Evaluation of osteogenic design factors in electrospun poly(ε-caprolactone) nanofiber scaffolds

Includes bibliographical references.Biodegradable bone tissue scaffolds have the potential to impact patients with numerous ailments. Starting with fabrication techniques that produce nano-scale features, the ability to manipulate architecture, alter surface chemistry, and deliver biological molecules allows for the design of elegant and highly effective bone scaffolds. This work aimed to develop a porous, nanofiber scaffold with osteogenic design features the capability to deliver an antibiotic molecule from within the nanofibers. Two osteogenic design factors with unique mechanisms of action were selected; hydroxyapatite nanoparticles and oleic acid. Hydroxyapatite (HAp) is the primary inorganic phase of natural bone tissue and has been used to more closely mimic the extracellular environment of synthetic bone tissue scaffolds. Oleic acid (OLA) is an ω-9 fatty acid with suspected osteogenic effects due to activation of peroxisome proliferator-activator receptors (PPARs). In separate in vitro evaluations, OLA significantly increased osteoblast phenotypic behaviors and led to differential expression of the three PPAR isoforms, suggesting that the OLA is activating its anticipated receptor. HAp produced mixed results by inducing a small increase in alkaline phosphatase activity, but decreasing expression levels of bone matrix proteins. An in vivo evaluation of biocompatibility revealed that neither design factor increased the inflammatory response over control nanofiber scaffolds in paravertebral muscle pouches. However, both factors separately increased new osteoid production. Scaffolds with both HAp and OLA elicited the greatest osteogenic response in vivo, suggesting positive synergy between the two design factors. Finally, rifampicin (RIF), an antibiotic molecule was loaded into the nanofibers, and its release into static bacterial culture was effective in inhibiting bacterial population growth for both a Gram-positive and Gram-negative bacterial strain, separately. Overall, these nanofiber scaffolds were demonstrated to be effective carriers of soluble (OLA, RIF) and insoluble signals (HAp) which can modulate cell behaviors. Future work will aim to incorporate additional osteogenic features into the scaffolds and to develop multiple antibiotic release mechanisms from the nanofibers

Electronic structure and band parameters for ZnX (X = O, S, Se, Te)

First-principles density-functional calculations have been performed for zinc monochalcogenides with zinc-blende- and wurtzite-type structures. It is shown that the local-density approximation underestimates the band gap, misplaces the energy levels of the Zn-3d states, and overestimates the crystal-field splitting energy. Without spinorbit coupling, the order of the states at the top of VB is found to be normal for all the ZnX phases considered. Upon inclusion of the spinorbit coupling in calculations, ZnO in zinc-blende- and wurtzite-type phases become anomalous. It is shown that the Zn-3d electrons are responsible for the anomalous order. The effective masses of electrons and holes have been calculated and found that holes are much anisotropic and heavier than the electrons in agreement with experimental findings. The typical errors in calculated band gaps and related parameters originate from strong Coulomb correlations, which are found to be highly significant in ZnO. The LDA+U approach is found to correct the strong correlation of the Zn-3d electrons, and thus improves the agreement with the experimentally established location of the Zn-3d levels. Consequently, it increases significantly the parameters underestimated in the pure LDA calculations.Comment: 7 pages, 3 figures, 2 tables, ICAM-ICMAT conference, 200

Promoting remyelination through cell transplantation therapies in a model of viral-induced neurodegenerative disease.

Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by chronic neuroinflammation, demyelination, and axonal damage. Infiltration of activated lymphocytes and myeloid cells are thought to be primarily responsible for white matter damage and axonopathy. Several United States Food and Drug Administration-approved therapies exist that impede activated lymphocytes from entering the CNS thereby limiting new lesion formation in patients with relapse-remitting forms of MS. However, a significant challenge within the field of MS research is to develop effective and sustained therapies that allow for axonal protection and remyelination. In recent years, there has been increasing evidence that some kinds of stem cells and their derivatives seem to be able to mute neuroinflammation as well as promote remyelination and axonal integrity. Intracranial infection of mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in immune-mediated demyelination and axonopathy, making this an excellent model to interrogate the therapeutic potential of stem cell derivatives in evoking remyelination. This review provides a succinct overview of our recent findings using intraspinal injection of mouse CNS neural progenitor cells and human neural precursors into JHMV-infected mice. JHMV-infected mice receiving these cells display extensive remyelination associated with axonal sparing. In addition, we discuss possible mechanisms associated with sustained clinical recovery. Developmental Dynamics 248:43-52, 2019. © 2018 Wiley Periodicals, Inc

Antibacterial Efficiency of Hydroxyapatite Biomaterials with Biodegradable Polylactic Acid and Polycaprolactone Polymers Saturated with Antibiotics

Publisher Copyright: © 2016 by Ingus Skadiņš. Copyright: Copyright 2016 Elsevier B.V., All rights reserved.Infections continue to spread in all fields of medicine, and especially in the field of implant biomaterial surgery, and not only during the surgery, but also after surgery. Reducing the adhesion of bacteria could decrease the possibility of biomaterial-associated infections. Bacterial adhesion could be reduced by local antibiotic release from the biomaterial. In this in vitro study, hydroxyapatite biomaterials with antibiotics and biodegradable polymers were tested for their ability to reduce bacteria adhesion and biofilm development. This study examined the antibacterial efficiency of hydroxyapatite biomaterials with antibiotics and biodegradable polymers against Staphylococcus epidermidis and Pseudomonas aeruginosa. The study found that hydroxyapatite biomaterials with antibiotics and biodegradable polymers show longer antibacterial properties than hydroxyapatite biomaterials with antibiotics against both bacterial cultures. Therefore, the results of this study demonstrated that biomaterials that are coated with biodegradable polymers release antibiotics from biomaterial samples for a longer period of time and may be useful for reducing bacterial adhesion on orthopedic implants.publishersversionPeer reviewe

Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice

We gratefully acknowledge the Progressive Multiple Sclerosis Alliance for financial support

Cellular and molecular mechanisms underpinning macrophage activation during remyelination

Remyelination is an example of central nervous system (CNS) regeneration, whereby myelin is restored around demyelinated axons, re-establishing saltatory conduction and trophic/metabolic support. In progressive multiple sclerosis, remyelination is limited or fails altogether which is considered to contribute to axonal damage/loss and consequent disability. Macrophages have critical roles in both CNS damage and regeneration, such as remyelination. This diverse range in functions reflects the ability of macrophages to acquire tissue microenvironment-specific activation states. This activation is dynamically regulated during efficient regeneration, with a switch from pro-inflammatory to inflammation-resolution/pro-regenerative phenotypes. Although, some molecules and pathways have been implicated in the dynamic activation of macrophages, such as NFκB, the cellular and molecular mechanisms underpinning plasticity of macrophage activation are unclear. Identifying mechanisms regulating macrophage activation to pro-regenerative phenotypes may lead to novel therapeutic strategies to promote remyelination in multiple sclerosis

Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis.

BACKGROUND: [corrected] Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments. RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination. CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis

Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models

Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients. Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination. As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation. However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure. Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent). To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination. Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination. We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1112-y) contains supplementary material, which is available to authorized users

Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo

Personalized medicine could revolutionize how primary care physicians treat chronic disease and how researchers study fundamental biological questions. To realize this goal, we need to develop more robust, modular tools and imaging approaches for in vivo monitoring of analytes. In this report, we demonstrate that synthetic nanosensors can measure physiologic parameters with photoacoustic contrast, and we apply that platform to continuously track lithium levels in vivo. Photoacoustic imaging achieves imaging depths that are unattainable with fluorescence or multiphoton microscopy. We validated the photoacoustic results that illustrate the superior imaging depth and quality of photoacoustic imaging with optical measurements. This powerful combination of techniques will unlock the ability to measure analyte changes in deep tissue and will open up photoacoustic imaging as a diagnostic tool for continuous physiological tracking of a wide range of analytes