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Self-Assembled, Peptide Based Biomaterials for Regenerative Medicine and Drug Delivery
Full text linkA focus of the field of biomaterials is to use directed design to create new materials which replicate and enhance the intricate functions of the human body. Nature's own building blocks, peptides, are an ideal material to create self-assembling biomaterials as they are biodegradable, relatively easy to synthesize, and can be designed with a wide array of functions. In this dissertation, self-assembling peptide materials were optimized for two important medical applications: regenerative medicine and drug delivery. Peptide amphiphiles (PAs), peptides conjugated to fatty acid tails, can self-assemble into both spherical micelles and worm-like micelles. PA worm-like micelles are of particular interest for regenerative medicine applications for their ability to form viscoelastic hydrogels at high concentration. Here we created PA hydrogel systems with active formation and stabilization triggers that are amenable to in situ gelation. Two different methods of in situ gel formation in PA systems were investigated, shear force and pH. Shear-induced formation of worm-like micelles is demonstrated in the PA termed C16-W3K. Before shearing, C16-W3K PAs form spherical micelles in solution and exhibit little to no viscoelasticity. As the solution is subjected to simple shear flow with increasing shear rate, spherical micelles form elongated worm-like micelles up to microns in length. In the C16-W3K PA system, shear force induced the change not only of the micelle structure but also of the peptide secondary structure simultaneously. Worm-like micelle formation was also demonstrated using pH modulation, in the PA termed C16GSH, which was designed with a branched peptide headgroup of histidine and serine amino acids. At low pH, the histidine side chains are protonated and hydrogen bonding does not occur, creating weakly elastic hydrogels. At pH 7.4, above the pKa of the histidine imidazole group, cooperative hydrogen bonding occurs, stabilizing the self-assembled worm-like micelles and creating a strong viscoelastic hydrogel. This unique architecture of C16GSH makes it possible to create hydrogels spanning a wide range of stiffness (0.1-10 kPa). C16GSH were optimized in vitro and in vivo for the application of peripheral nerve regeneration. Peripheral nerve injury is a debilitating condition for which new bioengineering solutions are needed. One strategy to enhance regeneration inside nerve guide conduits is to fill the conduits with a hydrogel to mimic the native extracellular matrix found in peripheral nerves. C16GSH hydrogels were compared to a commercially available collagen gel, which has been previously investigated as a nerve guide filler gel. Schwann cells, a cell type important in the peripheral nerve regenerative cascade, were able to spread, proliferate and migrate better on C16GSH gels in vitro when compared to cells seeded on collagen gels. Moreover, C16GSH gels were implanted subcutaneously in a murine model and were found to be biocompatible, degrade over time, and support angiogenesis without causing inflammation or a foreign body immune response. Taken together, these results help optimize and instruct the development of a new synthetic, hydrogel as a luminal filler for conduit-mediated peripheral nerve repair.In the second half of this dissertation, peptide based complex coacervates were optimized for delivery of protein therapeutics. Complex coacervation is a liquid-liquid phase separation based on the electrostatic association of two oppositely charged polymers in aqueous solution. Coacervation results in micron sized droplets of a dense polymer-rich phase (coacervate) which is separate from the dilute polymer-poor solution phase (aqueous phase). Complex coacervates based on synthetic polypeptides have many desirable features for therapeutic protein delivery. They can be synthetically produced, can be made to be biocompatible and biodegradable, and their formation can be tuned by a wide array of parameters. In this dissertation, a method to encapsulate proteins by complex coacervation using polypeptides is explored. Protein encapsulation with a model protein system: bovine serum albumin (BSA) was demonstrated. Rheological properties were studied to determine the viscoelasticity which may have implications for cell internalization. It was demonstrated that there is tradeoff between loading efficiency and total loading. Therefore, depending on the application, high loading capacity, up to 1:3 molar ratio of protein to polypeptide, or 100% loading of the protein can be achieved, depending on the process and cost of the protein which is often high. Encapsulated BSA retained its secondary structure when encapsulated and was released under conditions of low pH due to disassembly of the coacervate. Lastly, protein loaded coacervates were shown to be non-toxic in a cell viability assay.Polypeptide complex coacervates show promise at encapsulating proteins for therapeutic delivery, but it is difficult to control their size and stability to due dynamic rearrangement and coalescence. To control the size and stability of polypeptide coacervates, the crosslinker EDC was used to create a peptide bond between the amino acid side groups of poly(L-lysine) (PLys) and poly(D/L-glutamic acid) (PGlu). By changing the ratio of PGlu to PLys colloidal stability was achieved without the need for an additional excipient. Surface charge of the particles was also controlled by this method. Final particle size was controlled by both molecular weight and concentration of the polypeptides. A span of particle diameter from to 272nm to 1.3 µm was achieved. Lastly, stability at low pH, where non-crosslinked coacervates disassemble, was demonstrated. A simple and tunable method to control particle size, such as the one presented here provides a possible solution to a major limitation in the field of drug delivery, control of particle size
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Enclosed Microfluidic Platform Realizing Enhanced Stem-cell Survival
Full text linkHere we present a microfluidic culture platform for enhancing single stem cell survival. Traditional plate culture is inadequate for large scale single cell studies because of (1) less than 40% single stem cell survival leading to (2) possible inaccuracies in the biostatistics in single cell studies from lack of sufficient data. This platform mitigates these issues by doubling overall survival rates as well as increasing the available data points by two orders of magnitude, both factors which improve statistical certainty. The platform is fabricated using widely accepted biocompatible polymers and incorporates the novel integration of an enclosed microwell array with an upstream linear gradient generator. The device can selectively trap single cells, tightly control intercell spacing, and change the chemical microenvironment around the stem cells in real-time. In this dissertation, we first characterize the performance of the platform in improving single cell survivability. Subsequently, the system was tested using two difference stem cell types: mouse embryonic stem cells (mES) and induced pluripotent stem cells (iPS). Using this platform we are able to highlight the thresholds of leukemia inhibitory factor concentrations which lead to metastable gene expression of Nanog, a key stem cell pluripotency regulator in mES cells. The enhanced survival of single cells has also enabled the statistically significant observation of Nanog+, non-proliferative, single mES cells which are previously unreported in literature
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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