored its underlying mechanisms. Subcutaneous injection of cumulative doses of lappaconitine produced dose-dependent mechanical antiallodynia and thermal antihyperalgesia in spinal nerve ligation-induced neuropathic rats. The cumulative dose-response analysis exhibited their Emax values of 53.3 and 58.3% MPE, and ED50 values of 1.1 and 1.6mg/kg. Single intrathecal lappaconitine dose in neuropathy also dose- and time-dependently blocked mechanical allodynia, with an Emax of 66.1% MPE and an ED50 of 0.8μg. Its multiple twice-daily intrathecal administration over 7days did not induce mechanical antiallodynic tolerance. Subcutaneous cumulative doses of lappaconitine also produced dose-dependent blockade of mechanical allodynia in the rat bone cancer pain model induced by tibia implantation of cancer cells, with the Emax of 57.9% MPE and ED50 of 2.0mg/kg. Furthermore, lappaconitine treatment stimulated spinal dynorphin A expression in neuropathic rats, and in primary cultures of microglia but not neurons or astrocytes. Intrathecal pretreatment with the specific microglia depletor liposome-encapsulated clodronate, dynorphin A antibody, and κ-opioid receptor antagonist GNTI totally suppressed intrathecal and subcutaneous lappaconitine-induced mechanical antiallodynia. This study suggests that lappaconitine exhibits antinociception through directly stimulating spinal microglial dynorphin A expression. Graphical Abstract ᅟ.

When Would a Metal-Backed Component Become Cost-Effective Over an All-Polyethylene Tibia in Total Knee Arthroplasty?

The importance of cost control in total knee arthroplasty is increasing in the United States secondary to both changing economic realities of healthcare and the increasing prevalence of joint replacement. Surgeons play a critical role in cost containment and may soon be incentivized to make cost-effective decisions under proposed gainsharing programs. The purpose of this study is to examine the cost-effectiveness of all-polyethylene tibial (APT) components and determine what difference in revision rate would make modular metal-backed tibial (MBT) implants a more cost-effective intervention. Markov models were constructed using variable implant failure rates and previously published probabilities. Cost data were obtained from both our institution and published United States implant list prices, and modeled with a 3.0% discount rate. The decision tree was continued over a 20-year timeframe. Using our institutional cost data and model assumptions with a 1.0% annual failure rate for MBT components, an annual failure rate of 1.6% for APT components would be required to achieve equivalency in cost. Over a 20-year period, a failure rate of >27% for the APT component would be necessary to achieve equivalent cost compared with the proposed failure rate of 18% with MBT components. A sensitivity analysis was performed with different assumptions for MBT annual failure rates. Given our assumptions, the APT component is cost-saving if the excess cumulative revision rate increases by <9% in 20 years compared with that of the MBT implant. Surgeons, payers, and hospitals should consider this approach when evaluating implants. Consideration should also be given to the decreased utility associated with revision surgery.