Effect of Surgical Instrumentation Variables on the Osseointegration of Narrow- and Wide-Diameter Short Implants.

PURPOSE: The aim of the present study was to systematically analyze how a multifactorial surgical instrumentation approach affects osseointegration on both narrow-diameter and wide-diameter short implants. MATERIALS AND METHODS: Twelve skeletally mature female sheep were used in the study along with 144 plateau-root-form healing chamber titanium (Ti-6Al-4V) implants (Bicon LLC, Boston, MA), evenly distributed between narrow (3.5 mm) and wide (6.0 mm) diameters. The presence or the absence of irrigation, different drilling speeds, and 2 time points quantifying bone-implant contact (BIC) and bone area fraction occupancy (BAFO) to evaluate the osteogenic parameters around the implants. RESULTS: There were no signs of inflammation, infection, or failure of the implants observed at either healing period. The narrow 3.5-mm implant, at 6 weeks, yielded significant differences in terms of BIC at a drilling speed of 50 rotations per minute (RPM), with higher values of the samples using irrigation (30.6 ± 6.1%) compared with those without (19.7 ± 6.1%). No statistical differences were detected for 500 and 1,000 RPM with or without irrigation. The wide 6-mm diameter implant showed differences with respect to drilling speed, 500 and 1,000 RPM, with higher values associated with samples subjected to irrigation. BAFO results, for both diameters, only detected statistical differences between the 2 times (3 vs 6 weeks); no statistical differences were detected when evaluating as a function of time, drilling speed, and irrigation. CONCLUSIONS: Surgical instrumentation variables (ie, drilling speed [RPM] and irrigation) yielded to be more of an effect for BIC at longer healing time (6 weeks) for the wider implants. Furthermore, deploying narrow or wide plateau-root-form implants, where conditions allow, has shown to be a safe alternative, considering the high BIC and BAFO values observed, independent of irrigation.

Osteogenic parameters surrounding trabecular tantalum metal implants in osteotomies prepared via osseodensification drilling

BACKGROUND: Surgical fixation of implants into bone for the correction of bone deformities or defects is a traditional approach for skeletal stabilization. Important measures of efficacy of implants include implant stability and osseo integration-the direct interaction between living bone and an implant. Osseointegration depends on successful implant placement and subsequent bone remodeling. This study utilized osseo densification drilling (OD) in a low bone density model using trabecular metal (TM) implants. MATERIAL AND METHODS: Three osteotomy sites, Regular, OD-CW (clockwise), and OD-CCW (counterclockwise), were prepared in each ilium of three female sheep. Drilling was performed at 1100rpm with saline irrigation. Trabecular metal (TM) (Zimmer(R), Parsippany, NJ, USA) implants measuring 3.7mm in diameter X 10mm length were placed into respective osteotomies. A three-week period post-surgery was given to allow for healing to take place after which all three sheep were euthanized and the ilia were collected. Samples were prepared, qualitatively and quantitatively analyzed using histology micrographs and image analysis software (ImageJ, NIH, Bethesda, MD). Bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) were quantified to evaluate the osseointegration parameters. RESULTS: All implants exhibit successful bone formation in the peri-implant environment as well as within the open spaces of the trabecular network. Osseointegration within the TM (quantified by %BIC) as a function of drilling technique was more pronounced in OD samples (p > 0.05). The %BAFO however shows a significant difference (p = 0.036) between the CCW and R samples. Greater bone volume and frequency of bone chips are observed in OD samples. CONCLUSION: The utilization of OD as a design for improved fixation of hardware was supported by increased levels of stability, both primary and secondary. Histological data with OD provided notably different results from those of the regular drilling method

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Repair of Critical-Sized Long Bone Defects Using Dipyridamole-Augmented 3D-Printed Bioactive Ceramic Scaffolds.

There are over two million long bone defects treated in the United States annually, of which ~5% will not heal without significant surgical intervention. While autogenous grafting is the standard of care in simple defects, a customized scaffold for large defects in unlimited quantities is not available. Recently, a three-dimensionally (3D)-printed bioactive ceramic (3DPBC) scaffold has been successfully utilized in the of repair critical-sized (CSD) long bone defects in vivo. In this study, 3DPBC scaffolds were augmented with dipyridamole (DIPY), an adenosine A2A receptor (A2A R) indirect agonist, because of its known effect to enhance bone formation. CSD full thickness segmental defects (~11 mm × full thickness) defects were created in the radial diaphysis in New Zealand white rabbits (n = 24). A customized 3DPBC scaffold composed of ß-tricalcium phosphate was placed into the defect site. Groups included scaffolds that were collagen-coated (COLL), or immersed in 10, 100, or 1,000 µM DIPY solution. Animals were euthanized 8 weeks post-operatively and the radii/ulna-scaffold complex retrieved en bloc, for micro-CT, histological, and mechanical analysis. Bone growth was assessed exclusively within scaffold pores and evaluated by microCT and advanced reconstruction software. Biomechanical properties were evaluated utilizing nanoindentation to assess the newly regenerated bone for elastic modulus (E) and hardness (H). MicroCT reconstructions illustrated bone in-growth throughout the scaffold, with an increase in bone volume dependent on the DIPY dosage. The histological evaluation did not indicate any adverse immune response while revealing progressive remodeling of bone. These customized biologic 3DPBC scaffolds have the potential of repairing and regenerating bone. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2499-2507, 2019.

Absence of Healing Impairment in Osteotomies Prepared via Osseodensification Drilling.

This study sought to qualitatively and quantitatively evaluate the effect of osteotomy preparation by conventional (control group) or OD (OD group) instrumentation on osteotomy healing. An incision of 10 cm was made in the anteroposterior direction over the hip in five sheep, and 15 osteotomies were prepared in the left ilium of the sheep (n = 3/sheep). Three different instrumentation techniques were utilized: (1) conventional/regular drilling (R [recommended by manufacturer]) in a 3-step series of a 2-mm pilot, 3.2-mm, and 3.8-mm twist drills; (2) OD clockwise (OD-CW) drilling with Densah Bur (Versah) 2.0-mm pilot, 2.8-mm, and 3.8-mm multi-fluted tapered burs; and (3) OD counterclockwise (OD-CCW) drilling with Densah Bur 2.0-mm pilot, 2.8-mm, and 3.8-mm multi-fluted tapered burs. Drilling was performed at 1,100 rpm with saline irrigation. Qualitative histomorphometric analysis of the osteotomies after 6 weeks did not show any healing impairment due to the instrumentation. Histologic analysis shows bone remodeling and growth in all samples, irrespective of osteotomy preparation technique, with the presence of bone chips observed along the length of the osteotomy wall in sites subjected to osseodensification drilling.

Atemporal osseointegration: Early biomechanical stability through osseodensification.

Osseointegration, the direct functional and structural connection between device and bone is influenced by multiple factors such as implant macrogeometry and surgical technique. This study investigated the effects of osseodensification drilling techniques on implant stability and osseointegration using trabecular metal (TM) and tapered-screw vent (TSV) implants in a low-density bone. Six skeletally mature sheep were used where six osteotomy sites were prepared in each of the ilia, (n = 2/technique: Regular [R] (subtractive), clockwise [CW], and counterclockwise [CCW]). One TM and one TSV implant was subsequently placed with R osteotomy sites prepared using a conventional (subtractive) drilling protocol as recommended by the implant manufacturer for low density bone. CW and CCW drilling sites were subjected to osseodensification (OD) (additive) drilling. Evaluation of insertion torque as a function of drilling technique showed implants subjected to R drilling yielded a significant lower insertion torque relative to samples implanted in OD (CW/CCW) sites (p < 0.05). Histomorphometric analysis shows that the osseodensification demonstrates significantly greater values for bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). Histological analysis shows the presence of bone remnants, which acted as nucleating surfaces for osteoblastic bone deposition, facilitating the bridging of bone between the surrounding native bone and implant surface, as well as within the open spaces of the trabecular network in the TM implants. Devices that were implanted via OD demonstrated atemporal biomechanical stability and osseointegration. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2516-2523, 2018.

A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus NS2B-NS3 protease.

The flavivirus genome encodes a single polyprotein precursor requiring multiple cleavages by host and viral proteases in order to produce the individual proteins that constitute an infectious virion. Previous studies have revealed that the NS2B cofactor of the viral NS2B-NS3 heterocomplex protease displays a conformational dynamic between active and inactive states. Here, we developed a conformational switch assay based on split luciferase complementation (SLC) to monitor the conformational change of NS2B and to characterize candidate allosteric inhibitors. Binding of an active-site inhibitor to the protease resulted in a conformational change of NS2B and led to significant SLC enhancement. Mutagenesis of key residues at an allosteric site abolished this induced conformational change and SLC enhancement. We also performed a virtual screen of NCI library compounds to identify allosteric inhibitors, followed by in vitro biochemical screening of the resultant candidates. Only three of these compounds, NSC135618, 260594, and 146771, significantly inhibited the protease of Dengue virus 2 (DENV2) in vitro, with IC50 values of 1.8 µM, 11.4 µM, and 4.8 µM, respectively. Among the three compounds, only NSC135618 significantly suppressed the SLC enhancement triggered by binding of active-site inhibitor in a dose-dependent manner, indicating that it inhibits the conformational change of NS2B. Results from virus titer reduction assays revealed that NSC135618 is a broad spectrum flavivirus protease inhibitor, and can significantly reduce titers of DENV2, Zika virus (ZIKV), West Nile virus (WNV), and Yellow fever virus (YFV) on A549 cells in vivo, with EC50 values in low micromolar range. In contrast, the cytotoxicity of NSC135618 is only moderate with CC50 of 48.8 µM on A549 cells. Moreover, NSC135618 inhibited ZIKV in human placental and neural progenitor cells relevant to ZIKV pathogenesis. Results from binding, kinetics, Western blot, mass spectrometry and mutagenesis experiments unambiguously demonstrated an allosteric mechanism for inhibition of the viral protease by NSC135618.

Osseodensification for enhancement of spinal surgical hardware fixation.

Integration between implant and bone is an essential concept for osseous healing requiring hardware placement. A novel approach to hardware implantation, termed osseodensification, is described here as an effective alternative. 12 sheep averaging 65kg had fixation devices installed in their C2, C3, and C4 vertebral bodies; each device measured 4mm diameter×10mm length. The left-sided vertebral body devices were implanted using regular surgical drilling (R) while the right-sided devices were implanted using osseodensification drilling (OD). The C2 and C4 vertebra provided the t=0 in vivo time point, while the C3 vertebra provided the t=3 and t=6 week time points, in vivo. Structural competence of hardware was measured using biomechanical testing of pullout strength, while the quality and degree of new bone formation and remodeling was assessed via histomorphometry. Pullout strength demonstrated osseodensification drilling to provide superior anchoring when compared to the control group collapsed over time with statistical significance (p<0.01). On Wilcoxon rank signed test, C2 and C4 specimens demonstrated significance when comparing device pullout (p=0.031) for both, and C3 pullout tests at 3 and 6 weeks collapsed over time had significance as well (p=0.027). Percent bone-to-implant contact (%BIC) analysis as a function of drilling technique demonstrated an OD group with significantly higher values relative to the R group (p<0.01). Similarly, percent bone-area-fraction-occupancy (BAFO) analysis presented with significantly higher values for the OD group compared to the R group (p=0.024). As a function of time, between 0 and 3 weeks, a decrease in BAFO was observed, a trend that reversed between 3 and 6 weeks, resulting in a BAFO value roughly equivalent to the t=0 percentage, which was attributed to an initial loss of bone fraction due to remodeling, followed by regaining of bone fraction via production of woven bone. Histomorphological data demonstrated autologous bone chips in the OD group with greater frequency relative to the control, which acted as nucleating surfaces promoting new bone formation around the implants, providing superior stability and greater bone density. This alternative approach to a critical component of hardware implantation encourages assessment of current surgical approaches to hardware implantation.

Biomechanical and histologic basis of osseodensification drilling for endosteal implant placement in low density bone. An experimental study in sheep.

A bone drilling concept, namely osseodensification, has been introduced for the placement of endosteal implants to increase primary stability through densification of the osteotomy walls. This study investigated the effect of osseodensification on the initial stability and early osseointegration of conical and parallel walled endosteal implants in low density bone. Five male sheep were used. Three implants were inserted in the ilium, bilaterally, totaling 30 implants (n=15 conical, and n=15 parallel). Each animal received 3 implants of each type, inserted into bone sites prepared as follows: (i) regular-drilling (R: 2mm pilot, 3.2mm, and 3.8mm twist drills), (ii) clockwise osseodensification (CW), and (iii) counterclockwise (CCW) osseodensification drilling with Densah Bur (Versah, Jackson, MI, USA): 2.0mm pilot, 2.8mm, and 3.8mm multi-fluted burs. Insertion torque as a function of implant type and drilling technique, revealed higher values for osseodensification relative to R-drilling, regardless of implant macrogeometry. A significantly higher bone-to-implant contact (BIC) for both osseodensification techniques (p<0.05) was observed compared to R-drilling. There was no statistical difference in BIC as a function of implant type (p=0.58), nor in bone-area-fraction occupancy (BAFO) as a function of drilling technique (p=0.22), but there were higher levels of BAFO for parallel than conic implants (p=0.001). Six weeks after surgery, new bone formation along with remodeling sites was observed for all groups. Bone chips in proximity with the implants were seldom observed in the R-drilling group, but commonly observed in the CW, and more frequently under the CCW osseodensification technique. In low-density bone, endosteal implants present higher insertion torque levels when placed in osseodensification drilling sites, with no osseointegration impairment compared to standard subtractive drilling methods.