Engineering Commons^™

Voxel-Level Absorbed Dose Calculations With A Deterministic Grid-Based Boltzmann Solver For Nuclear Medicine And The Clinical Value Of Voxel-Level Calculations, Justin Mikell

Dissertations and Theses (Open Access)

Voxel-level absorbed dose (VLAD) is rarely calculated for nuclear medicine (NM) procedures involving unsealed sources or 90Y microspheres (YM). The current standard of practice for absorbed dose calculations in NM utilizes MIRD S-values, which 1) assume a uniform distribution in organs, 2) do not use patient specific geometry, and 3) lack a tumor model. VLADs overcome these limitations. One reason VLADs are not routinely performed is the difficulty in obtaining accurate absorbed doses in a clinically acceptable time. The deterministic grid-based Boltzmann solver (GBBS) was recently applied to radiation oncology where it was reported as fast and accurate for both …

Effects Of Growth Factor Supplementation And Environmental Conditions On Human Adipose-Derived Stem Cell Differentiation Towards Urothelial Lineage, James Turner

All Dissertations

In recent years, tissue engineering of the bladder has undergone many technological advances. Autologous urothelial cells have been used in animal models and have shown increased performance for ureteral reconstruction compared to unseeded grafts. However, since patients may lack a reliable source of native urothelial cells due to the nature of their specific bladder disease, autologous cells are not an ideal source clinically, and an alternate cell source must be explored. Adipose derived stem cells (ADSCs) are an attractive cell source for such regenerative medicine applications as they have been extensively studied for their multipotential differentiation, immunosuppressive properties, ease of …

Identifying And Predicting Rat Behavior Using Neural Networks, Jonathan A. Gettner

Master's Theses

The hippocampus is known to play a critical role in episodic memory function. Understanding the relation between electrophysiological activity in a rat hippocampus and rat behavior may be helpful in studying pathological diseases that corrupt electrical signaling in the hippocampus, such as Parkinson’s and Alzheimer’s. Additionally, having a method to interpret rat behaviors from neural activity may help in understanding the dynamics of rat neural activity that are associated with certain identified behaviors.

In this thesis, neural networks are used as a black-box model to map electrophysiological data, representative of an ensemble of neurons in the hippocampus, to a T-maze, …

Feasibility Of Using Raman-Based Techniques For Breast Cancer Detection, Sara Mollamohammada

Department of Civil and Environmental Engineering: Dissertations, Theses, and Student Research

Breast cancer is one of the common types of cancer among women all over the world. Early diagnosis is an effective way that improve the treatment process and gives the patients a better chance of survival. Many of the patients infected by breast cancer choose breast conservation surgery (BCS). However, some of those will be subjected to mastectomy, and many will have tumor recurrence as there is no precise technique to show the tumor margins. Raman-based methods are powerful techniques with potential to rapidly differentiate normal from tumor tissues and provides a solution to detect tumor margin. This is because …

Compounds Released From Biomass Deconstruction: Understanding Their Effect On Cellulose Enzyme Hydrolysis And Their Biological Activity, Angele Djioleu

Graduate Theses and Dissertations

The effect of compounds produced during biomass pretreatment on cellulolytic enzyme was investigated. Liquid prehydrolyzates were prepared by pretreating switchgrass using 24 combinations of temperature, time, and sulfuric acid concentration based on a full factorial design. Temperature was varied from 140°C to 180°C; time ranged from 10 to 40 min; and the sulfuric acid concentrations were 0.5% or 1% (v/v). Identified products in the prehydrolyzates included xylose, glucose, hydroxymethylfurfural (HMF), furfural, acetic acid, formic acid, and phenolic compounds at concentration ranging from 0 to 21.4 g/L. Pretreatment conditions significantly affected the concentrations of compounds detected in prehydrolyzates. When assayed in …

Storage Of Round And Square Switchgrass Bales: Effect Of Storage Time And Fungal Inoculation On Saccharification Efficiency, Noaa Frederick

Graduate Theses and Dissertations

To produce fermentable sugars from lignocellulosic biomass feedstock, severe pretreatment conditions are needed (either high acid concentration, temperature, or retention times). High severities can produce toxic byproducts which inhibit enzymatic hydrolysis or fermentation. In order to reduce pretreatment severities (and thus increase enzyme and fermentation efficiency), the white-rot fungus Pleurotus ostreastus was seeded into square and round bales of Kanlow switchgrass (Panicum virgastum L.) and left in the field over a period of 9 month. The laccase producing fungus is believed to selectively degrade lignin, a common plant structural polymer, which can function as an enzymatic inhibitor. Samples were taken …

Design And Development Of A Wearable Wireless Health Monitoring System: A Smart Watch Approach, Keerthi Paranikumar

Graduate Theses and Dissertations

According to Statistics, every year, about 610,000 people die because of heart disease in United States of America. (i.e. 1 in every 4 deaths.*) Heart disease is common for both men and women. Annually, about 370,000 people die because of coronary heart disease, which is the most common type of heart disease [1]. About 735,000 Americans have heart attack every year. In this, 210,000 people gets heart attack who already has heart problems and 525,000 people get heart attack for the first time [2]. Not many people know that they have heart problems. Around 47% of the people in United …

Retinal Architecture In ​Rgs9- And ​R9ap-Associated Retinal Dysfunction (Bradyopsia), Rupert W. Strauss, Adam M. Dubis, Robert F. Cooper, Rola Ba-Abbad, Anthony T. Moore, Andrew R. Webster, Alfredo Dubra, Joseph Carroll, Michel Michaelides

Biomedical Engineering Faculty Research and Publications

Purpose

To characterize photoreceptor structure and mosaic integrity in subjects with RGS9- and R9AP-associated retinal dysfunction (bradyopsia) and compare to previous observations in other cone dysfunction disorders such as oligocone trichromacy.

Design

Observational case series.

Methods

setting: Moorfields Eye Hospital (United Kingdom) and Medical College Wisconsin (USA). study population: Six eyes of 3 subjects with disease-causing variants in RGS9 or R9AP. main outcome measures: Detailed retinal imaging using spectral-domain optical coherence tomography and confocal adaptive-optics scanning light ophthalmoscopy.

Results

Cone density at 100 μm from foveal center ranged from 123 132 cones/mm²to 140 013 cones/mm^{2 …}

Increased Lower Limb Spasticity But Not Strength Or Function Following A Single-Dose Serotonin Reuptake Inhibitor In Chronic Stroke, Krishnaj Gourab, Brian D. Schmit, T. George Hornby

Biomedical Engineering Faculty Research and Publications

Objective: To investigate the effects of single doses of a selective serotonin reuptake inhibitor (SSRI) on lower limb voluntary and reflex function in individuals with chronic stroke.

Design: Double-blind, randomized, placebo-controlled crossover trial.

Setting: Outpatient research setting.

Participants: Individuals (N=10; 7 men; mean age ± SD, 57±10y) with poststroke hemiplegia of >1 year duration who completed all assessments.

Interventions: Patients were assessed before and 5 hours after single-dose, overencapsulated 10-mg doses of escitalopram (SSRI) or placebo, with 1 week between conditions.

Main Outcome Measures: Primary assessments included maximal ankle and knee isometric strength, and velocity-dependent (30°/s–120°/s) plantarflexor stretch reflexes under …

Biomineralization And Biocompatibility Studies Of Bone Conductive Scaffolds Containing Poly(3,4-Ethylenedioxythiophene):Poly(4-Styrene Sulfonate) (Pedot:Pss), Mostafa Yazdimamaghani, Mehdi Razavi, Masoud Mozafari, Daryoosh Vashaee, Hari Kotturi, Lobat Tayebi

Chemical and Biochemical Engineering Faculty Research & Creative Works

Considering the well-known phenomenon of enhancing bone healing by applying electromagnetic stimulation, manufacturing conductive bone scaffolds is on demand to facilitate the delivery of electromagnetic stimulation to the injured region, which in turn significantly expedites the healing procedure in tissue engineering methods. For this purpose, hybrid conductive scaffolds composed of poly(3,4-ethylenedioxythiophene), poly (4-styrene sulfonate) (PEDOT:PSS), gelatin (Gel), and bioactive glass (BaG) were produced employing freeze drying technique. Concentration of PEDOT:PSS were optimized to design the most appropriate conductive scaffold in terms of biocompatibility and cell proliferation. More specifically, scaffolds with four different compositions of 0, 0.1, 0.3 and 0.6 % …

Improved Sensitivity To Fluorescence For Cancer Detection In Wide-Field Image-Guided Neurosurgery, Michael Jermyn, Yoann Gosselin, Pablo A. Valdes, Mira Sibai, Kolbein Kolste

Dartmouth Scholarship

In glioma surgery, Protoporphyrin IX (PpIX) fluorescence may identify residual tumor that could be resected while minimizing damage to normal brain. We demonstrate that improved sensitivity for wide-field spectroscopic fluorescence imaging is achieved with minimal disruption to the neurosurgical workflow using an electron-multiplying charge-coupled device (EMCCD) relative to a state-of-the-art CMOS system. In phantom experiments the EMCCD system can detect at least two orders-of-magnitude lower PpIX. Ex vivo tissue imaging on a rat glioma model demonstrates improved fluorescence contrast compared with neurosurgical fluorescence microscope technology, and the fluorescence detection is confirmed with measurements from a clinically-validated spectroscopic probe. Greater PpIX …

Optofluidic Spectroscopy Platform For Detection Of Hemolysis, Edikan Archibong

USF Tampa Graduate Theses and Dissertations

In the United States alone, hundreds of millions of blood tests are performed annually, and a significant number of those tests are compromised due to hemolysis: e.g., 31% compromised in emergency rooms (inpatient) and 10% at blood banks, clinics, and other outpatient venues. Currently there is no way to reliably detect hemolysis without plasma separation. As a result, significant delays ensue, potentially negatively affecting patient diagnosis and treatment. In addition to in vitro hemolysis, which compromises the quality of blood tests, hemolysis can also occur in vivo. The in vivo occurrence of hemolysis is an indication of life-threatening complications. …

Calibration And Optimization Of 3d Digital Breast Tomosynthesis Guided Near Infrared Spectral Tomography, Kelly E. Michaelsen, Venkataramanan Krishnaswamy, Linxi Shi, Srinivasan Vedantham, Steven Poplack, Andrew Karellas, Brian Pogue, Keith Paulsen

Dartmouth Scholarship

Calibration of a three-dimensional multimodal digital breast tomosynthesis (DBT) x-ray and non-fiber based near infrared spectral tomography (NIRST) system is challenging but essential for clinical studies. Phantom imaging results yielded linear contrast recovery of total hemoglobin (HbT) concentration for cylindrical inclusions of 15 mm, 10 mm and 7 mm with a 3.5% decrease in the HbT estimate for each 1 cm increase in inclusion depth. A clinical exam of a patient's breast containing both benign and malignant lesions was successfully imaged, with greater HbT was found in the malignancy relative to the benign abnormality and fibroglandular regions (11 μM vs. …

Determination Of The Frequency Response Of An End Tidal Co2 Analyser, Kabita Shakya, Catherine Deegan, Fran Hegarty

The ITB Journal

In a health care environment, mechanical ventilation is used to support patients during acute illness and surgery. Mechanical ventilation is the process by which the patient’s respiratory function is artificially supported using a respirator. During mechanical ventilation, it is necessary to ensure the adequacy of ventilation. The patient is thus monitored for several ventilatory parameters. The end-tidal CO2 (EtCO2) is one of the primary monitoring parameters. EtCO2 is the partial pressure or maximal concentration of carbon dioxide (CO2) at the end of an exhaled breath, which is expressed as a percentage of CO2 or mmHg . Capnography is the technique …

Leveraging Large Data Sets In Continuous Chromatography Applications: Monitoring Critical Process Parameters Using Mvda, Engin Ayturk

Integrated Continuous Biomanufacturing II

Continuous multicolumn chromatography is gaining momentum in the industry as an enabling technology to establish continuous biomanufacturing platforms for monoclonal antibodies and recombinant proteins. Some companies are exploring continuous multicolumn chromatography processes as a stand-alone unit operation to improve specific productivity and/or reduce buffer consumption, while other companies are considering an integrated continuous downstream process based on continuous multicolumn chromatography.

One of the key features of continuous multicolumn chromatography is the amount of data generated during a single manufacturing batch or campaign. Traditional chromatography processes typically yield one (or a few) elution peaks per batch. Continuous chromatography processes, on the …

Cder's Emerging Technology Team, Kurt Brorson, Sau Lee

Integrated Continuous Biomanufacturing II

The newly formed Emerging Technology Team (ETT) draws membership from all CDER quality review, research and inspection functions, including Office of Biotechnology Products. The goal of the ETT is provide a primary point of contact for external inquiries regarding emerging technology in pharmaceutical and biotechnology manufacturing and quality control. The ETT will partner with review offices in a cross-functional manner and identify regulatory strategy and resolve roadblocks to new technologies relating to existing guidance, policy or practices related to review or inspection. The ETT’s initial focus will be innovation on novel products, manufacturing processes, or testing technologies or processes to …

Monitoring And Control Of Reproducibility In Quasi-Continuous Integrated Production Processes Of Active Pharmaceutical Ingredients, Reiner Luttman, Sven Oliver Borchert, Jan Patrick Voss, Gesine Cornelissen

Integrated Continuous Biomanufacturing II

The development of integrated production processes include the combination and transformation of current batch oriented unit operations into linked sequential/parallel production strategies.

The presented process starts with a two-stage upstream consisting of cell cultivation and subsequent protein production, which in turn results in a five step downstream process, consisting of cell clarification via a separator, retention of cellular debris using microfiltration, concentration of the secreted product by ultrafiltration with subsequent buffer exchange through diafiltration, followed by a final purification using column chromatography.

The three main operations cell breeding, protein production and the complete downstream line are running in series, but …

Exploring Continuous And Integrated Strategies For The Up- And Downstream Processing Of Human Mesenchymal Stem Cells, Barbara Cunha, Tiago Aguiar, Ricardo Silva, Cristina Peixoto, Manuel Carrondo, Margarida Serra, Paula Alves

Integrated Continuous Biomanufacturing II

The integration of up- and downstream unit operations can result in the elimination of hold steps, thus decreasing the footprint, and ultimately can create robust closed system operations. This type of design is desirable for the bioprocess of human mesenchymal stem cells (hMSC), where high numbers of pure cells, at low volumes, need to be delivered for therapy applications. The aim of this work is to perform a proof of concept of the integration of a continuous perfusion culture in bioreactors with a tangential flow filtration (TFF) system for the concentration and washing of hMSC. In particular, we have evaluated …

Pat Concepts For Chromatography: Real-Time Monitoring, Real-Time Control, And Cause Of Error Diagnostics, Nina Brestrich, Tobias Hahn, Adrian Sanden, Till Briskot, Jurgen Hubbuch

Integrated Continuous Biomanufacturing II

In the recent years, the growing competition in the biopharmaceutical industry due to biosimilars combined with market fluctuations and increasing product pipelines have given rise to the evaluation of continuous processing. Advantages include smaller equipment that may be disposable, an overall process intensification as well as steady-state operation. As variability should be managed by the continuous process itself to insure a consistent product quality, the development of advanced Process Analytical Technology (PAT) concepts is one crucial aspect for the implementation of continuous processing.

In chromatographic protein purification, process variability can lead to variations in retention volumes or peak shapes of …

Quality Systems For Continuous Manufacturing, Ron Branning

Integrated Continuous Biomanufacturing II

Continuous manufacturing is a familiar concept in large volume commercial commodity operations such as glass and plastic production. In the wake of the Tylenol cyanide poison scare in the 1970’s, pharmaceutical production at the J&J subsidiary McNeil converted to virtually closed, continuous manufacturing. Several Biotech firms tried to develop fermentation unit operations in the 1990’s that were based on the continuous manufacturing concept. Today there are a number of initiatives to update and realize the concept from bench top, such as MIT and Novartis’ sponsorship of start up firm Continuus’ production of solid dosage forms in Boston, to biodefense tractor-trailer …

Dynamic Oncolytic Measles Virus Production, Tanja Grein, Denise Salzig, Michael Muehlebach, Peter Czermak

Integrated Continuous Biomanufacturing II

Oncolytic viruses can be effective weapons against cancer with few treatment options. For example the tissue culture–adapted Edmonston strains of measles virus (MV) have altered its receptor specificity and became selectively oncolytic with attenuated pathogenicity. Russel et al. showed in 2014 full remission in an advanced stage multiple myeloma patient after systemic application of genetically modified MV. In this clinical trial, the patient was treated by intravenous infusion of 10¹¹ TCID₅₀ (50% tissue culture infectious dose) - of an engineered MV encoding human sodium iodide symporter. Appropriate medical treatment with oncolytic viruses calls for high concentrations and absolute …

Transforming The Present Into The Future With Uncertainty And Imprecision, Chales Cooney

Integrated Continuous Biomanufacturing II

No abstract provided.

How Continuous-Like Processes Improve Affordability For Viral Vaccines - Example Of Laiv, Jose Castillo

Integrated Continuous Biomanufacturing II

Designing a continuous process for a life viral vaccine could be seen useless, and challenging, as the virus infection will kill the cell substrate after 2-5 days of infection.

From the technical perspective, chaining the operations of cell culture under perfusion and viral production, clarification and capture / concentration is an efficient option to setup a small scale continuous automated process to manufacture massive amounts of viral vaccines.

We will show how beneficial it can be in terms of process development, manufacturing simplicity, capital expenditure and cost of production. Also, we will show how this approach can help producers of …

Advanced Computational Tools To Enhance Continuous Monoclonal Antibody Production, Maria M. Papathanasiou, Ana Quiroga, Athanasios Mantalaris, Efstratios Pistikopoulos

Integrated Continuous Biomanufacturing II

Leading pharmaceutical companies invest high percentage of their revenue in the improvement of existing technologies used for the production of monoclonal antibodies (mAbs). Recently, there has been a paradigm shift towards the development of continuous/quasi-continuous purification operations, aiming to reduce capital and operational costs [1]. At the moment, however, there are no standardized methods and/or tools that can be used for global control and monitoring of integrated processes.

Mathematical models and advanced computational tools can be the key for the development of robust, integrated processes, as they can provide valuable insight in the process dynamics and ensure optimal operation [2]. …

Protein Refinery Operations Lab (Pro Lab): A Sandbox For Continuous Protein Production & Advanced Process Control, Mark Brower, David Pollard, Finn Hung

Integrated Continuous Biomanufacturing II

Significant strides towards implementation of continuous bioprocessing are being made at an ever increasing rate. Advances in technology for traditional unit operations such as cell-retention devices in perfusion cell culture, continuous multi-column chromatography (CMCC) and single-pass tangential flow filtration have led to demonstrations of both semi-continuous and fully-continuous protein production processes operating at periodic steady states at the pilot-scale. Previous proof of concept work at Merck & Co., Inc. has shown an automated (DeltaV) and single-use monoclonal antibody (mAb) purification scheme through Protein A CMCC and pH viral inactivation with minimal human interaction for 30 days fed from a perfusion …

A Regulatory Perspective On Continuous Perfusion Production Of Rfviii, Robert Kozak

Integrated Continuous Biomanufacturing II

Continuous perfusion production has enabled flexible manufacturing of rFVIII, a large complex Biotech Product, for over two decades. Continuous improvement has driven frequent process, equipment and facility changes successfully performed utilizing comparability exercises.

Challenges in evaluating changes made to a continuous perfusion process includes assessment of impact to quality product attributes throughout the entire fermentation campaign which can be months in duration. Examples of process changes requiring more studies, those successfully supported by small scale development runs and API commercial characterization and an example resulting in non-implementation will be reviewed. Impact of changing Regulatory Environment on submission package requests will …

Small-Scale Platform For Rapid On-Demand Manufacturing Of Recombinant Proteins, J. Christopher Love

Integrated Continuous Biomanufacturing II

The current timeline for manufacturing high-quality recombinant proteins used for therapeutics and vaccines, and delivering them to patients, typically requires many months. There are many circumstances, however, where the rapid production, release, and delivery of these biologics could address unmet medical needs, including shortages, emergency situations, and pandemics. This talk will present a new platform developed to produce biologic medicines on demand called Integrated and Scalable Cyto-Technology (InSCyT). This platform comprises an integrated, subliter-scale portable system for the (semi)continuous operation of fermentation, filtration of cell debris from secreted product, innovative affinity-based purification, polishing, and finishing. This program also emphasizes integrated …

Regulatory Challenges Of Continuous Biomanufacturing, Andy Papas

Integrated Continuous Biomanufacturing II

The interaction with regulatory agencies on the biomanufacturing of therapeutic proteins, mAbs, or other large molecules occurs throughout the drug development of the biologic; it begins with the original IND, accelerates at the licensing phase and continues throughout the product’s life cycle. There are many regulatory challenges along this journey.

Because of uniqueness of continuous biomanufacturing, one challenge that occurs throughout the product’s lifecycle is the inevitable change in Agency product reviewers who many times need to be educated on the nuances of your process or have a different opinion or expectation on how things should be done. As such, …

2d Cine Dense With Low Encoding Frequencies Accurately Quantifies Cardiac Mechanics With Improved Image Characteristics, Gregory J. Wehner, Jonathan D. Grabau, Jonathan D. Suever, Christopher M. Haggerty, Linyuan Jing, David Powell, Sean M. Hamlet, Moriel H. Vandsburger, Xiaodong Zhong, Brandon K. Fornwalt

Biomedical Engineering Faculty Publications

BACKGROUND: Displacement Encoding with Stimulated Echoes (DENSE) encodes displacement into the phase of the magnetic resonance signal. The encoding frequency (k_e) maps the measured phase to tissue displacement while the strength of the encoding gradients affects image quality. 2D cine DENSE studies have used a k_e of 0.10 cycles/mm, which is high enough to remove an artifact-generating echo from k-space, provide high sensitivity to tissue displacements, and dephase the blood pool. However, through-plane dephasing can remove the unwanted echo and dephase the blood pool without relying on high k_e. Additionally, the high sensitivity comes …

Design And Control Of Chromatography Step In An Integrated Column Sequence, Bernt Nilsson, Niklas Andersson, Anders Holmqvist, Anton Sellberg, Peter Tiainen, Arne Staby

Integrated Continuous Biomanufacturing II

Integration of the purification steps in downstream processing is one way to minimize the number of storage tanks and reduce hold-up time. The result is an integrated column sequence that performs straight through processing of the target protein, with minimal time from expression to formulation. This paper discusses the overall integration design and its expected performance, together with a more detailed analysis of the step behavior based on column simulations. The optimal design of the individual steps in the sequence is presented, both with robustness margins and local control system, as well as with and without local recycle.

An optimization …