A resorbable polymeric microreservoir device for controlled release drug delivery

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2003.Includes bibliographical references.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.The method by which a drug is delivered can have a significant effect on the drug's therapeutic efficacy. Pulsatile delivery of certain drugs and molecules (such as hormones) has been shown to more efficacious than continuous delivery, as the fluctuation in concentration levels in vivo more closely mimics the natural physiological processes of the human body. However, there is a shortage of systems that are capable of delivering drugs in this manner, particularly if it is desired to have a self-contained system that does not require external stimulation to trigger device function. The objectives of this thesis were to design, fabricate, test, and characterize a biodegradable polymeric microreservoir device that is capable of delivering multiple pulses of drugs in a reproducible manner. This polymeric microreservoir device contains an array of reservoirs that are each covered by a thin membrane of a degradable polymer. Control over the release of drugs from the device was achieved by changing the molecular weight of the reservoir membranes. The current prototypes have 36 reservoirs, but the size and geometry of the polymeric chip could be designed to optimize device performance depending on the application for which it will be used. Changing the membrane materials or thicknesses could change the time at which the chemicals are released from the reservoirs. Each reservoir on the device could potentially have a different set of membrane characteristics, enabling release of the contents of each reservoir at a different time. A fabrication process for these devices was developed, that consists of two compression-molding steps, followed by microinjection of the reservoir membranes from solution and subsequent drying of the membranes under vacuum and elevated temperature. The devices are then loaded with the drugs to be released and sealed at room temperature. This fabrication process avoids exposure of the drugs to solvents and high temperatures that may adversely affect their stability. Further, the compression-molding process used to fabricate the main body of the device, as well as minimal solvent used in the fabrication of the reservoir membranes, were designed to minimize adverse effects upon in vivo implantation due to residual solvent. Poly(L-lactic acid) was selected as the component material for the device substrate, while(cont.) the reservoir membranes were made from copolymers of poly(lactic-co-glycolic acid) having varying molecular weights. The degradation behaviors of these materials have been extensively studied both in vitro and in vivo, and they have been shown to be quite biocompatible. Studies showed that the degradation of the reservoir membranes in vitro and subsequent release times of chemicals from the reservoirs is a function of both the membrane thicknesses and environmental temperature. Proof-of-principle release studies showed up to four pulses of radiolabeled molecules (¹⁴C-dextran, ³H-heparin, and ¹²⁵I-HGH) from single devices, both with one chemical per device (four pulses per chemical) as well as two chemicals per device (two pulses per chemical). Bioactivity measurements showed that heparin released from the devices in vitro retains activity up to at least 143 days ...by Amy Catherine Richards Grayson.Ph.D

Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys

Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks. Objective: In the present primate study, we used radioautography to describe the distribution and intensity of 3H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated. Methods: Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3-10mg/kg, and on the CDMP, subjects were tested at 1-3 or 3-10mg/kg. Results: Radioautography revealed a relatively low level of 3H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP. Conclusions: The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functionin

Forces During Bacteriophage DNA Packaging and Ejection

The conjunction of insights from structural biology, solution biochemistry, genetics and single molecule biophysics has provided a renewed impetus for the construction of quantitative models of biological processes. One area that has been a beneficiary of these experimental techniques is the study of viruses. In this paper we describe how the insights obtained from such experiments can be utilized to construct physical models of processes in the viral life cycle. We focus on dsDNA bacteriophages and show that the bending elasticity of DNA and its electrostatics in solution can be combined to determine the forces experienced during packaging and ejection of the viral genome. Furthermore, we quantitatively analyze the effect of fluid viscosity and capsid expansion on the forces experienced during packaging. Finally, we present a model for DNA ejection from bacteriophages based on the hypothesis that the energy stored in the tightly packed genome within the capsid leads to its forceful ejection. The predictions of our model can be tested through experiments in vitro where DNA ejection is inhibited by the application of external osmotic pressure

Isotopic and zooarchaeological approaches towards understanding aquatic resource use in human economies and animal management in the prehistoric Scottish North Atlantic Islands

Despite being surrounded by aquatic resources, the Prehistoric populations of the North Atlantic Islands have a complex history of aquatic resource that until now has been little understood. Specifically the changing importance and uses of aquatic resources through time, and the role of aquatic resources in the management of animals in prehistory requires further attention. This paper presents results of faunal isotopic analysis in combination with existing human isotopic evidence and zooarchaeological datasets from Neolithic, Bronze Age and Iron Age sites in the Western Isles (also known as the Outer Hebrides) and Orkney to explore the importance of aquatic resources in the lives of these prehistory populations. In Orkney coastal grazing was an important aspect in the management of sheep throughout prehistory, whereas in the Western Isles this was only evident in the Bronze Age. Aquatic protein was also used in the management of pigs in the Western Isles during the Middle Iron Age. There is little evidence of humans consuming aquatic resources in the Neolithic, and only minor evidence of consumption in the Bronze Age. During the Iron Age aquatic resources become more important in the diet of humans. The Prehistoric Atlantic Islanders of Scotland had a complex and dynamic relationship with aquatic resources, especially in the role of animal management that changed throughout the course of prehistory.The authorswould like to express thanks to NERC for funding this research (Grant number NE/F021054/1, PI Richard Evershed), and the NERC Life Sciences Mass Spectrometry Facility in East Kilbride (EK158- 03/10) for their financial assistance with the analytical researc

Ionizable Amphiphilic Dendrimer-Based Nanomaterials with Alkyl-Chain-Substituted Amines for Tunable siRNA Delivery to the Liver Endothelium In Vivo

A library of dendrimers was synthesized and optimized for targeted small interfering RNA (siRNA) delivery to different cell subpopulations within the liver. Using a combinatorial approach, a library of these nanoparticle-forming materials was produced wherein the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length, and evaluated for their ability to deliver siRNA to liver cell subpopulations. Interestingly, two lead delivery materials could be formulated in a manner to alter their tissue tropism within the liver—with formulations from the same material capable of preferentially delivering siRNA to 1) endothelial cells, 2) endothelial cells and hepatocytes, or 3) endothelial cells, hepatocytes, and tumor cells in vivo. The ability to broaden or narrow the cellular destination of siRNA within the liver may provide a useful tool to address a range of liver diseases.National Institutes of Health (U.S.) Centers of Cancer and Nanotechnology Excellence (Grant U54 CA151884)Armed Forces Institute of Regenerative Medicine (Grant W81XWH-08-2-0034)Alnylam Pharmaceuticals (Firm

Spatially explicit models of dynamic histories: examination of the genetic consequences of Pleistocene glaciation and recent climate change on the American Pika

A central goal of phylogeography is to identify and characterize the processes underlying divergence. One of the biggest impediments currently faced is how to capture the spatiotemporal dynamic under which a species evolved. Here, we described an approach that couples species distribution models (SDMs), demographic and genetic models in a spatiotemporally explicit manner. Analyses of American Pika ( Ochotona princeps ) from the sky islands of the central Rocky Mountains of North America are used to provide insights into key questions about integrative approaches in landscape genetics, population genetics and phylogeography. This includes (i) general issues surrounding the conversion of time‐specific SDMs into simple continuous, dynamic landscapes from past to current, (ii) the utility of SDMs to inform demographic models with deme‐specific carrying capacities and migration potentials as well as (iii) the contribution of the temporal dynamic of colonization history in shaping genetic patterns of contemporary populations. Our results support that the inclusion of a spatiotemporal dynamic is an important factor when studying the impact of distributional shifts on patterns of genetic data. Our results also demonstrate the utility of SDMs to generate species‐specific predictions about patterns of genetic variation that account for varying degrees of habitat specialization and life history characteristics of taxa. Nevertheless, the results highlight some key issues when converting SDMs for use in demographic models. Because the transformations have direct effects on the genetic consequence of population expansion by prescribing how habitat heterogeneity and spatiotemporal variation is related to the species‐specific demographic model, it is important to consider alternative transformations when studying the genetic consequences of distributional shifts.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92413/1/j.1365-294X.2012.05640.x.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/92413/2/MEC_5640_sm_FigureS3.pd

Amyloid as a Depot for the Formulation of Long-Acting Drugs

Amyloids are highly organized protein aggregates that are associated with both neurodegenerative diseases such as Alzheimer disease and benign functions like skin pigmentation. Amyloids self-polymerize in a nucleation-dependent manner by recruiting their soluble protein/peptide counterpart and are stable against harsh physical, chemical, and biochemical conditions. These extraordinary properties make amyloids attractive for applications in nanotechnology. Here, we suggest the use of amyloids in the formulation of long-acting drugs. It is our rationale that amyloids have the properties required of a long-acting drug because they are stable depots that guarantee a controlled release of the active peptide drug from the amyloid termini. This concept is tested with a family of short- and long-acting analogs of gonadotropin-releasing hormone (GnRH), and it is shown that amyloids thereof can act as a source for the sustained release of biologically active peptides

Interweaving Monitoring Activities and Model Development towards Enhancing Knowledge of the Soil-Plant-Atmosphere Continuum

The study of water pathways from the soil to the atmosphere through plants-the so-called soil-plant-atmosphere continuum (SPAC)-has always been central to agronomy, hydrology, plant physiology, and other disciplines, using a wide range of approaches and tools. In recent years, we have been witnessing a rapid expansion of interweaving monitoring activities and model development related to SPAC in climatic, ecological, and applications other than the traditional agrohydrological, and it is therefore timely to review the current status of this topic and outline future directions of research. The initiative for the special section of Vadose Zone Journal on SPAC emanated from several sessions we recently organized in international conferences and meetings. With a view to the specific research questions covered in this special section, this article introduces and reviews SPAC underlying issues and then provides a brief overview of the invited contributions. We have grouped together the 15 contributions under three main sections related to the local, field, and landscape spatial scales of interests. Within these sections, the papers present their innovative results using different measuring techniques (from classic tensiometers and TDR sensors to more advanced and sophisticated equipment based on tomography and geophysics) and different modeling tools (from mechanistic models based on the Richards equation to more parametrically parsimonious hydrologic balance models). They provide a snapshot of the current state of the art while emphasizing the significant progress attained in this field of research. New technological developments and applications are also highlighted