Silsesquioxane polymer as a potential scaffold for laryngeal reconstruction

Cancer, disease and trauma to the larynx and their treatment can lead to permanent loss of structures critical to voice, breathing and swallowing. Engineered partial or total laryngeal replacements would need to match the ambitious specifications of replicating functionality, outer biocompatibility, and permissiveness for an inner mucosal lining. Here we present porous polyhedral oligomeric silsesquioxane-poly(carbonate urea) urethane (POSS-PCUU) as a potential scaffold for engineering laryngeal tissue. Specifically, we employ a precipitation and porogen leaching technique for manufacturing the polymer. The polymer is chemically consistent across all sample types and produces a foam-like scaffold with two distinct topographies and an internal structure composed of nano- and micro-pores. Whilst the highly porous internal structure of the scaffold contributes to the complex tensile behaviour of the polymer, the surface of the scaffold remains largely non-porous. The low number of pores minimise access for cells, although primary fibroblasts and epithelial cells do attach and proliferate on the polymer surface. Our data show that with a change in manufacturing protocol to produce porous polymer surfaces, POSS-PCUU may be a potential candidate for overcoming some of the limitations associated with laryngeal reconstruction and regeneration

Priorities for disclosure of the elements of informed consent for research: a comparison between parents and investigators

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73134/1/j.1460-9592.2002.00851.x.pd

Micro- and nanoparticulates for DNA vaccine delivery

DNA vaccination has emerged as a promising alternative to traditional protein-based vaccines for the induction of protective immune responses. DNA vaccines offer several advantages over traditional vaccines, including increased stability, rapid and inexpensive production, and flexibility to produce vaccines for a wide variety of infectious diseases. However, the immunogenicity of DNA vaccines delivered as naked plasmid DNA is often weak due to degradation of the DNA by nucleases and inefficient delivery to immune cells. Therefore, biomaterial-based delivery systems based on micro- and nanoparticles that encapsulate plasmid DNA represent the most promising strategy for DNA vaccine delivery. Microparticulate delivery systems allow for passive targeting to antigen presenting cells through size exclusion and can allow for sustained presentation of DNA to cells through degradation and release of encapsulated vaccines. In contrast, nanoparticle encapsulation leads to increased internalization, overall greater transfection efficiency, and the ability to increase uptake across mucosal surfaces. Moreover, selection of the appropriate biomaterial can lead to increased immune stimulation and activation through triggering innate immune response receptors and target DNA to professional antigen presenting cells. Finally, the selection of materials with the appropriate properties to achieve efficient delivery through administration routes conducive to high patient compliance and capable of generating systemic and local (i.e. mucosal) immunity can lead to more effective humoral and cellular protective immune responses. In this review, we discuss the development of novel biomaterial- based delivery systems to enhance the delivery of DNA vaccines through various routes of administration and their implications for generating immune responses

Micro- and nanoparticulates for DNA vaccine delivery

DNA vaccination has emerged as a promising alternative to traditional protein-based vaccines for the induction of protective immune responses. DNA vaccines offer several advantages over traditional vaccines, including increased stability, rapid and inexpensive production, and flexibility to produce vaccines for a wide variety of infectious diseases. However, the immunogenicity of DNA vaccines delivered as naked plasmid DNA is often weak due to degradation of the DNA by nucleases and inefficient delivery to immune cells. Therefore, biomaterial-based delivery systems based on micro- and nanoparticles that encapsulate plasmid DNA represent the most promising strategy for DNA vaccine delivery. Microparticulate delivery systems allow for passive targeting to antigen presenting cells through size exclusion and can allow for sustained presentation of DNA to cells through degradation and release of encapsulated vaccines. In contrast, nanoparticle encapsulation leads to increased internalization, overall greater transfection efficiency, and the ability to increase uptake across mucosal surfaces. Moreover, selection of the appropriate biomaterial can lead to increased immune stimulation and activation through triggering innate immune response receptors and target DNA to professional antigen presenting cells. Finally, the selection of materials with the appropriate properties to achieve efficient delivery through administration routes conducive to high patient compliance and capable of generating systemic and local (i.e. mucosal) immunity can lead to more effective humoral and cellular protective immune responses. In this review, we discuss the development of novel biomaterial- based delivery systems to enhance the delivery of DNA vaccines through various routes of administration and their implications for generating immune responses

Effects of neuromuscular gait modification strategies on indicators of knee joint load in people with medial knee osteoarthritis:A systematic review and meta-analysis

OBJECTIVES: This systematic review aimed to determine the effects of neuromuscular gait modification strategies on indicators of medial knee joint load in people with medial knee osteoarthritis. METHODS: Databases (Embase, MEDLINE, Cochrane Central, CINAHL and PubMed) were searched for studies of gait interventions aimed at reducing medial knee joint load indicators for adults with medial knee osteoarthritis. Studies evaluating gait aids or orthoses were excluded. Hedges’ g effect sizes (ES) before and after gait retraining were estimated for inclusion in quality-adjusted meta-analysis models. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Seventeen studies (k = 17; n = 362) included two randomised placebo-controlled trials (RCT), four randomised cross-over trials, two case studies and nine cohort studies. The studies consisted of gait strategies of ipsilateral trunk lean (k = 4, n = 73), toe-out (k = 6, n = 104), toe-in (k = 5, n = 89), medial knee thrust (k = 3, n = 61), medial weight transfer at the foot (k = 1, n = 10), wider steps (k = 1, n = 15) and external knee adduction moment (KAM) biofeedback (k = 3, n = 84). Meta-analyses found that ipsilateral trunk lean reduced early stance peak KAM (KAM1, ES and 95%CI: -0.67, -1.01 to -0.33) with a dose-response effect and reduced KAM impulse (-0.37, -0.70 to -0.04) immediately after single-session training. Toe-out had no effect on KAM1 but reduced late stance peak KAM (KAM2; -0.42, -0.73 to -0.11) immediately post-training for single-session, 10 or 16-week interventions. Toe-in reduced KAM1 (-0.51, -0.81 to -0.20) and increased KAM2 (0.44, 0.04 to 0.85) immediately post-training for single-session to 6-week interventions. Visual, verbal and haptic feedback was used to train gait strategies. Certainty of evidence was very-low to low according to the GRADE approach. CONCLUSION: Very-low to low certainty of evidence suggests that there is a potential that ipsilateral trunk lean, toe-out, and toe-in to be clinically helpful to reduce indicators of medial knee joint load. There is yet little evidence for interventions over several weeks

A TSC signaling node at the peroxisome regulates mTORC1 and autophagy in response to ROS

Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signaling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by PEX19 and PEX5, respectively, and peroxisome-localized TSC functioned as a Rheb GAP to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, abrogated peroxisome localization, Rheb GAP activity, and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS and peroxisome-localization deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signaling organelle involved in regulation of mTORC1

Chitosan-zein nano-in-microparticles Capable of Mediating in vivo Transgene Expression Following Oral Delivery

The oral route is an attractive delivery route for the administration of DNA-based therapeutics, specifically for applications in gene therapy and DNA vaccination. However, oral DNA delivery is complicated by the harsh and variable conditions encountered throughout gastrointestinal (GI) transit, leading to degradation of the delivery vector and DNA cargo, and subsequent inefficient delivery to target cells. In this work, we demonstrate the development and optimization of a hybrid-dual particulate delivery system consisting of two natural biomaterials, zein (ZN) and chitosan (CS), to mediate oral DNA delivery. Chitosan-Zein Nano-in-Microparticles (CS-ZN-NIMs), consisting of core Chitosan/DNA nanoparticles (CS/DNA NPs) prepared by ionic gelation with sodium tripolyphosphate (TPP), further encapsulated in ZN microparticles, were formulated using a water-in-oil emulsion (W/O). The resulting particles exhibited high CS/DNA NP loading and encapsulation within ZN microparticles. DNA release profiles in simulated gastric fluid (SGF) were improved compared to un-encapsulated CS/ DNA NPs. Further, site-specific degradation of the outer ZN matrix and release of transfection competent CS/ DNA NPs occurred in simulated intestinal conditions with CS/DNA NP cores successfully mediating transfection in vitro. Finally, CS-ZN-NIMs encoding GFP delivered by oral gavage in vivo induced the production of anti-GFP IgA antibodies, demonstrating in vivo transfection and expression. Together, these results demonstrate the successful formulation of CS-ZN-NIMs and their potential to improve oral gene delivery through improved protection and controlled release of DNA cargo