Effects of Incorporating Carboxymethyl Chitosan into PMMA Bone Cement Containing Methotrexate.
ABSTRACT: Treatment of bone metastases usually includes surgical resection with local filling of methotrexate (MTX) in polymethyl methacrylate (PMMA) cement. We investigated whether incorporating carboxymethyl chitosan (CMCS) in MTX-PMMA cement might overcome disadvantages associated with MTX. To determine the optimal CMCS+MTX concentration to suppress the viability of cancer cells, an integrated microfluidic chip culturing highly metastatic lung cancer cells (H460) was employed. The mechanical properties, microstructure, and MTX release of (CMCS+MTX)-PMMA cement were evaluated respectively by universal mechanical testing machine, scanning electron microscopy (SEM), and incubation in simulated body fluid with subsequent HPLC-MS. Implants of MTX-PMMA and (CMCS+MTX)-PMMA cement were evaluated in vivo in guinea pig femurs over time using spiral computed tomography with three-dimensional image reconstruction, and SEM at 6 months. Viability of H460 cells was significantly lowest after treatment with 57 ?g/mL CMCS + 21 ?g/mL MTX, which was thus used in subsequent experiments. Incorporation of 1.6% (w/w) CMCS to MTX-PMMA significantly increased the bending modulus, bending strength, and compressive strength by 5, 2.8, and 5.2%, respectively, confirmed by improved microstructural homogeneity. Incorporation of CMCS delayed the time-to-plateau of MTX release by 2 days, but increased the fraction released at the plateau from 3.24% (MTX-PMMA) to 5.34%. Relative to the controls, the (CMCS+MTX)-PMMA implants integrated better with the host bone. SEM revealed pores in the cement of the (CMCS+MTX)-PMMA implants that were not obvious in the controls. In conclusion, incorporation of CMCS in MTX-PMMA appears a feasible and effective modification for improving the anti-tumor properties of MTX-PMMA cement.
Project description:Poly(methyl methacrylate) (PMMA)-based bone cement, which is widely used to affix orthopedic metallic implants, is considered bio-tolerant but lacks osteoconductivity and is cytotoxic. Implant loosening and toxic complications are significant and recognized problems. Here we devised two strategies to improve PMMA-based bone cement: (1) adding 4-methacryloyloxylethyl trimellitate anhydride (4-META) to MMA monomer to render it hydrophilic; and (2) using tri-n-butyl borane (TBB) as a polymerization initiator instead of benzoyl peroxide (BPO) to reduce free radical production. Rat bone marrow-derived osteoblasts were cultured on PMMA-BPO, common bone cement ingredients, and 4-META/MMA-TBB, newly formulated ingredients. After 24 h of incubation, more cells survived on 4-META/MMA-TBB than on PMMA-BPO. The mineralized area was 20-times greater on 4-META/MMA-TBB than PMMA-BPO at the later culture stage and was accompanied by upregulated osteogenic gene expression. The strength of bone-to-cement integration in rat femurs was 4- and 7-times greater for 4-META/MMA-TBB than PMMA-BPO during early- and late-stage healing, respectively. MicroCT and histomorphometric analyses revealed contact osteogenesis exclusively around 4-META/MMA-TBB, with minimal soft tissue interposition. Hydrophilicity of 4-META/MMA-TBB was sustained for 24 h, particularly under wet conditions, whereas PMMA-BPO was hydrophobic immediately after mixing and was unaffected by time or condition. Electron spin resonance (ESR) spectroscopy revealed that the free radical production for 4-META/MMA-TBB was 1/10 to 1/20 that of PMMA-BPO within 24 h, and the substantial difference persisted for at least 10 days. The compromised ability of PMMA-BPO in recruiting cells was substantially alleviated by adding free radical-scavenging amino-acid N-acetyl cysteine (NAC) into the material, whereas adding NAC did not affect the ability of 4-META/MMA-TBB. These results suggest that 4-META/MMA-TBB shows significantly reduced cytotoxicity compared to PMMA-BPO and induces osteoconductivity due to uniquely created hydrophilic and radical-free interface. Further pre-clinical and clinical validations are warranted.
Project description:Fracture of the tibial tray is a rarely observed complication of total knee arthroplasty (TKA), predominately in implants placed greater than a decade ago. This case highlights a case of baseplate fracture in a contemporary prosthesis. The patient presented 1 year after TKA with medial knee pain consistent with pes bursitis. The implant-cement-bone construct was intact and she was managed with corticosteroids. She had persistent pain, acutely developed new varus deformity, and presented with a tibial tray fracture. Retrieval analysis suggested fatigue fracture as the likely mechanism. At time of revision, necrotic bone was found at the medial plateau, which likely caused cantilever bending relative to the well-supported portion of the tray and resultant failure. The patient continues to do well 5 years after revision TKA.
Project description:Powder-liquid poly (methyl methacrylate) (PMMA) bone cements are widely utilized for augmentation of bone fractures and fixation of orthopedic implants. These cements typically have an abundance of beneficial qualities, however their lack of bioactivity allows for continued development. To enhance osseointegration and bioactivity, calcium phosphate cements prepared with hydroxyapatite, brushite or tricalcium phosphates have been introduced with rather unsuccessful results due to increased cement viscosity, poor handling and reduced mechanical performance. This has limited the use of such cements in applications requiring delivery through small cannulas and in load bearing. The goal of this study is to design an alternative cement system that can better accommodate calcium-phosphate additives while preserving cement rheological properties and performance. In the present work, a number of brushite-filled two-solution bone cements were prepared and characterized by studying their complex viscosity-versus-test frequency, extrusion stress, clumping tendency during injection through a syringe, extent of fill of a machined void in cortical bone analog specimens, and compressive strength. The addition of brushite into the two-solution cement formulations investigated did not affect the pseudoplastic behavior and handling properties of the materials as demonstrated by rheological experiments. Extrusion stress was observed to vary with brushite concentration with values lower or in the range of control PMMA-based cements. The materials were observed to completely fill pre-formed voids in bone analog specimens. Cement compressive strength was observed to decrease with increasing concentration of fillers; however, the materials exhibited high enough strength for consideration in load bearing applications. The results indicated that partially substituting the PMMA phase of the two-solution cement with brushite at a 40% by mass concentration provided the best combination of the properties investigated. This alternative material may find applications in systems requiring highly injectable and viscous cements such as in the treatment of spinal fractures and bone defects.
Project description:Rationale: Poly (methyl methacrylate) (PMMA) bone cement is one of the most commonly used biomaterials for augmenting/stabilizing osteoporosis-induced vertebral compression fractures (OVCFs), such as percutaneous vertebroplasty (PVP) and balloon kyphoplasty (BKP). However, its clinical applications are limited by its poor performance in high compressive modulus and weak bonding to bone. To address these issues, a bioactive composite bone cement was developed for the treatment of osteoporotic vertebral compression fractures, in which mineralized collagen (MC) was incorporated into the PMMA bone cement (MC-PMMA). Methods: The in vitro properties of PMMA and MC-PMMA composite bone cement were determined, including setting time, compressive modulus, adherence, proliferation, and osteogenic differentiation of rat bone mesenchymal stem cells. The in vivo properties of both cements were evaluated in an animal study (36 osteoporotic New Zealand female rabbits divided equally between the two bone cement groups; PVP at L5) and a small-scale and short-term clinical study (12 patients in each of the two bone cement groups; follow-up: 2 years). Results: In terms of value for PMMA bone cement, the handling properties of MC-PMMA bone cement were not significantly different. However, both compressive strength and compressive modulus were found to be significantly lower. In the rabbit model study, at 8 and 12 weeks post-surgery, bone regeneration was more significant in MC-PMMA bone cement (cortical bone thickness, osteoblast area, new bone area, and bone ingrowth %; each significantly higher). In the clinical study, at a follow-up of 2 years, both the Visual Analogue Score and Oswestry Disability Index were significantly reduced when MC-PMMA cement was used. Conclusions: MC-PMMA bone cement demonstrated good adaptive mechanical properties and biocompatibility and may be a promising alternative to commercial PMMA bone cements for the treatment of osteoporotic vertebral fractures in clinical settings. While the present results for MC-PMMA bone cement are encouraging, further study of this cement is needed to explore its viability as an ideal alternative for use in PVP and BKP.
Project description:Poly(methyl methacrylate) (PMMA) is the most frequently used bone void filler in orthopedic surgery. However, the interface between the PMMA-based cement and adjacent bone tissue is typically weak as PMMA bone cement is inherently bioinert and not ideal for bone ingrowth. The present study aims to improve the affinity between the polymer and ceramic interphases. By surface modifying nano-sized hydroxyapatite (nHAP) with ethylene glycol and poly(?-caprolactone) (PCL) sequentially via a two-step ring opening reaction, affinity was improved between the polymer and ceramic interphases of PCL-grafted ethylene glycol-HAP (gHAP) in PMMA. Due to better affinity, the compressive strength of gHAP/PMMA was significantly enhanced compared with nHAP/PMMA. Furthermore, PMMA with 20 wt.% gHAP promoted pre-osteoblast cell proliferation in vitro and showed the best osteogenic activity between the composites tested in vivo. Taken together, gHAP/PMMA not only improves the interfacial adhesion between the nanoparticles and cement, but also increases the biological activity and affinity between the osteoblast cells and PMMA composite cement. These results show that gHAP and its use in polymer/bioceramic composite has great potential to improve the functionality of PMMA cement.
Project description:This research investigated the mechanical properties and bioactivity of polymethylmethacrylate (PMMA) bone cement after addition of the nano-hydroxyapatite(HA) coated bone collagen (mineralized collagen, MC).The MC in different proportions were added to the PMMA bone cement to detect the compressive strength, compression modulus, coagulation properties and biosafety. The MC-PMMA was embedded into rabbits and co-cultured with MG 63 cells to exam bone tissue compatibility and gene expression of osteogenesis.15.0%(wt) impregnated MC-PMMA significantly lowered compressive modulus while little affected compressive strength and solidification. MC-PMMA bone cement was biologically safe and indicated excellent bone tissue compatibility. The bone-cement interface crosslinking was significantly higher in MC-PMMA than control after 6 months implantation in the femur of rabbits. The genes of osteogenesis exhibited significantly higher expression level in MC-PMMA.MC-PMMA presented perfect mechanical properties, good biosafety and excellent biocompatibility with bone tissues, which has profoundly clinical values.
Project description:Polymethyl methacrylate (PMMA) bone cement has been widely used in clinics as bone repair materials for its excellent mechanical properties and good injection properties. However, it also has defects such as poor biological performance, high temperature, and the monomer has certain toxicity. Our study tried to modify the PMMA bone cement by doping with various particle weight fractions (5, 10 and 15%) of SCPP particles and polydopamine-coated SCPP particles (D/SCPP) to overcome its clinical application disadvantages. Our study showed that all results of physical properties of samples are in accordance with ISO 5833. The 15% D/SCPP/PMMA composite bone cement had much better biocompatibility compared with pure PMMA bone cement and SCPP/PMMA composite bone cement due to the best cell growth-promoting mineralization deposition on the surface of 15% D/SCPP/PMMA composite bone cements and Sr2+ released from SCPP particles. Our research also revealed that the reaction temperature was found to be reduced with an increase in doped particles after incorporating the particles into composite bone cements. The novel PMMA bone cements modified by D/SCPP particles are promising materials for bone repair.
Project description:PMMA is the most common bone substitute used for vertebroplasty. An increased fracture rate of the adjacent vertebrae has been observed after vertebroplasty. Decreased failure strength has been noted in a laboratory study of augmented functional spine units (FSUs), where the adjacent, non-augmented vertebral body always failed. This may provide evidence that rigid cement augmentation may facilitate the subsequent collapse of the adjacent vertebrae. The purpose of this study was to evaluate whether the decrease in failure strength of augmented FSUs can be avoided using low-modulus PMMA bone cement. In cadaveric FSUs, overall stiffness, failure strength and stiffness of the two vertebral bodies were determined under compression for both the treated and untreated specimens. Augmentation was performed on the caudal vertebrae with either regular or low-modulus PMMA. Endplate and wedge-shaped fractures occurred in the cranial and caudal vertebrae in the ratios endplate:wedge (cranial:caudal): 3:8 (5:6), 4:7 (7:4) and 10:1 (10:1) for control, low-modulus and regular cement group, respectively. The mean failure strength was 3.3 +/- 1 MPa with low-modulus cement, 2.9 +/- 1.2 MPa with regular cement and 3.6 +/- 1.3 MPa for the control group. Differences between the groups were not significant (p = 0.754 and p = 0.375, respectively, for low-modulus cement vs. control and regular cement vs. control). Overall FSU stiffness was not significantly affected by augmentation. Significant differences were observed for the stiffness differences of the cranial to the caudal vertebral body for the regular PMMA group to the other groups (p < 0.003). The individual vertebral stiffness values clearly showed the stiffening effect of the regular cement and the lesser alteration of the stiffness of the augmented vertebrae using the low-modulus PMMA compared to the control group (p = 0.999). In vitro biomechanical study and biomechanical evaluation of the hypothesis state that the failure strength of augmented functional spine units could be better preserved using low-modulus PMMA in comparison to regular PMMA cement.
Project description:Study Design Biomechanical analysis of lateral mass screw pullout strength. Objective We compare the pullout strength of our bone cement-revised lateral mass screw with the standard lateral mass screw. Methods In cadaveric cervical spines, we simulated lateral mass screw "cutouts" unilaterally from C3 to C7. We salvaged fixation in the cutout side with polymethyl methacrylate (PMMA) or Cortoss cement (Orthovita, Malvern, Pennsylvania, United States), allowed the cement to harden, and then drilled and placed lateral mass screws back into the cement-augmented lateral masses. On the contralateral side, we placed standard lateral mass screws into the native, or normal lateral, masses and then compared pullout strength of the cement-augmented side to the standard lateral mass screw. For pullout testing, each augmentation group was fixed to a servohydraulic load frame and a specially designed pullout fixture was attached to each lateral mass screw head. Results Quick-mix PMMA-salvaged lateral mass screws required greater force to fail when compared with native lateral mass screws. Cortoss cement and PMMA standard-mix cement-augmented screws demonstrated less strength of fixation when compared with control-side lateral mass screws. Attempts at a second round of cement salvage of the same lateral masses led to more variations in load to failure, but quick-mix PMMA again demonstrated greater load to failure when compared with the nonaugmented control lateral mass screws. Conclusion Quick-mix PMMA cement revision equips the spinal surgeon with a much needed salvage option for a failed lateral mass screw in the subaxial cervical spine.
Project description:Antibiotic-loaded bone cement (ALBC) is commonly used in joint replacement therapy for prevention and treatment of bone infection and mechanical properties of the cement is still an important issue. The effects of ciprofloxacin and vancomycin was investigated on mechanical characterization of PMMA bone cement. Different properties of cement containing (0, 2.5, 5 and 10% W/W) antibiotics, including compressive and bending properties, microstructural, porosity and density were evaluated. Both antibiotics significantly reduced the density values and mechanical properties (compressive and flexural strength and modulus) in all groups in comparison to control over first two weeks (p?<?0.05). This reduction was due to increased porosity upon antibiotic addition (3.05 and 3.67% for ciprofloxacin and vancomycin, respectively) in comparison to control (2.08%) (p?<?0.001) and exposure to aqueous medium. Vancomycin as antibiotic with higher molecular weight (MW?=?1485) had significant effect on compressive strength reduction of the cement at high amount compared to ciprofloxacin (MW?=?367) (P?<?0.01), there was no difference between two antibiotics at lower concentrations (P?>?0.05). The effect of antibiotic loading is both molecular weight and drug content dependent. The time is also an important parameter and the second week is the probably optimum time to study mechanical behavior of ALBC.