Faculty Bibliography

Sodium glucose cotransporter-2 inhibitors (SGLT2is) promote urinary glucose excretion and decrease plasma glucose levels independent of insulin. Canagliflozin (CANA) is an SGLT2i, which is widely prescribed, to reduce cardiovascular complications, and as a second-line therapy after metformin in the treatment of type 2 diabetes mellitus. Despite the robust metabolic benefits, reductions in bone mineral density (BMD) and cortical fractures were reported for CANA-treated subjects. In collaboration with the National Institute on Aging (NIA)-sponsored Interventions Testing Program (ITP), we tested skeletal integrity of UM-HET3 mice fed control (137 mice) or CANA-containing diet (180 ppm, 156 mice) from 7 to 22 months of age. Micro-computed tomography (micro-CT) revealed that CANA treatment caused significant thinning of the femur mid-diaphyseal cortex in both male and female mice, did not affect trabecular bone architecture in the distal femur or the lumbar vertebra-5 in male mice, but was associated with thinning of the trabeculae at the distal femur in CANA-treated female mice. In male mice, CANA treatment is associated with significant reductions in cortical bone volumetric BMD by micro-CT, and by quantitative backscattered scanning electron microscopy. Raman microspectroscopy, taken at the femur mid-diaphyseal posterior cortex, showed significant reductions in the mineral/matrix ratio and an increased carbonate/phosphate ratio in CANA-treated male mice. These data were supported by thermogravimetric assay (TGA) showing significantly decreased mineral and increased carbonate content in CANA-treated male mice. Finally, the sintered remains of TGA were subjected to X-ray diffraction and showed significantly higher fraction of whitlockite, a calcium orthophosphate mineral, which has higher resorbability than hydroxyapatite. Overall, long-term CANA treatment compromised bone morphology and mineral composition of bones, which likely contribute to increased fracture risk seen with this drug.

BACKGROUND/UNASSIGNED:" osseodensification rotary drilling compacts the bone fragments into the osteotomy walls, creating nucleating sites for regeneration. METHODS/UNASSIGNED:This study aimed to compare both manual versus rotary Osseodensification (OD) instrumentation as well as two different pedicle screw thread designs in a controlled split animal model in posterior lumbar stabilization to determine the feasibility and potential advantages of each variable with respect to mechanical stability and histomorphology. A total of 164 single thread (82 per thread configuration), pedicle screws (4.5 × 35 mm) were used for the study. Each animal received eight pedicles (four per thread design) screws, which were placed in the lumbar spine of 21 adult sheep. One side of the lumbar spine underwent rotary osseodensification instrumentation, while the contralateral underwent conventional, hand, instrumentation. The animals were euthanized after 6- and 24-weeks of healing, and the vertebrae were removed for biomechanical and histomorphometric analyses. Pullout strength and histologic analysis were performed on all harvested samples. RESULTS/UNASSIGNED: = 0.026) greater pullout strength (1060.6 N ± 181) relative to hand instrumentation (769.3 N ± 181) at the 24-week healing time point. Histomorphometric analysis exhibited significantly higher degrees of bone to implant contact for the rotary instrumentation only at the early healing time point (6 weeks), whereas bone area fraction occupancy was statistically higher for rotary instrumentation at both healing times. The levels of soft tissue infiltration were lower for pedicle screws placed in osteotomies prepared using OD instrumentation relative to hand instrumentation, independent of healing time. CONCLUSION/UNASSIGNED:The rotary instrumentation yielded enhanced mechanical and histologic results relative to the conventional hand instrumentation in this lumbar spine stabilization model.

The field of additive manufacturing, 3D printing (3DP), has experienced an exponential growth over the past four decades, in part due to increased accessibility. Developments including computer-aided design and manufacturing, incorporation of more versatile materials, and improved printing techniques/equipment have stimulated growth of 3DP technologies within various industries, but most specifically the medical field. Alternatives to metals including ceramics and polymers have been garnering popularity due to their resorbable properties and physiologic similarity to extracellular matrix. 3DP has the capacity to utilize an assortment of materials and printing techniques for a multitude of indications, each with their own associated benefits. Within the field of medicine, advances in medical imaging have facilitated the integration of 3DP. In particular, the field of orthopedics has been one of the earliest medical specialties to implement 3DP. Current indications include education for patients, providers, and trainees, in addition to surgical planning. Moreover, further possibilities within orthopedic surgery continue to be explored, including the development of patient-specific implants. This review aims to highlight the use of current 3DP technology and materials by the orthopedic community, and includes comments on current trends and future direction(s) within the field.

Silicon carbide (SiC) is one of the hardest known materials. Its exceptional mechanical properties combined with its high thermal conductivity make it a very attractive material for a variety of technological applications. Recently, it is discovered that two-layer epitaxial graphene films on SiC can undergo a pressure activated phase transition into a sp³ diamene structure at room temperature. Here, it is shown that epitaxial graphene films grown on SiC can increase the hardness of SiC up to 100% at low loads (up to 900 µN), and up to 30% at high loads (10 mN). By using a Berkovich diamond indenter and nanoindentation experiments, it is demonstrated that the 30% increase in hardness is present even for indentations depths of 175 nm, almost three hundred times larger than the graphene film thickness. The experiments also show that the yield point of SiC increases up to 77% when the SiC surface is coated with epitaxial graphene. These improved mechanical properties are explained with the formation of diamene under the indenter's pressure.

BACKGROUND:Successful osseointegration of endosteal dental implants has been attributed to implant design, including the macro-, micro- and nano- geometric properties. Based on current literature pertaining to implant design, the resultant cellular and bone healing response is unknown when the thread thickness of the implants is increased, resulting in an increased contact area in implants designed with healing chambers. The aim of this study was to evaluate the effect of two implant designs with different thread profiles on the osseointegration parameters and implant stability at 3- and 6-weeks in vivo using a well-established preclinical dog model. MATERIAL AND METHODS/METHODS:A total of 48 type V Ti alloy implants were divided in two groups according to their thread design (D1= +0.1x/mm and D2= +0.15x/mm) and placed in an interpolated fashion into the radii of six beagles. Insertion torque was measured at time of placement, radii were extracted for histological processing following 3- and 6-week healing intervals. Histologic and histomorphometric analyses were performed in terms of bone to implant contact (%BIC) and bone area fraction occupancy within implant threads (%BAFO). Statistical analyses were performed through a linear mixed model with fixed factors of time and implant thread design. RESULTS:Surface roughness analysis demonstrated no significant differences in Sa and Sq between D1 and D2 implant designs, which confirmed that both implant designs were homogenous except for their respective thread profiles. For insertion torque, statistically significant lower values were recorded for D1 in comparison to D2 (59.6 ± 11.1 and 78.9 ± 10.1 N⋅cm, respectively). Furthermore, there were no significant differences with respect to histological analysis and histomorphometric parameters, between D1 and D2 at both time points. CONCLUSIONS:Both thread profiles presented equivalent potential to successfully osseointegrate in the osteotomies, with D2 yielding higher mechanical retention upon placement without detrimental bone resorption.

The calvaria (top part of the skull) is made of pieces of bone as well as multiple soft tissue joints called sutures. The latter is crucial to the growth and morphogenesis of the skull, and thus a loss of calvarial sutures can lead to severe congenital defects in humans. During embryogenesis, the calvaria develops from the cranial mesenchyme covering the brain, which contains cells originating from the neural crest and the mesoderm. While the mechanism that patterns the cranial mesenchyme into bone and sutures is not well understood, function of Lmx1b, a gene encoding a LIM-domain homeodomain transcription factor, plays a key role in this process. In the current study, we investigated a difference in the function of Lmx1b in different parts of the calvaria using neural crest-specific and mesoderm-specific Lmx1b mutants. We found that Lmx1b was obligatory for development of the interfrontal suture and the anterior fontanel along the dorsal midline of the skull, but not for the posterior fontanel over the midbrain. Also, Lmx1b mutation in the neural crest-derived mesenchyme, but not the mesoderm-derived mesenchyme, had a non-cell autonomous effect on coronal suture development. Furthermore, overexpression of Lmx1b in the neural crest lineage had different effects on the position of the coronal suture on the apical part and the basal part. Other unexpected phenotypes of Lmx1b mutants led to an additional finding that the coronal suture and the sagittal suture are of dual embryonic origin. Together, our data reveal a remarkable level of regional specificity in regulation of calvarial development.

BACKGROUND:While autografts to date remain the "gold standard" for bone void fillers, synthetic bone grafts have garnered attention due to their advantages such as ability to be tailored in terms of its physical and chemical properties. Bioactive glass (BG), an inorganic material, has the capacity to form a strong bond with bone by forming a bone-like apatite surface, enhancing osteogenesis. Coupled with three-dimensional printing it is possible to maximize bone regenerative properties of the BG. OBJECTIVE:The objective of this study was to synthesize and characterize 3D printed mesoporous bioactive glass (MBG), BG 45S5, and compare to β-Tricalcium phosphate (β-TCP) based scaffolds; test cell viability and osteogenic differentiation on human osteoprogenitor cells in vitro. METHODS:MBG, BG 45S5, and β-TCP were fabricated into colloidal gel suspensions, tested with a rheometer, and manufactured into scaffolds using a 3D direct-write micro-printer. The materials were characterized in terms of microstructure and composition with Thermogravimetric Analyzer/Differential Scanning Calorimeter (TGA/DSC), Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Micro-Computed Tomography (μ-CT), Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDS), and Mattauch-Herzog-Inductively Coupled Plasma-Mass Spectrometry (MH-ICP-MS). RESULTS:Scaffolds were tested for cell proliferation and osteogenic differentiation using human osteoprogenitor cells. Osteogenic media was used for differentiation, and immunocytochemistry for osteogenic markers Runx-2, Collagen-I, and Osteocalcin. The cell viability results after 7 days of culture yielded significantly higher (p < 0.05) results in β-TCP scaffolds compared to BG 45S5 and MBG groups. CONCLUSION/CONCLUSIONS:All materials expressed osteogenic markers after 21 days of culture in expansion and osteogenic media.

BACKGROUND:The bulk metallic glass (BMG), Pd79Ag3.5P6Si9.5Ge2, has a high fracture toughness and has been found to accommodate post-yield stress, unlike most other BMG. Moreover, due to its greater noble gas composition it has a intrinsic corrosion resistance, ideal for dental and orthopedic implants. OBJECTIVE:This present study aimed to evaluate the in vivo application of Pd79Ag3.5P6Si9.5Ge2 in a large translational sheep model to assess its efficacy to be utilized as an endosteal device. METHODS:Twelve implants in the form of cylindrical rods (3 mm in diameter) were produced through rapid quenching. Each sheep (n = 12) received one osteotomy in the mandibular region using rotary instrumentation, which was subsequently filled with Pd79Ag3.5P6Si9.5Ge2. After 6- and 24-weeks the animals were euthanized, and samples collected en bloc to conduct histomorphometric analysis. The level/degrees of osseointegration were assessed through bone-to-implant contact (BIC). RESULTS:Favorable BIC was observed with fibrous connective tissue layers at both 6- and 24-weeks. Bone along with interfacial remodeling was observed in proximity with the metallic glass surface at 6 weeks with higher degrees of bone organization being observed at the later healing time, 24 weeks. CONCLUSIONS:The introduced BMG revealed potential to serve as an alternative biomaterial to commonly used Ti alloys given its unique combination of toughness and strength.