Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis

Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation(1). As gut-derived serotonin (GDS) inhibits bone formation(2), we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Multiple UAV Coalitions for a Search and Prosecute Mission

Unmanned aerial vehicles (UAVs) have the potential to carry resources in support of search and prosecute operations. Often to completely prosecute a target, UAVs may have to simultaneously attack the target with various resources with different capacities. However, the UAVs are capable of carrying only limited resources in small quantities, hence, a group of UAVs (coalition) needs to be assigned that satisfies the target resource requirement. The assigned coalition must be such that it minimizes the target prosecution delay and the size of the coalition. The problem of forming coalitions is computationally intensive due to the combinatorial nature of the problem, but for real-time applications computationally cheap solutions are required. In this paper, we propose decentralized sub-optimal (polynomial time) and decentralized optimal coalition formation algorithms that generate coalitions for a single target with low computational complexity. We compare the performance of the proposed algorithms to that of a global optimal solution for which we need to solve a centralized combinatorial optimization problem. This problem is computationally intensive because the solution has to (a) provide a coalition for each target, (b) design a sequence in which targets need to be prosecuted, and (c) take into account reduction of UAV resources with usage. To solve this problem we use the Particle Swarm Optimization (PSO) technique. Through simulations, we study the performance of the proposed algorithms in terms of mission performance, complexity of the algorithms and the time taken to form the coalition. The simulation results show that the solution provided by the proposed algorithms is close to the global optimal solution and requires far less computational resources.

Development, in vitro and in vivo characterization of zoledronic acid functionalized hydroxyapatite nanoparticle based formulation for treatment of osteoporosis in animal model

We investigated the potential of using novel zoledronic acid (ZOL)-hydroxyapatite (HA) nanoparticle based drug formulation in a rat model of postmenopausal osteoporosis. By a classical adsorption method, nanoparticles of HA loaded with ZOL (HNLZ) drug formulation with a size range of 100-130 nm were prepared. 56 female Wistar rats were ovariectomized (OVX) or sham-operated at 3 months of age. Twelve weeks post surgery, rats were randomized into seven groups and treated with various doses of HNLZ (100, 50 and 25 mu g/kg, intravenous single dose), ZOL (100 mu g/kg, intravenous single dose) and HA nanoparticle (100 mu g/kg, intravenous single dose). Untreated OVX and sham OVX served as controls. After three months treatment period, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for trabecular microarchitecture. Sensitive biochemical markers of bone formation and bone resorption in serum were also determined. With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the therapy with HNLZ drug formulation was more effective than ZOL therapy in OVX rats. Moreover, HNLZ drug therapy preserved the trabecular microarchitecture better than ZOL therapy in OVX rats. Furthermore, the HNLZ drug formulation corrected increase in serum levels of bone-specific alkaline phosphatase, procollagen type I N-terminal propeptide, osteocalcin, tartrate-resistant acid phosphatase 5b and C-telopeptide of type 1 collagen better than ZOL therapy in OVX rats. The results strongly suggest that HNLZ novel drug formulation appears to be more effective approach for treating severe osteoporosis in humans. (C) 2014 Elsevier B.V. All rights reserved.

Biocompatibility property of 100% strontium-substituted SiO2-Al2O3-P2O5-CaO-CaF2 glass ceramics over 26 weeks implantation in rabbit model: Histology and micro-Computed Tomography analysis

One of the desired properties for any new biomaterial composition is its long-term stability in a suitable animal model and such property cannot be appropriately assessed by performing short-term implantation studies. While hydroxyapatite (HA) or bioglass coated metallic biomaterials are being investigated for in vivo biocompatibility properties, such study is not extensively being pursued for bulk glass ceramics. In view of their inherent brittle nature, the implant stability as well as impact of long-term release of metallic ions on bone regeneration have been a major concern. In this perspective, the present article reports the results of the in vivo implantation experiments carried out using 100% strontium (Sr)-substituted glass ceramics with the nominal composition of 4.5 SiO2-3Al(2)O(3)-1.5P(2)O(5)-3SrO-2SrF(2) for 26 weeks in cylindrical bone defects in rabbit model. The combination of histological and micro-computed tomography analysis provided a qualitative and quantitative understanding of the bone regeneration around the glass ceramic implants in comparison to the highly bioactive HA bioglass implants (control). The sequential polychrome labeling of bone during in vivo osseointegration using three fluorochromes followed by fluorescence microscopy observation confirmed homogeneous bone formation around the test implants. The results of the present study unequivocally confirm the long-term implant stability as well as osteoconductive property of 100% Sr-substituted glass ceramics, which is comparable to that of a known bioactive implant, that is, HA-based bioglass. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 1168-1179, 2015.

Strength reliability and in vitro degradation of three-dimensional powder printed strontium-substituted magnesium phosphate scaffolds

Strontium ions (Sr2+) are known to prevent osteoporosis and also encourage bone formation. Such twin requirements have motivated researchers to develop Sr-substituted biomaterials for orthopaedic applications. The present study demonstrates a new concept of developing Sr-substituted Mg-3(PO4)(2) - based biodegradable scaffolds. In particular, this work reports the fabrication, mechanical properties with an emphasis on strength reliability as well as in vitro degradation of highly biodegradable strontium-incorporated magnesium phosphate cements. These implantable scaffolds were fabricated using three-dimensional powder printing, followed by high temperature sintering and/or chemical conversion, a technique adaptable to develop patient-specific implants. A moderate combination of strength properties of 36.7 MPa (compression), 242 MPa (bending) and 10.7 MPa (tension) were measured. A reasonably modest Weibull modulus of up to 8.8 was recorded after uniaxial compression or diametral tensile tests on 3D printed scaffolds. A comparison among scaffolds with varying compositions or among sintered or chemically hardened scaffolds reveals that the strength reliability is not compromised in Sr-substituted scaffolds compared to baseline Mg-3(PO4)(2). The micro-computed tomography analysis reveals the presence of highly interconnected porous architecture in three-dimension with lognormal pore size distribution having median in the range of 17.74-26.29 mu m for the investigated scaffolds. The results of extensive in vitro ion release study revealed passive degradation with a reduced Mg2+ release and slow but sustained release of Sr2+ from strontium-substituted magnesium phosphate scaffolds. Taken together, the present study unequivocally illustrates that the newly designed Sr-substituted magnesium phosphate scaffolds with good strength reliability could be used for biomedical applications requiring consistent Sr2+-release, while the scaffold degrades in physiological medium. Statement of significance The study investigates the additive manufacturing of scaffolds based on different strontium-substituted magnesium phosphate bone cements by means of three-dimensional powder printing technique (3DPP). Magnesium phosphates were chosen due to their higher biodegradability compared to calcium phosphates, which is due to both a higher solubility as well as the absence of phase changes (to low soluble hydroxyapatite) in vivo. Since strontium ions are known to promote bone formation by stimulating osteoblast growth, we aimed to establish such a highly degradable magnesium phosphate ceramic with an enhanced bioactivity for new bone ingrowth. After post-processing, mechanical strengths of up to 36.7 MPa (compression), 24.2 MPa (bending) and 10.7 MPa (tension) could be achieved. Simultaneously, the failure reliability of those bioceramic implant materials, measured by Weibull modulus calculations, were in the range of 4.3-8.8. Passive dissolution studies in vitro proved an ion release of Mg2+ and PO43- as well as Sr2+, which is fundamental for in vivo degradation and a bone growth promoting effect. In our opinion, this work broadens the range of bioceramic bone replacement materials suitable for additive manufacturing processing. The high biodegradability of MPC ceramics together with the anticipated promoting effect on osseointegration opens up the way for a patient-specific treatment with the prospect of a fast and complete healing of bone fractures. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

A Bayesian incentive compatible mechanism for decentralized supply chain formation

In this paper we consider a decentralized supply chain formation problem for linear multi-echelon supply chains when the managers of the individual echelons are autonomous, rational, and intelligent. At each echelon, there is a choice of service providers and the specific problem we solve is that of determining a cost-optimal mix of service providers so as to achieve a desired level of end-to-end delivery performance. The problem can be broken up into two sub-problems following a mechanism design approach: (1) Design of an incentive compatible mechanism to elicit the true cost functions from the echelon managers; (2) Formulation and solution of an appropriate optimization problem using the true cost information. In this paper we propose a novel Bayesian incentive compatible mechanism for eliciting the true cost functions. This improves upon existing solutions in the literature which are all based on the classical Vickrey-Clarke-Groves mechanisms, requiring significant incentives to be paid to the echelon managers for achieving dominant strategy incentive compatibility. The proposed solution, which we call SCF-BIC (Supply Chain Formation with Bayesian Incentive Compatibility), significantly reduces the cost of supply chain formation. We illustrate the efficacy of the proposed methodology using the example of a three echelon manufacturing supply chain.

Optimal scheduling of multiple chlorine sources in water distribution systems

The specified range of free chlorine residual (between minimum and maximum) in water distribution systems needs to be maintained to avoid deterioration of the microbial quality of water, control taste and/or odor problems, and hinder formation of carcino-genic disinfection by-products. Multiple water quality sources for providing chlorine input are needed to maintain the chlorine residuals within a specified range throughout the distribution system. The determination of source dosage (i.e., chlorine concentrations/chlorine mass rates) at water quality sources to satisfy the above objective under dynamic conditions is a complex process. A nonlinear optimization problem is formulated to determine the chlorine dosage at the water quality sources subjected to minimum and maximum constraints on chlorine concentrations at all monitoring nodes. A genetic algorithm (GA) approach in which decision variables (chlorine dosage) are coded as binary strings is used to solve this highly nonlinear optimization problem, with nonlinearities arising due to set-point sources and non-first-order reactions. Application of the model is illustrated using three sample water distribution systems, and it indicates that the GA,is a useful tool for evaluating optimal water quality source chlorine schedules.

Methionine down-regulates TLR4/MyD88/NF-kappa B signalling in osteoclast precursors to reduce bone loss during osteoporosis

Background and PurposeStudies have demonstrated that a moderate intake of amino acids is associated with development of bone health. Methionine, a sulphur-containing essential amino acid, has been largely implicated for improving cartilage formation, however its physiological significance on bone integrity and functionality have not been elucidated. We investigated whether methionine can prevent osteoporotic bone loss. Experimental ApproachThe anti-resorptive effect of methionine, (250mgkg(-1) body wt administered in drinking water for 10 weeks), was evaluated in ovariectomized (OVX) rats by monitoring changes in bone turnover, formation of osteoclasts from blood-derived mononuclear cells and changes in the synthesis of pro-osteoclastogenic cytokines. Key resultsMethionine improved bone density and significantly decreased the degree of osteoclast development from blood mononuclear cells in OVX rats, as indicated by decreased production of osteoclast markers tartarate resistant acid phosphatase b (TRAP5b) and MIP-1. siRNA-mediated knockdown of myeloid differentiation primary response 88 MyD88], a signalling molecule in the toll-like receptor (TLR) signalling cascade, abolished the synthesis of both TRAP5b and MIP-1 in developing osteoclasts. Methionine supplementation disrupted osteoclast development by inhibiting TLR-4/MyD88/NF-B pathway. Conclusions and ImplicationsTLR-4/MyD88/NF-B signalling pathway is integral for osteoclast development and this is down-regulated in osteoporotic system on methionine treatment. Methionine treatment could be beneficial for the treatment of postmenopausal osteoporosis.

Optimal values of bipartite entanglement in a tripartite system

For a general tripartite system in some pure state, an observer possessing any two parts will see them in a mixed state. By the consequence of Hughston-Jozsa-Wootters theorem, each basis set of local measurement on the third part will correspond to a particular decomposition of the bipartite mixed state into a weighted sum of pure states. It is possible to associate an average bipartite entanglement ((S) over bar) with each of these decompositions. The maximum value of (S) over bar is called the entanglement of assistance (E-A) while the minimum value is called the entanglement of formation (E-F). An appropriate choice of the basis set of local measurement will correspond to an optimal value of (S) over bar; we find here a generic optimality condition for the choice of the basis set. In the present context, we analyze the tripartite states W and GHZ and show how they are fundamentally different. (C) 2014 Elsevier B.V. All rights reserved.

Chemical Functionalization of Graphene To Augment Stem Cell Osteogenesis and Inhibit Biofilm Formation on Polymer Composites for Orthopedic Applications

Toward designing the next generation of resorbable biomaterials for orthopedic applications, we studied poly(epsilon-caprolactone) (PCL) composites containing graphene. The role, if any, of the functionalization of graphene on mechanical properties, stem cell response, and biofilm formation was systematically evaluated. PCL composites of graphene oxide (GO), reduced GO (RGO), and amine-functionalized GO (AGO) were prepared at different filler contents (1%, 3%, and 5%). Although the addition of the nanoparticles to PCL markedly increased the storage modulus, this increase was largest for GO followed by AGO and RGO. In vitro cell studies revealed that the AGO and GO particles significantly increased human mesenchymal stem cell proliferation. AGO was most effective in augmenting stem cell osteogenesis leading to mineralization. Bacterial studies revealed that interaction with functionalized GO induced bacterial cell death because of membrane damage, which was further accentuated by amine groups in AGO. As a result, AGO composites were best at inhibiting biofilm formation. The synergistic effect of oxygen containing functional groups and amine groups on AGO imparts the optimal combination of improved modulus, favorable stem cell response, and biofilm inhibition in AGO-reinforced composites desired for orthopedic applications. This work elucidates the importance of chemical functionalization of graphene in polymer composites for biomedical applications.

Multicomponent Adducts of Pyridoxine: An Evaluation of the Formation of Eutectics and Molecular Salts

Cocrystallization of pyridoxine (vitamin B6) with several biologically important molecules was undertaken with the intent of successfully designing various hydrogen bonded adducts such as salts, cocrystals, and eutectics. Pyridoxine formed eutectics with isoniazid (an antitubercular drug) and nicotinic acid (vitamin B3) and molecular salts with para-aminobenzoic acid (a bioactive) and saccharin (an artificial sweetener), respectively, in accordance to our design strategy. A salt cocrystal, a precisely conjugate acid-base cocrystal, was obtained for the pyridoxine-para-nitrobenzoic acid combination. The role of supramolecular affinity of hydrogen bonding functional groups and Delta pK(a) differences leading to the formation of above diverse adducts was discussed. This study underpins the need for full-fledged supramolecular compatibility studies of multivitamin/drug combinations toward the development of optimal and/or synergistic combination formulations.

Three-dimensional plotted hydroxyapatite scaffolds with predefined architecture: comparison of stabilization by alginate cross-linking versus sintering

Scaffolds for bone tissue engineering are essentially characterized by porous three-dimensional structures with interconnected pores to facilitate the exchange of nutrients and removal of waste products from cells, thereby promoting cell proliferation in such engineered scaffolds. Although hydroxyapatite is widely being considered for bone tissue engineering applications due to its occurrence in the natural extracellular matrix of this tissue, limited reports are available on additive manufacturing of hydroxyapatite-based materials. In this perspective, hydroxyapatite-based three-dimensional porous scaffolds with two different binders (maltodextrin and sodium alginate) were fabricated using the extrusion method of three-dimensional plotting and the results were compared in reference to the structural properties of scaffolds processed via chemical stabilization and sintering routes, respectively. With the optimal processing conditions regarding to pH and viscosity of binder-loaded hydroxyapatite pastes, scaffolds with parallelepiped porous architecture having up to 74% porosity were fabricated. Interestingly, sintering of the as-plotted hydroxyapatite-sodium alginate (cross-linked with CaCl2 solution) scaffolds led to the formation of chlorapatite (Ca9.54P5.98O23.8Cl1.60(OH)(2.74)). Both the sintered scaffolds displayed progressive deformation and delayed fracture under compressive loading, with hydroxyapatite-alginate scaffolds exhibiting a higher compressive strength (9.5 +/- 0.5MPa) than hydroxyapatite-maltodextrin scaffolds (7.0 +/- 0.6MPa). The difference in properties is explained in terms of the phase assemblage and microstructure.

Engineering a multi-biofunctional composite using poly(ethylenimine) decorated graphene oxide for bone tissue regeneration

Toward preparing strong multi-biofunctional materials, poly(ethylenimine) (PEI) conjugated graphene oxide (GO_PEI) was synthesized using poly(acrylic acid) (PAA) as a spacer and incorporated in poly( e-caprolactone) (PCL) at different fractions. GO_PEI significantly promoted the proliferation and formation of focal adhesions in human mesenchymal stem cells (hMSCs) on PCL. GO_PEI was highly potent in inducing stem cell osteogenesis leading to near doubling of alkaline phosphatase expression and mineralization over neat PCL with 5% filler content and was approximate to 50% better than GO. Remarkably, 5% GO_ PEI was as potent as soluble osteoinductive factors. Increased adsorption of osteogenic factors due to the amine and oxygen containing functional groups on GO_ PEI augment stem cell differentiation. GO_ PEI was also highly efficient in imparting bactericidal activity with 85% reduction in counts of E. coli colonies compared to neat PCL at 5% filler content and was more than twice as efficient as GO. This may be attributed to the synergistic effect of the sharp edges of the particles along with the presence of the different chemical moieties. Thus, GO_ PEI based polymer composites can be utilized to prepare bioactive resorbable biomaterials as an alternative to using labile biomolecules for fabricating orthopedic devices for fracture fixation and tissue engineering.