Biomechanical evaluation of CIBOR spine interbody fusion device.

BACKGROUND: The CIBOR PEEK spinal interbody fusion device is an anterior lumbar interbody fusion construct with a hollow center designed to accommodate an osteoinductive carbon foam insert to promote bony ingrowth to induce fusion where rigid stabilization is needed. METHODS: Three different sizes of the device were investigated. Part-I: implants were tested under axial compression and rotation using polyurethane foam blocks. Part-II: simulated 2-legged stance using cadaveric specimen using the L5-S1 lumbar spine segment. Part-III: a survey feedback form was used to investigate two orthopedic surgeons concern regarding the implant. RESULTS: In Part-I, the subsidence hysteresis under axial compression loading was found to be statistical significant difference between these three implant sizes. It was noted that the implants had migration as rotation applied, and the amount of subsidence was a factor of the axial compression loads applied. In Part-II, a minor subsidence and carbon foam debris were observed when compared to each implant size. Poor contact surface of the implant with the end plates of the L5 or S1 vertebrae from the anterior view under maximum loads was observed; however, the implant seemed to be stable. Each surgeon has their own subjective opinion about the CIBOR implant. DISCUSSION: Two out of the three different sizes of the device (medium and large sizes) provided appropriate rigid stabilization at the physiological loads. Neither orthopedic surgeon was 100% satisfied with overall performance of the implant, but felt potential improvement could be made. CLINICAL RELEVANCE: This study indicates an option for operative treatment of spine interbody fusion, as the CIBOR spine interbody fusion device has a hollow center. This hollow center is designed to accommodate a carbon foam insert to promote bony ingrowth. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1157-1168, 2017.

Quiescent pluripotent stem cells reside within murine peripheral nerves that can be stimulated to proliferate by recombinant human bone morphogenic protein 2 or by nerve trauma.

BACKGROUND: The clinical use of recombinant human bone morphogenic protein 2 (rhBMP-2, Infuse) has been associated with nerve-related complications including new-onset sciatica, and retrograde ejaculation. PURPOSE: To better understand the interaction of rhBMP-2 and peripheral nerves with the intent of making procedures safer. STUDY DESIGN/SETTING: Using a mouse model to examine the direct effect of diluted rhBMP-2 (Infuse) on murine sciatic nerves. METHODS: Animal studies were approved by the Institutional Animal Care and Use Committee. Balb/c mouse sciatic nerves were surgically exposed and 60 ng (in 10 µL) of rhBMP-2 was applied to the nerve. In separate experiments, the sciatic nerves were subjected to mechanical compression using forceps (and not exposed to rhBMP-2). The third group of mice received direct injection of the same amount of rhBMP-2, or sterile saline as a control, into the hamstring area of the posterior thigh without surgery. Mouse limbs with intact sciatic nerve were collected at 24, 48, or 72 hours after treatment for histology processing. A separate set of identically treated sciatic nerves were retrieved from mice at the same time points and cells were isolated by collagenase and trypsin digestion. The isolated cells were cultured in a stem cell medium containing 20% knockout serum and human leukemia inhibitory factor. Immunohistochemical or immunofluorescent cell stains against KLF4, Sox2, c-Myc, and Oct4 were performed on the mouse tissue sections and cell culture slides. In addition, real-time polymerase chain reaction (PCR) was performed to quantify the mRNA expression profiles of the stem cell marker genes in cultured cells. RESULTS: Profound morphological changes of the mouse sciatic nerves were noted after exposure to rhBMP-2, with a rapid and robust cell proliferation within the nerves followed by migration of these cells into surrounding tissue. Immunohistochemical stain revealed strong nuclear stains of KLF4, Sox2, Oct4, and c-Myc on the overwhelming majority of these proliferating cells in the nerve. Intramuscular injections of rhBMP-2 or willful physical compression of the nerves showed similar cell proliferation effects as the direct application of Infuse to the sciatic nerve. The cells in stem cell culture medium grew steadily without feeder cells and appeared fairly uniform. They were adherent to substrate and were motile. Double fluorescent staining on the cells indicated colocalizationof all pairs of the four stem cell markers in the cell nuclei. Real-time PCR confirmed the strong mRNA expressions of KLF4, Sox2, Oct4, and c-Myc in these isolated cells. CONCLUSION: Exposure to BMP-2 causes a marked proliferation of previously quiescent cells within peripheral nerves. These cells simultaneously express KLF4, Sox2, Oct4, and c-Myc, the transcription factors that confer embryonic pluripotency. Work described in the companion paper reveals some of the differentiation capacity of the cells and their likely clinical significance. In addition, the effects of direct exposure of nerves to rhBMP-2 as described here should clearly illuminate the mechanism of BMP-2-related nerve complications. We would suggest that the use of this agent in proximity to known neural structures should only be done with extreme caution.

Specific material effects of wear-particle-induced inflammation and osteolysis at the bone-implant interface: A rat model.

INTRODUCTION: Wear particles produced from prosthetic joints may play critical roles in periprosthetic inflammatory reactions and osteolysis. The objective of this study was to quantify and compare the response to wear debris from different biomaterials at the bone-implant interface in a rat knee model. METHODS: Sixty rats were divided into titanium alloy (Ti-6Al-4V), cobalt chromium (Co-Cr), ceramic (Al2O3), ultrahigh molecular weight polyethylene (UHMWPE), and control (phosphate buffered saline) groups with 12 animals per group. A nonweight-bearing titanium rod was implanted into the right distal femur of each rat followed by intra-articular injections of the biomaterial particles to the surgical knees for up to 16 weeks. Micro-computed tomography scanning was performed monthly and at the time of sacrifice to determine bone densities around the bone-implant interface. Histological evaluations were executed to quantify local inflammatory reactions and osteoclastogenesis. RESULTS: Co-Cr particles resulted in the most severe reductions in bone density. UHMWPE and ceramic particles resulted in a rapid reduction in bone density followed by a recovery. Inflammatory pseudo-membranes were ubiquitously present close to the femoral condyle and pin insertion site. Ceramic particles significantly promoted periprosthetic tissue formation compared with the other groups (p < 0.05). Cathepsin K positive cells were dominantly present at the peri-implant site following challenges of metallic alloy and ceramic particles. CONCLUSION: Different biomaterials in particulate form exert different forms of adverse effects in terms of the amount of osteolysis and inflammatory reactions on bone tissue at the bone-implant interface. It provides information for engineering more appropriate materials for arthroplasty components.

Intrusion Characteristics of Three Bone Cements for Tibial Component of Total Knee Arthroplasty in a Cadaveric Bone Model.

The purpose of this study was to evaluate and compare the intrusion characteristics of Simplex-HV to Simplex-P and Palacos-R in cadaveric proximal tibial bone. Eighteen fresh-frozen cadaver proximal tibiae were examined with standard arthroplasty tibial cuts. Each tibia was randomly assigned to receive one of the three bone cements for use with finger packing technique. Sagittal sections were prepared and analyzed using digital photography and stereoscopic micrographs to evaluate cement intrusion characteristics. The cement penetration depth was measured from the tibial bone cut surface, which did not include the cement thickness under the tibial base plate. Significant differences were detected in the bone cement penetration between the three cements. Penetration was increased using the Simplex-HV (average, 2.7 mm; range, 2.0-3.0 mm) compared with Simplex-P (average, 2.2 mm) and Palacos-R (average, 1.8 mm). These depths approximate to 3.7, 3.2, and 2.8 mm of total cement penetration, respectively. The data suggest that high-viscosity bone cement may provide good fixation of the tibial component of a total knee arthroplasty when using the finger packing technique.

Validation of Improvement of Basic Competency in Arthroscopic Knot Tying Using a Bench Top Simulator in Orthopaedic Residency Education.

PURPOSE: To validate basic competency in arthroscopic knot tying using a unique simulator device to compare the level of training needed for learning and tying the arthroscopic knot by evaluating the tensile properties of the arthroscopic knots. METHODS: Three groups of surgeons of various experience levels (postgraduate year [PGY] 1, PGY 3, and experienced surgeons) tied 2 different arthroscopic knots (Tennessee Slider, considered easier, and Weston, considered more difficult) over a 10-week period. Each group went through 3 separate stages of knot tying: stage 1, tying 8 knots without cannula or knot pusher; stage 2, tying 12 knots with knot pusher; and stage 3, tying 20 knots with knot pusher through a cannula that simulates knot tying during surgery. A single load-to-failure test was performed and ultimate clinical failure loads were recorded. Time needed to tie each knot was also recorded. RESULTS: At stages 1 and 2, the PGY 1 group had a significantly weak knot tensile strength (Tennessee Slider stage 1: 60 v 129 N, P = .001; Tennessee Slider stage 2: 69 v 132 N, P = .0029; Weston stage 1: 73 v 184 N, P = .0000; Weston stage 2: 125 v 173 N, P = .0045) and were slower (Weston: 56 v 30 seconds, P = .0010) than the experienced surgeon group for both knots. At stage 3, only the initial 2 weeks of Tennessee Slider showed a significant difference between groups 1 and 3 (week 6: 87 v 118 N, P = .0492; week 7: 89 v 126, P = .01485). Even though the Tennessee Slider knot is one of the easier arthroscopic knots to learn to tie, the results showed a slow trend of improvement in this knot-tying skill for group 1 after each stage. CONCLUSIONS: The data validated an important learning effect in all trainees in arthroscopic knot tying over a 10-week period and showed that inexperienced trainees will be able to improve their knot-tying skill with training in 3 stages with a simulator environment. CLINICAL RELEVANCE: The findings of this study indicated the importance of hands-on experience in performing arthroscopic knot tying, as determined by both knot performance and ultimate suture loop strength. In addition, each orthopaedic resident learned and developed his or her arthroscopic knot-tying skills and provided a foundation for his or her future practice in orthopaedic medicine.

Macrophage Polarization in IL-10 Treatment of Particle-Induced Inflammation and Osteolysis.

This study investigated the therapeutic influence and potential mechanism of IL-10 in ameliorating orthopedic debris particle-induced inflammation and osteolysis. A murine air pouch with bone implantation and polyethylene particles was also used to evaluate the therapeutic effects of IL-10. The data suggested that the particle challenges significantly promoted macrophage activation and osteoclastogenesis, with dramatically increased macrophage infiltration into the pouch membranes and elevated tartrate-resistant acid phosphatase-positive cell deposition. Immunohistochemical stains revealed a significantly higher ratio of induced nitric oxide synthase-expressing cells in the particle-challenged group; treatment with IL-10 resulted in marked switching to CD163(+) cells. Also, IL-10 effectively reduced tartrate-resistant acid phosphatase-positive stained cells in the pouch membranes, and minimized the bone mineral density loss compared with untreated samples. Real-time PCR and Western blot examination indicated that IL-10 treatment significantly diminished the particle-induced IL-1ß expression but promoted expression of CD163, transforming growth factor-ß1, and CCR2. Furthermore, IL-10 significantly inhibited the ultra-high-molecular-weight polyethylene particle-elevated phospho-STAT1 and phospho-NF-κB p65 productions, and promoted phospho-STAT3 expression. Overall, the data indicate the pivotal effects of IL-10 on macrophage polarization. The effects of IL-10 in ameliorating local inflammation and osteolysis may be associated with macrophage polarization through the up-regulation of the Janus activating kinase/STAT3 signaling pathway, and the down-regulation of NF-κB and Janus activating kinase/STAT1 expression.

Long-term elastic durability of polymer matrix composite materials after repeated steam sterilization.

We compared the durability of 3 different selected composite materials that underwent repeated steam sterilization with the durability of traditional metal materials. Composite materials Tepex, CFR-PPS (carbon-fiber-reinforced polyphenylene sulfide), and HTN-53 (Zytel HTN53G50HSLR NC010) were evaluated for durability and water retention after repeated steam sterilization. These composites were compared with stainless steel and aluminum. The structural properties of these materials were measured (short-beam load-to-failure and cyclic compression loading tests) before, during, and after repeated steam sterilization. The relative radiographic density of these materials was also compared. There was no significant difference in the moisture retention of these composite materials before and after repeated sterilization. The composite materials were significantly more radiolucent than the metals. For all the composite materials, load to failure deteriorated after repeated sterilization. The cyclic compression loading tests showed HTN-53 had the poorest performance, with complete failure after 400 cycles of repeated sterilization. CFR-PPS performed slightly better, with 33% failure at final testing. Tepex had no failures at final testing. Although HTN-53 has shown promise in other orthopedic applications, its performance after repeated sterilization was relatively poor. Tepex showed the most potential for durability after repeated sterilization. Further study is needed to identify specific applications for these materials in the orthopedic industry.

Evaluation of Different Experience Levels of Orthopaedic Residents Effect on Polymethylmethacrylate (PMMA) Bone Cement Mechanical Properties.

BACKGROUND: PMMA bone cement is a brittle material and the creation of defects that increase porosity during mixing or injecting is a significant factor in reducing its mechanical properties. The goal during residency training is to learn how to avoid creating increased porosity during mixing and injecting the material. The aim of this study was to evaluate and compare tensile and compression strength for PMMA cement mixed by intern orthopaedic residents (PGY-1) and senior orthopaedic residents (PGY-5). The hypothesis was that the mechanical properties of PMMA cement mixed by PGY-5 would be significantly better than PMMA cement mixed by PGY-1 residents. METHODS: Four PGY-1 and four PGY-5 orthopaedic residents each prepared eight tensile specimens. The bone cement used was Simplex™ P bone cement (Stryker Howmedica Osteonics, Mahwah, NJ) under vacuum mixing in a cement-delivery system. Tensile testing of the specimens was performed in an MTS Bionix servohydraulic materials testing system with loading rate of 2.54 mm/min at room temperature. The mean and standard deviation of the ultimate tensile strength (UTS) for each orthopaedic resident group was calculated. The compression specimens were cylinders formed with a central core to mimic a prosthetic implant. Ten samples from each orthopaedic resident were tested using the same MTS system under identical conditions at room temperature. The specimens were loaded from -50 N to complete structural failure at the rate of 20 mm/min. The ultimate compressive strength (UCS) was then determined and the mean and standard deviation calculated for each group. RESULTS: The average UTS of the bone cement for the PGY-1 and PGY-5 residents was 37.5 ± 4.5 MPa and 39.2 ± 5.0 MPa, respectively, and there was no statistically significant difference between the two groups. For the tensile elastic modulus of the bone cement, the results for the PGY-1 and PGY-5 residents were 2.40 ± 0.09 GPa and 2.44 ± 0.08 GPa, respectively, and again there was no statistically significant difference. For the compression elastic modulus of the bone cement, the results for the PGY-1 and PGY-5 residents were 1.19 ± 0.13 GPa and 1.21 ± 0.18 GPa, respectively, with no statistically significant difference. However, the UCS of the bone cement for the PGY-1 and PGY-5 residents was 87.4 ± 5.8 MPa and 91.1 ± 4.5 MPa, respectively, and there was a statistically significant difference between the groups. DISCUSSION: The PMMA specimens prepared by both the PGY-1 and PGY-5 resident groups had similar characteristics during tensile and compression testing, and were similar to known standards. Although mixing and applying bone cement is an important skill for joint replacement surgery, our results indicate that no special training appears to be necessary for orthopaedic residents. Rather, a basic training video demonstrating manufacturer standard procedure is all that is necessary. CLINICAL RELEVANCE: The results of this study indicate the importance of experience in bone cement mixing and injecting on cement mechanical properties, but indicate that no special training appears to be necessary for orthopaedic residents.

In vitro and in situ characterization of arthroscopic loop security and knot security of braided polyblend sutures: a biomechanical study.

We conducted a study to evaluate biomechanical performance during destructive testing of several different suture materials in various arthroscopic knot configurations under both in vitro and in situ conditions. Surgeons of different levels of experience tied the knots. Three different arthroscopic knots (static surgeon's, Weston, Tennessee slider) with 3 reverse half-hitches on alternating posts were tested using Fiberwire, ForceFiber, Orthocord, and Ultrabraid suture materials under both in vitro and in situ (blood plasma at 37°C) conditions. Three surgeons of different experience levels tied the knots on a post 30 mm in circumference. A single load-to-failure test was performed. There were no significant in vitro-in situ differences for Ultrabraid in the different knot configurations or with the different experience levels. Surgeon B (intermediate experience) showed no significant differences between test conditions for any knot configuration or suture material. With Tennessee slider knots, surgeon C (least experience) showed significantly lower clinical failure load under both test conditions and had a higher percentage of complete knot slippage. Surgeon B had no knot slippage with use of Fiberwire. Both the aqueous environment and the surgeon's familiarity with certain knots have an effect on knot security.

Different influence of Ti, PMMA, UHMWPE, and Co-Cr particles on peripheral blood monocytes during periprosthetic inflammation.

This study investigated cellular trafficking and inflammatory markers in orthopedic biomaterial particle-challenged human peripheral blood monocytes (PBMCs) using a murine immunodeficiency (SCID) model. Periprosthetic tissues from aseptic loosening patients were transplanted into muscles of SCID mice. PBMCs from the same patients were stimulated in vitro with Ti-6Al-4V, PMMA, UHMWPE, or Co-Cr particles for 3 days before administered intraperitoneally to the periprosthetic tissue-implanted mice. The xenografts were harvested 2 weeks later for histological and molecular analyses. Significant cell infiltration was obvious in the transplanted tissues from mice transfused with Ti-alloy, PMMA and UHMWPE-provoked PBMCs compared to controls, and UHMWPE-provoked PBMCs group accumulated significantly more cells among all groups. There were ubiquitous TRAP+ stained cells in all xenografts from particle-stimulated PBMCs mice. Immunohistochemical staining indicated that significantly more IL-1ß and TNF positive cells occurred in Ti and PMMA groups; while the UHMWPE group resulted in stronger positive MCP-1 and IL-6 stains. Polymerase chain reaction (PCR) confirmed overexpression of both IL-1ß and TNF in Ti and PMMA-stimulated groups; and more MIP-1α gene expression developed in the UHMWPE group. Overall, different type of orthopedic materials influenced the trafficking ability of particle-activated PBMCs which may depend on upregulation of various proinflammatory cytokines and chemokines.

Harvesting bone graft from the olecranon: a quantitative and biomechanical comparison of proximal and dorsal cortical windows.

We conducted a study to compare 2 techniques of harvesting ulna bone graft from the olecranon, one using a proximal cortical window (PCW), the other using a dorsal cortical window (DCW), in terms of cancellous bone graft quantity and ulna fracture strength after graft harvest. Cancellous bone was harvested from 8 pairs of embalmed cadaver proximal ulna. Each side of a matched pair was randomly assigned to graft harvest using either a PCW or a DCW approach. Packed bone volume (PBV) was determined by placing the harvested bone into a 3-mL syringe and compacting it with a quasi-static 25-N load. Biomechanical cantilever bending was performed on each elbow to determine load at failure (LF). Paired Student t tests were used to compare PBV and LF between the experimental and control groups. The graft PBV obtained from the matched-pair specimens was not statistically different between the PCW and DCW approaches. Ulnas subjected to proximal bone harvest exhibited higher LF than ulnas subjected to dorsal bone harvest, though the difference was not statistically significant. Compared with bone graft harvest using the traditional DCW approach, harvest using a PCW approach provides similar cancellous graft amounts and exhibits similar fracture resistance.

How has the introduction of new bearing surfaces altered the biological reactions to byproducts of wear and modularity?

BACKGROUND: Biological responses to wear debris were largely elucidated in studies focused on conventional ultrahigh-molecular-weight polyethylene (UHMWPE) and some investigations of polymethymethacrylate cement and orthopaedic metals. However, newer bearing couples, in particular metal-on-metal but also ceramic-on-ceramic bearings, may induce different biological reactions. QUESTIONS/PURPOSES: Does wear debris from the newer bearing surfaces result in different biological responses compared with the known responses observed with conventional metal-on-UHMWPE bearings? METHODS: A Medline search of articles published after 1996 supplemented by a hand search of reference lists of included studies and relevant conference proceedings was conducted to identify the biological responses to orthopaedic wear debris with a focus on biological responses to wear generated from metal-on-highly crosslinked polyethylene, metal-on-metal, ceramic-on-ceramic, and ceramic-on-polyethylene bearings. Articles were selected using criteria designed to identify reports of wear debris particles and biological responses contributing to prosthesis failure. Case reports and articles focused on either clinical outcomes or tribology were excluded. A total of 83 papers met the criteria and were reviewed in detail. RESULTS: Biological response to conventional UHMWPE is regulated by the innate immune response. It is clear that the physical properties of debris (size, shape, surface topography) influence biological responses in addition to the chemical composition of the biomaterials. Highly crosslinked UHMWPE particles have the potential to alter, rather than eliminate, the biological response to conventional UHMWPE. Metal wear debris can generate elevated plasma levels of cobalt and chromium ions. These entities can provoke responses that extend to the elicitation of an acquired immune response. Wear generated from ceramic devices is significantly reduced in volume and may provide the impression of an "inert" response, but clinically relevant biological reactions do occur, including granulomatous responses in periprosthetic tissues. CONCLUSIONS: The material composition of the device, the physical form of the debris, and disease pathophysiology contribute to complex interactions that determine the outcome to all wear debris. Metal debris does appear to increase the complexity of the biological response with the addition of immunological responses (and possibly direct cellular cytotoxicity) to the inflammatory reaction provoked by wear debris in some patients. However, the introduction of highly crosslinked polyethylene and ceramic bearing surfaces shows promising signs of reducing key biological mechanisms in osteolysis.

Novel flexible suture fixation for the distal tibiofibular syndesmotic joint injury: a cadaveric biomechanical model.

Syndesmotic injuries of the ankle commonly occur by an external rotation force applied to the ankle joint. Ten fresh-frozen lower extremities from cadavers were used. A specially designed apparatus was used to stabilize the specimen and rotate the ankle joint from internally rotated 25° to externally rotated 35° at a rate of 6°/s for 10 cycles. Two stages were tested (stage I, specimens intact; and stage II, simulated pronation external rotation type injury with fixation). Group 1 was fixed with a novel suture construct across the syndesmotic joint, and group 2 was fixed with a single metallic screw. The torque, rotational angle, and 3-dimensional syndesmotic diastasis readings were recorded. Three-dimensional tibiofibular diastasis was identified. The fibula of the intact specimens displaced an average of 8.6 ± 1.7, 2.4 ± 1.0, and 1.4 ± 1.0 mm in the anterior, lateral, and superior direction, respectively, when the foot was externally rotated 35°. The sectioning of the syndesmostic ligaments and deltoid ligament resulted in a significant decrease in syndesmotic diastasis and foot torsional force (p < .05). The ligament-sectioned specimen lost 57% (externally rotated) and 17% (internally rotated) torsional strength compared with the intact specimen. Groups 1 and 2 provided similar biomechanical stability in this cadaveric model of a syndesmosis deficiency.

Therapeutic potentials of naringin on polymethylmethacrylate induced osteoclastogenesis and osteolysis, in vitro and in vivo assessments.

Wear debris associated periprosthetic osteolysis represents a major pathological process associated with the aseptic loosening of joint prostheses. Naringin is a major flavonoid identified in grapefruit. Studies have shown that naringin possesses many pharmacological properties including effects on bone metabolism. The current study evaluated the influence of naringin on wear debris induced osteoclastic bone resorption both in vitro and in vivo. The osteoclast precursor cell line RAW 264.7 was cultured and stimulated with polymethylmethacrylate (PMMA) particles followed by treatment with naringin at several doses. Tartrate resistant acid phosphatase (TRAP), calcium release, and gene expression profiles of TRAP, cathepsin K, and receptor activator of nuclear factor-kappa B were sequentially evaluated. PMMA challenged murine air pouch and the load bearing tibia titanium pin-implantation mouse models were used to evaluate the effects of naringin in controlling PMMA induced bone resorption. Histological analyses and biomechanical pullout tests were performed following the animal experimentation. The in vitro data clearly demonstrated the inhibitory effects of naringin in PMMA induced osteoclastogenesis. The naringin dose of 10 µg/mL exhibited the most significant influence on the suppression of TRAP activities. Naringin treatment also markedly decreased calcium release in the stimulated cell culture medium. The short-term air pouch mouse study revealed that local injection of naringin ameliorated the PMMA induced inflammatory tissue response and subsequent bone resorption. The long-term tibia pin-implantation mouse model study suggested that daily oral gavage of naringin at 300 mg/kg dosage for 30 days significantly alleviated the periprosthetic bone resorption. A significant increase of periprosthetic bone volume and regaining of the pin stability were found in naringin treated mice. Overall, this study suggests that naringin may serve as a potential therapeutic agent to treat wear debris associated osteolysis.

Albumin-based nanocomposite spheres for advanced drug delivery systems.

A novel drug delivery system incorporating human serum albumin, poly(lactic-co-glycolic acid, magnetite nanoparticles, and therapeutic agent(s) was developed for potential application in the treatment of diseases such as rheumatoid arthritis and skin cancer. An oil-in-oil emulsion/solvent evaporation (O/OSE) method was modified to produce a drug delivery system with a diameter of 0.5­2 µm. The diameter was mainly controlled by adjusting the viscosity of albumin in the discontinuous phase of the O/OSE method. The drug-release study showed that the release of drug and albumin was mostly dependent on the albumin content of the drug delivery system, which is very similar to the drug occlusion-mesopore model. Cytotoxicity tests indicated that increasing the albumin content in the drug delivery system increased cell viability, possibly due to the improved biocompatibility of the system. Overall, these studies show that the proposed system could be a viable option as a drug delivery system in the treatment of many illnesses, such as rheumatoid arthritis, and skin and breast cancers.

Biomimetic composites by surface-initiated polymerization of cyclic lactones at anorganic bone: preparation and in vitro evaluation of osteoblast and osteoclast competence.

Biomimetic composites were constructed using anorganic bone to initiate the polymerization of cyclic lactones. The resulting anorganic bone/polylactone composites preserve the inorganic structure and the mechanical properties of the original bone. Thermal conditions used to prepare the anorganic bone were shown to control the surface functionalities, surface area, and crystallinity, all of which influence the rates of subsequent polymerizations. Thermal pretreatment of anorganic bone was examined as a function of time and temperature, ranging from 400°C to 800°C. Polymerization rates of different monomers were also compared. Additionally, in vitro evaluations of anorganic bone/poly-L-lactide and anorganic bone/polyglycolide composites for osteoblast and osteoclast competence suggest that these composites are good candidates for potential in vivo use, since both composites promoted osteoblast differentiation. The anorganic bone/poly-L-lactide composite also promoted osteoclast differentiation.

Local gene transfer of OPG prevents joint damage and disease progression in collagen-induced arthritis.

This study examined the influence of osteoprotegerin (OPG) gene transfer on a murine collagen-induced arthritis model. A single periarticular injection of AAV-OPG or AAV-LacZ on the arthritic paw successfully incorporated the exogenous gene to the local tissue and resulted in marked transgene expression in the joint homogenate for at least three weeks. Clinical disease scores were significantly improved in OPG treated mice starting at 28-day post-treatment (P < 0.05). Histological assessment demonstrated that OPG gene transfer dramatically protected mice from erosive joint changes compared with LacZ controls (P < 0.05), although treatment appeared less effective on the local inflammatory progress. MicroCT data suggested significant protection against subchondral bone mineral density changes in OPG treated CIA mice. Interestingly, mRNA expressions of IFN-g and MMP3 were noticeably diminished following OPG gene transfer. Overall, gene transfer of OPG effectively inhibited the arthritis-associated periarticular bone erosion and preserved the architecture of arthritic joints, and the study provides evidence that the cartilage protection of the OPG gene therapy may be associated with the down-regulation of MMP3 expression.

Effects of Ti, PMMA, UHMWPE, and Co-Cr wear particles on differentiation and functions of bone marrow stromal cells.

This study investigates the roles of orthopedic biomaterial particles [Ti-alloy, poly(methyl methacrylate) (PMMA), ultrahigh-molecular-weight polyethylene (UHMWPE), Co-Cr alloy] on the differentiation and functions of bone marrow stromal cells (BMSCs). Cells were isolated from femurs of BALB/c mice and cultured in complete osteoblast-induction medium in presence of micron-sized biomaterial particles at various doses. 3-(4,5)-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase assay were performed for cell proliferation and cytotoxicity. Differentiation and function of osteoblasts were evaluated by alkaline phosphatase (ALP), osteocalcin, RANKL, OSX, and Runx2 expressions. Murine interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α in culture media were determined by enzyme-linked immunosorbent assay. Challenge with low doses of Ti, UHMWPE, or Co-Cr particles markedly promoted the bone marrow cell proliferation while high dose of Co-Cr significantly inhibited cell growth (p < 0.05). Cells challenged with low dose of PMMA or UHMWPE particles (0.63 mg/mL) exhibited strong ALP activity, whereas Ti and Co-Cr groups showed minimal effects (p < 0.05). UHMWPE and Ti particles also promoted higher expression of proinflammatory cytokines. Real-time polymerase chain reaction data suggested that cells treated with low dose (0.5 mg/mL) particles resulted in distinctly diminished RANKL expression compared to those exposed to high concentrated (3 mg/mL) particles. In conclusion, various types of wear debris particles behaved differently in the differentiation, maturation, and functions of osteogenic cells; and the particulate debris-interacted BMSCs may play an important role in the pathogenesis and process of the debris-associated aseptic prosthetic loosening.

Current research in the pathogenesis of aseptic implant loosening associated with particulate wear debris.

Periprosthetic osteolysis is the most common long-term complication of a total joint arthroplasty, often resulting in aseptic loosening of the implant, which occurs in up to 34% of younger implant recipients and usually requires surgical revision. Particulate wear debris, continuously generated by articulating motion at the bearing surfaces, has been implicated as one of the primary causes of periprosthetic bone loss and implant loosening. With developing implants and bearing surfaces designs, various types of wear particles with specific chemical nature, dimension and shape are formed, which may initiate different immune or inflammatory responses. Wear debris induces down-regulation or up-regulation of various pro-inflammatory cytokines and chemokines in a range of cell types at the interface between implants and the surrounding bone, such as macrophages, osteoclast precursor cells, osteoblasts, lymphocytes, fibroblasts etc. Concomitantly, these mediators further affect functions of cells through distinct signaling mechanisms in either an autocrine or a paracrine manner. This review summarizes current concepts of how wear debris causes osteolysis, and describes the interaction and effects of wear debris on functions of primary cell types involved in osteolysis.

Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis.

BACKGROUND: Osteoporosis is a common pathological condition that influences 20 % of women over 50 years of age. This condition decreases bone strength and increases the risk of bone fracture. Naringin is a major flavonoid found in grapefruit and an active compound extracted from a Chinese herbal medicine (Rhizoma Drynariae). Studies have shown that naringin possesses many pharmacological effects. The current study evaluated the influence of naringin on osteoblastic cell differentiation and proliferation, and assessed its therapeutic effects on a rat osteoporosis model. METHOD: The proliferation, differentiation, and function of rat bone marrow stromal cells (BMSCs) were determined following treatment with various concentrations of naringin. Ovariectomy (OVX)-induced osteoporotic rats were orally administered naringin daily at low, medium, and high dosages, while a control group received PBS for 2 months. Femoral X-ray images and microCT scans were used for bone mineral density (BMD) and BV/TV (bone volume/total volume) analyses, and histological assessments of left tibiae were employed to check for changes in trabecular thickness (Tb.Th) and trabecular space (Tb.Sp) in the groups. RESULTS: Naringin was effective at enhancing the proliferation and osteogenic differentiation of BMSCs, and a concentration of 10 µg/ml prompted the highest levels of osteocalcin expression among the in vitro study groups. There appeared to be a delayed response pattern of BMSCs to the naringin treatment. Naringin also effectively reversed OVX-induced bone loss via increasing BMD, bone volume, and trabecular thickness. The medium dose (300 mg/kg) appeared to be the optimal dosage for delivering satisfactory therapeutic effects. CONCLUSION: Naringin promotes the proliferation and differentiation of BMSCs, and increases osteocalcin expression. Naringin also effectively reverses ovariectomy-induced osteoporosis in rats. The study suggests that naringin administration may represent an effective treatment for osteoporosis.