Role of Carrier Size, Hemodynamics and Hemorheology in the Efficacy of Vascular-Targeted Spherical Drug Carriers.

Spherical polymeric particles in the submicron down to tens nanometers size range are extensively proposed for use as vascular-targeted drug carriers (VTDCs); however, very limited studies have explored their capacity to efficiently localize and adhere to the vascular wall. The studies presented in this dissertation are focused on characterizing the role of particle size, blood flow dynamics (hemodynamics) and blood cells (hemorheology) on dictating the targeting (localization and binding) efficiency of VTDCs at the vascular wall in physiological human bulk blood flow via in vitro parallel plate flow assays. The presented results show that the binding efficiency of VTDCs is a function of particle size in all flow types (i.e. laminar, pulsatile and recirculating flow) and is strongly modulated by the presence of red blood cells (RBCs). Specifically, the migration of RBCs away from the wall under shear flow creating the RBC-free layer (CFL) at the wall vicinity where leukocytes and microspheres are disproportionally concentrated whereas nanospheres tend to get trapped within the RBC core. The binding of localized particle is either enhanced or hindered depending on the ratio of particle size to the CFL width that can vary with the volume fraction of RBCs (% Hct), blood vessel size and wall shear rate. White blood cells (WBCs) tend to hinder microsphere binding due to their collision with bound particles associated with their tethering on the vascular wall, which increases the drag force on particles leading to particle removal. Overall, the presented results suggest that intermediate-size microspheres, 2–5 micrometers, not nanospheres or large microspheres, are the optimal particle sizes for targeting the wall from human blood flow in medium to large-sized blood vessels relevant in several cardiovascular diseases. The relevance of the presented in vitro results were valid with ex vivo model of mouse blood where it is found that the subtle differences in RBC sizes and hemorheology among various animal models utilized in drug delivery research can differently manipulate the particle dynamics and their eventual adhesion in blood flow; thus, raising the awareness of possible result deviation from animal models to human.Ph.D.Chemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91589/1/phapanin_1.pd

Effect of excessive trichloroisocyanuric acid in swimming pool water on tooth erosion

The effect of chlorinated water on tooth erosion was studied. Tooth specimens were bathed in a pH cycling system of chlorinated water and artificial saliva under one of the following conditions: I) a 4 hour continuous cycle, and II) a 1 hour/ day cycle for 4 weeks. Each group was divided into four subgroups for testing in chlorinated water with pH of 2, 3, 4 or 5. Enamel loss and percentage of surface microhardness change (%SMC) were measured. After 4 hour, chlorinated water with pH 2, 3, 4 and 5 produced enamel loss of 1.4, 0.4, 0.0 and 0.0 micrometers, and %SMC was reduced by 57.2, 13.7, 2.9 and -0.2% respectively. After 4 weeks, erosion was recorded at 63.3, 1.0, 0.0 and 0.0 micrometers, and %SMC was reduced by 97.2, 52.1, 5.7 and 1.5%, respectively. The study revealed that the pH level of chlorinated water and the duration of exposure are important factors in enamel erosion

Laminar shear stress elicit distinct endothelial cell e‐selectin expression pattern via TNFα and IL‐1β activation

The ability to discriminate cell adhesion molecule expression between healthy and inflamed endothelium is critical for therapeutic intervention in many diseases. This study explores the effect of laminar flow on TNFα‐induced E‐selectin surface expression levels in human umbilical vein endothelial cells (HUVECs) relative to IL‐1β‐induced expression via flow chamber assays. HUVECs grown in static culture were either directly (naïve) activated with cytokine in the presence of laminar shear or pre‐exposed to 12 h of laminar shear (shear‐conditioned) prior to simultaneous shear and cytokine activation. Naïve cells activated with cytokine in static served as control. Depending on the cell shear history, fluid shear is found to differently affect TNFα‐induced relative to IL‐1β‐induced HUVEC expression of E‐selectin. Specifically, E‐selectin surface expression by naïve HUVECs is enhanced in the 8–12 h activation time range with simultaneous exposure to shear and TNFα (shear‐TNFα) relative to TNFα static control whereas enhanced E‐selectin expression is observed in the 4–24 h range for shear‐IL‐1β treatment relative to IL‐1β static control. While exposure of HUVECs to shear preconditioning mutes shear‐TNFα‐induced E‐selectin expression, it enhances or down‐regulates shear‐IL‐1β‐induced expression dependent on the activation period. Under dual‐cytokine‐shear conditions, IL‐1β signaling dominates. Overall, a better understanding of E‐selectin expression pattern by human ECs relative to the combined interaction of cytokines, shear profile and history can help elucidate many disease pathologies. Biotechnol. Bioeng. 2013; 110: 999–1003. © 2012 Wiley Periodicals, Inc. Naïve or shear‐preconditioned endothelial cell (EC) monolayers were exposed to TNFα or IL‐1β in static or in the presence of high laminar shear. Simultaneous presence of shear generally enhanced E‐selectin expression relative to static activation in naïve ECs in response to either TNFα or IL‐1β stimulation. Prior exposure to shear preconditioning mutes E‐selectin expression with shear‐TNFα activation, while enhancing or down‐regulating shear‐IL‐1b induced expression, dependent on the activation period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96255/1/24746_ftp.pd

IgA and IgM protein primarily drive plasma coronaâ induced adhesion reduction of PLGA nanoparticles in human blood flow

The high abundance of immunoglobulins (Igs) in the plasma protein corona on poly(lacticâ coâ glycolic) acid (PLGA)â based vascularâ targeted carriers (VTCs) has previously been shown to reduce their adhesion to activated endothelial cells (aECs) in human blood flow. However, the relative role of individual Ig classes (e.g., IgG, IgA, and IgM) in causing adhesion reduction remains largely unknown. Here, we characterized the influence of specific Ig classes in prescribing the binding efficiency of PLGA nanoâ sized VTCs in blood flow. Specifically, we evaluated the flow adhesion to aECs of PLGA VTCs with systematic depletion of various Igs in their corona. Adhesion reduction was largely eliminated for PLGA VTCs when all Igs were removed from the corona. Furthermore, reâ addition of IgA or IgM to the Igsâ depleted corona reinstated the low adhesion of PLGA VTCs, as evidenced by â ¼40â 70% reduction relative to particles with an Igsâ deficient corona. However, reâ addition of a high concentration of IgG to the Igsâ depleted corona did not cause significant adhesion reduction. Overall, the presented results reveal that PLGA VTC adhesion reduction in blood flows is primarily driven by high adsorption of IgA and IgM in the particle corona. Preâ coating of albumin on PLGA VTCs mitigated the extent of adhesion reduction in plasma for some donors but was largely ineffective in general. Overall, this work may shed light into effective control of protein corona composition, thereby enhancing VTC functionality in vivo for eventual clinical use.The high abundance of immunoglobulins (Igs) in the plasma protein corona formed on vascularâ targeted carriers (VTCs) has previously been shown to reduce their adhesion to activated endothelial cells. Here, we report that high adsorption of IgA and IgM, and not IgG, primarily drives VTC adhesion reduction in human blood flows.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137722/1/btm210064_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137722/2/btm210064.pd

Using robust statistical methodology to evaluate the performance of project delivery systems: A case study of horizontal construction

The objective of this study is to demonstrate the application of the bootstrapping M-estimator (a robust Analysis of Variance, ANOVA) to test the null hypotheses of means equality among the cost and schedule performance of the three project delivery systems (PDS). A statistical planned contrast methodology is utilized after the robust ANOVA analysis to further determine where the differences of the means lie. The results of this research concluded that traditional PDS (Design-Bid-Build, DBB) outperformed the two alternative PDS (“Design-Build (DB) and Construction Manager/General Contractor (CMGC)”), DBB and CMGC outperformed DB, and DBB outperformed CMGC, for the Cost Growth and the Change Order Cost Factor performance. On the other hand, alternative PDS (“DB & CMGC”) outperformed DBB, DB and CMGC (separately) outperformed DBB, and between the two alternative PDS, CMGC outperformed DB, for the Schedule Cost Growth performance. These findings can help decision makers/owners making an informed decision, regarding cost and schedule related aspects, when choosing PDS for their projects. Though the case study of this research is based on the sample data obtained from the construction industry, the same methodology and statistical process can be applied to other industries and factors/variables of interest when the study sample data are unbalanced and the normality and homogeneity of variance assumptions are violated

การเปรียบเทียบความถูกต้องของฐานฟันเทียมทั้งปากระหว่างผลิตด้วยวิธีการกลึงด้วยเทคนิคแคดแคมและการสร้างต้นแบบเร็ว (พิมพ์สามมิติ): การศึกษาในห้องปฏิบัติการ

Master of Science (Oral Health Sciences), 2022Background and objectives: With the advent of computer-aided design and computer-aided manufacturing, a novel technique for fabricating complete dentures has evolved. Digital complete denture fabrication can be accomplished by an additive or subtractive approach which minimal distortion during processing contributes to effective denture base adaption, which leads to good denture retention. The aim of this study was to compare the accuracy of milled and 3D-printed complete denture bases. Materials and Methods: The reference edentulous maxillary arch model was scanned to generate virtual denture bases using computer-aided manufacturing (CAD) software that exports as standard tessellation language (STL) files. Denture bases were constructed using a milling and printing technique called digital light processing (DLP) (10 specimens per technique). Denture bases' intaglio surfaces were scanned and superimposed on the reference model. The accuracy was quantified as root mean square error (RMSE) and evaluated statistically using independent T-test comparisons with a significance level of 0.05. Results: The measurement area was divided into three regions. Milled dentures were significantly more accurate than 3D-printed dentures in the overall intaglio area and primary bearing area of denture bases. Denture bases printed demonstrated significantly greater accuracy than milling dentures in the peripheral/posterior palatal seal area. Conclusion: According to the study's findings, milled dentures fit better in the overall and primary stress-bearing areas than 3D-printed dentures, while 3D-printed dentures appeared more accurate in the peripheral seal area.วัตถุประสงค์: การศึกษานี้ทําเพื่อเพื่อเปรียบเทียบความถูกต้องของฐานฟันเทียมทั้งปากผลิตด้วยวิธีการกลึงและการพิมพ์สามมิติ วัสดุและวิธีการ: นําแบบจําลองอ้างอิงสันเหงือกไร้ฟันบนมาแปลงข้อมูลดิจิทัลโดยสแกนด้วยเครื่องแสแกนนอกช่องปาก กลุ่มตัวอย่างทั้งหมด 20 ชิ้น แบ่งออกเป็น 2 กลุ่ม ได้แก่ ผลิตด้วยวิธีการกลึง และผลิตด้วยการพิมพ์สามมิติผลิตตามคําแนะนําของผู้ผลิต วัดความถูกต้องด้วยโปรแกรมสามมิติโดยการซ้อนทับเอสทีแอลไฟล์ระหว่างด้านเนื้อเยื่อของฟันเทียมและแบบจําลองอ้างอิง โดยแบ่งบริเวณออกเป็น 3 บริเวณ 1. บริเวณทั่วทั้งฐานฟันปลอม 105 จุด 2. บริเวณขอบโดยรอบและส่วนกั้นท้ายเพดาน 72 จุด และ 3. บริเวณส่วนรองรับปฐมภูมิ140 จุด วิเคราะห์ข้อมูลทางสถิติด้วยสถิติทดสอบที ผลการทดลอง: ในบริเวณทั่วทั้งฐานฟันเทียมการผลิตด้วยวิธีการกลึงให้ค่าความถูกต้อง 0.0964 ซึ่งดีกว่าวิธีการพิมพ์สามมิติให้ค่าความถูกต้อง 0.1219 ที่ระดับนัยสําคัญที่ p<0.001 ในบริเวณขอบโดยรอบและส่วนกั้นท้ายเพดานปากค่าความถูกต้องวิธีการพิมพ์สามมิติได้ค่าความถูกต้อง 0.1635 ซึ่งดีกว่าวิธีการกลึง 0.839 ที่ระดับนัยสําคัญที่ p=0.009 และบริเวณรองรับปฐมภูมิค่าความถูกต้องด้วยวิธีการกลึง 0.0207 ดีกว่าการผลิตด้วยวิธีพิมพ์สามมิติ0.0498 ที่ระดับนัยสําคัญที่ p<0.001 สรุปผลการทดลอง: การสร้างฐานฟันเทียมทั้งปากบนวิธีการกลึงมีค่าความถูกต้องที่ดีกว่าการพิมพ์สามมิติในบริเวณทั่วทั้งฐานฟันเทียมและบริเวณรองรับปฐมภูมิ ในขณะที่บริเวณขอบโดยรอบและส่วนกั้นท้ายเพดานปากการพิมพ์สามมิติให้ความถูกต้องที่ดีกว่

Design and application of multifunctional DNA nanocarriers for therapeutic delivery

The unique programmability of nucleic acids offers versatility and flexibility in the creation of self-assembled DNA nanostructures. To date, many three-dimensional DNA architectures have been precisely formed of varying sizes and shapes. Their biocompatibility, biodegradability, and high intrinsic stability in physiological environments emphasize their emerging use as carriers for drug and gene delivery. Furthermore, DNA nanocarriers have been shown to enter cells efficiently and without the aid of transfection reagents. A key strength of DNA nanocarriers over other delivery systems is their modularity and their ability to control the spatial distribution of cargoes and ligands. Optimizing DNA nanocarrier properties to dictate their localization, uptake, and intracellular trafficking is also possible. In this review, we present design considerations for DNA nanocarriers and examples of their use in the context of therapeutic delivery applications. The assembly of DNA nanocarriers and approaches for loading and releasing cargo are described. The stability and safety of DNA nanocarriers is also discussed, with particular attention to the in vivo physiological environment. Mechanisms of cellular uptake and intracellular trafficking are examined, and we conclude with strategies to enhance the delivery efficiency of DNA nanocarriers

Design and application of multifunctional DNA nanocarriers for therapeutic delivery

El tema que intentamos abordar en el presente trabajo en lo que supone simplemente una primera aproximación, es uno de los que mayor debate está provocando en los últimos años dentro del estudio de la cultura fenicio-púnica. En ella la cuestión de los rituales funerarios infantiles nos lleva directamente a los tofets y a la existencia de sacrificios de niños.También disponible en: http://hdl.handle.net/10234/4412

Aptamer-Targeted DNA Nanostructures for Therapeutic Delivery

[Image: see text] DNA-based nanostructures have been widely used in various applications due to their structural diversity, programmability, and uniform structures. Their intrinsic biocompatibility and biodegradability further motivates the investigation of DNA-based nanostructures as delivery vehicles. Incorporating AS1411 aptamers into DNA pyramids leads to enhanced intracellular uptake and selectively inhibits the growth of cancer cells, achieved without the use of transfection reagents. Furthermore, aptamer-displaying pyramids are found to be substantially more resistant to nuclease degradation than single-stranded aptamers. These findings, along with their modularity, reinforce the potential of DNA-based nanostructures for therapeutic applications