Biocompatibility of platinum-based bulk metallic glass in orthopedic applications.

Bulk metallic glasses (BMGs) are a class of amorphous metals that exhibit high strength, ductility paired with wear and corrosion resistance. These properties suggest that they could serve as an alternative to conventional metallic implants that suffer wear and failure. In the present study, we investigated Platinum (Pt)-BMG biocompatibility in bone applications. Specifically, we investigated osteoclast formation on flat and nanopatterned Pt57.5Cu14.7Ni5.3P22.5(atomic percent) as well as titanium (control). Specifically, receptor activator of NF-κB (RANK) ligand-induced murine bone marrow derived mononuclear cell fusion was measured on multiple nanopatterns and was found to be reduced on nanorods (80 and 200 nm in diameter) and was associated with reduced tartrate-resistant acid phosphatase (TRAP) and matrix metalloproteinase (MMP9) expression. Evaluation of mesenchymal stem cell (MSC) to osteoblast differentiation on nanopatterned Pt-BMG showed significant reduction in comparison to flat, suggesting that further exploration of nanopatterns is required to have simultaneous induction of osteoblasts and inhibition of osteoclasts.Invivo studies were also pursued to evaluate the biocompatibility of Pt-BMG in comparison to titanium. Rods of each material were implanted in the femurs of mice and evaluated by x-ray, mechanical testing, micro-computed tomography (micro-CT), and histological analysis. Overall, Pt-BMG showed similar biocompatibility with titanium suggesting that it has the potential to improve outcomes by further processing at the nanoscale.

Thrombospondin-2 regulates extracellular matrix production, LOX levels, and cross-linking via downregulation of miR-29.

Collagen fibrillogenesis and crosslinking have long been implicated in extracellular matrix (ECM)-dependent processes such as fibrosis and scarring. However, the extent to which matricellular proteins influence ECM protein production and fibrillar collagen crosslinking has yet to be determined. Here we show that thrombospondin 2 (TSP2), an anti-angiogenic matricellular protein, is an important modulator of ECM homeostasis. Specifically, through a fractionated quantitative proteomics approach, we show that loss of TSP2 leads to a unique ECM phenotype characterized by a significant decrease in fibrillar collagen, matricellular, and structural ECM protein production in the skin of TSP2 KO mice. Additionally, TSP2 KO skin displays decreased lysyl oxidase (LOX), which manifests as an increase in fibrillar collagen solubility and decreased levels of LOX-mediated fibrillar collagen crosslinking. We show that these changes are indirectly mediated by miR-29, a major regulator of ECM proteins and LOX, as miR-29 expression is increased in the TSP2 KO. Altogether, these findings indicate that TSP2 contributes to ECM production and assembly by regulating miR-29 and LOX.

Regulation of Mesenchymal Stem Cell Differentiation by Nanopatterning of Bulk Metallic Glass.

Mesenchymal stem cell (MSC) differentiation is regulated by surface modification including texturing, which is applied to materials to enhance tissue integration. Here, we used Pt57.5Cu14.7Ni5.3P22.5 bulk metallic glass (Pt-BMG) with nanopatterned surfaces achieved by thermoplastic forming to influence differentiation of human MSCs. Pt-BMGs are a unique class of amorphous metals with high strength, elasticity, corrosion resistance, and an unusual plastic-like processability. It was found that flat and nanopattened Pt-BMGs induced osteogenic and adipogenic differentiation, respectively. In addition, osteogenic differentiation on flat BMG exceeded that observed on medical grade titanium and was associated with increased formation of focal adhesions and YAP nuclear localization. In contrast, cells on nanopatterned BMGs exhibited rounded morphology, formed less focal adhesions and had mostly cytoplasmic YAP. These changes were preserved on nanopatterns made of nanorods with increased stiffness due to shorter aspect ratios, suggesting that MSC differentiation was primarily influenced by topography. These observations indicate that both elemental composition and nanotopography can modulate biochemical cues and influence MSCs. Moreover, the processability and highly tunable nature of Pt-BMGs enables the creation of a wide range of surface topographies that can be reproducibly and systematically studied, leading to the development of implants capable of engineering MSC functions.

Nanopatterned Bulk Metallic Glass Biosensors.

Nanopatterning as a surface area enhancement method has the potential to increase signal and sensitivity of biosensors. Platinum-based bulk metallic glass (Pt-BMG) is a biocompatible material with electrical properties conducive for biosensor electrode applications, which can be processed in air at comparably low temperatures to produce nonrandom topography at the nanoscale. Work presented here employs nanopatterned Pt-BMG electrodes functionalized with glucose oxidase enzyme to explore the impact of nonrandom and highly reproducible nanoscale surface area enhancement on glucose biosensor performance. Electrochemical measurements including cyclic voltammetry (CV) and amperometric voltammetry (AV) were completed to compare the performance of 200 nm Pt-BMG electrodes vs Flat Pt-BMG control electrodes. Glucose dosing response was studied in a range of 2 mM to 10 mM. Effective current density dynamic range for the 200 nm Pt-BMG was 10-12 times greater than that of the Flat BMG control. Nanopatterned electrode sensitivity was measured to be 3.28 µA/cm2/mM, which was also an order of magnitude greater than the flat electrode. These results suggest that nonrandom nanotopography is a scalable and customizable engineering tool which can be integrated with Pt-BMGs to produce biocompatible biosensors with enhanced signal and sensitivity.

Exploring a wider range of Mg-Ca-Zn metallic glass as biocompatible alloys using combinatorial sputtering.

In order to bypass the limitation of bulk metallic glasses fabrication, we synthesized thin film metallic glasses to study the corrosion characteristics of a wide atomic% composition range, Mg(35.9-63%)Ca(4.1-21%)Zn(17.9-58.3%), in simulated body fluid. We highlight a clear relationship between Zn content and corrosion current such that Zn-medium metallic glasses exhibit minimum corrosion. In addition, we found higher Zn content leads to a poor in vitro cell viability. These results showcase the benefit of evaluating a larger alloy compositional space to probe the limits of corrosion resistance and prescreen for biocompatible applications.

Spatiotemporal gait compensations following medial collateral ligament and medial meniscus injury in the rat: correlating gait patterns to joint damage.

INTRODUCTION: After transection of the medial collateral ligament and medial meniscus (MCLT + MMT) in the rat, focal cartilage lesions develop over 4-6 weeks; however, sham surgery (MCLT alone) does not result in cartilage damage over a similar period. Thus, comparison of MCLT + MMT with the MCLT sham group offers an opportunity to investigate behavioral modifications related to focal cartilage and meniscus damage in the rat. METHODS: MCLT or MCLT + MMT surgery was performed in the right knees of male Lewis rats, with spatiotemporal gait patterns and hind limb sensitivity assessed at 1, 2, 4, and 6 weeks postsurgery (n = 8 rats per group per time point, n = 64 total). After the animals were euthanized, Histology was performed to assess joint damage. RESULTS: MCLT + MMT animals had unilateral gait compensations at early time points, but by week 6 bilateral gait compensations had developed in both the MCLT sham and MCLT + MMT groups. Conversely, heightened tactile sensitivity was detected in both MCLT sham and MCLT + MMT animals at week 1, but only the MCLT + MMT animals maintained heightened sensitivity to week 6. Cartilage lesions were found in the MCLT + MMT group but not in the MCLT sham group. Correlations could be identified between joint damage and gait changes in MCLT + MMT animals; however, the same gait changes were found with MCLT sham animals despite a lack of joint damage. CONCLUSIONS: Combined, our data highlight a common conundrum in osteoarthritis (OA) research: Some behavioral changes correlate to cartilage damage in the OA group, but the same changes can be identified in non-OA controls. Of the behavioral changes detected, allodynia was maintained in MCLT + MMT animals but not in the MCLT sham group. However, the correlation between cartilage damage and hind limb sensitivity is relatively weak (R = -0.4498), and the range of sensitivity measures overlaps between groups. The factors driving gait abnormalities in MCLT and MCLT + MMT animals also remain uncertain. The gait modifications are similar between groups and do not appear until weeks after surgery, despite cartilage damage being focused in the MCLT + MMT group. Combined, our data highlight the need to evaluate the links between noncartilage changes and behavioral changes following joint injury in the rat.