Assessing Chemokine Delivery Strategies for Neural Regenerative Medicine

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Description
Annually, approximately 1.7 million people suffer a traumatic brain injury (TBI) in the United States. After initial insult, a TBI persists as a series of molecular and cellular events that lead to cognitive and motor deficits which have no treatment.…

Annually, approximately 1.7 million people suffer a traumatic brain injury (TBI) in the United States. After initial insult, a TBI persists as a series of molecular and cellular events that lead to cognitive and motor deficits which have no treatment. In addition, the injured brain activates the regenerative niches of the adult brain presumably to reduce damage. The subventricular zone (SVZ) niche contains neural progenitor cells (NPCs) that generate astrocytes, oligodendrocyte, and neuroblasts. Following TBI, the injury microenvironment secretes signaling molecules like stromal cell derived factor-1a (SDF-1a). SDF-1a gradients from the injury contribute to the redirection of neuroblasts from the SVZ towards the lesion which may differentiate into neurons and integrate into existing circuitry. This repair mechanism is transient and does not lead to complete recovery of damaged tissue. Further, the mechanism by which SDF-1a gradients reach SVZ cells is not fully understood. To prolong NPC recruitment to the injured brain, exogenous SDF-1a delivery strategies have been employed. Increases in cell recruitment following stroke, spinal cord injury, and TBI have been demonstrated following SDF-1a delivery. Exogenous delivery of SDF-1a is limited by its 28-minute half-life and clearance from the injury microenvironment. Biomaterials-based delivery improves stability of molecules like SDF-1a and offer control of its release. This dissertation investigates SDF-1a delivery strategies for neural regeneration in three ways: 1) elucidating the mechanisms of spatiotemporal SDF-1a signaling across the brain, 2) developing a tunable biomaterials system for SDF-1a delivery to the brain, 3) investigating SDF-1a delivery on SVZ-derived cell migration following TBI. Using in vitro, in vivo, and in silico analyses, autocrine/paracrine signaling was necessary to produce SDF-1a gradients in the brain. Native cell types engaged in autocrine/paracrine signaling. A microfluidics device generated injectable hyaluronic-based microgels that released SDF-1a peptide via enzymatic cleavage. Microgels (±SDF-1a peptide) were injected 7 days post-TBI in a mouse model and evaluated for NPC migration 7 days later using immunohistochemistry. Initial staining suggested complex presence of astrocytes, NPCs, and neuroblasts throughout the frontoparietal cortex. Advancement of chemokine delivery was demonstrated by uncovering endogenous chemokine propagation in the brain, generating new approaches to maximize chemokine-based neural regeneration.
Date Created
2021
Agent

Characterization of Norbornene-Modified Cellulose Electrospun Fibers in Different Solvent Systems for Biomedical Applications

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Description

We utilized biomaterial scaffolds created from an electrospinning apparatus to create fibrous scaffolds with controllable morphology. To create consistent stable fibers, norbornene-modified cellulose acetate (nor-CA) was used as the polymer in solvent solutions of trifluoroacetic acid (TFA) and acetone/N,N-dimethylacetamide (DMAc).…

We utilized biomaterial scaffolds created from an electrospinning apparatus to create fibrous scaffolds with controllable morphology. To create consistent stable fibers, norbornene-modified cellulose acetate (nor-CA) was used as the polymer in solvent solutions of trifluoroacetic acid (TFA) and acetone/N,N-dimethylacetamide (DMAc). Solution rheology was used to determine a baseline for the nor-CA concentration used within each solvent system for electrospinning. The fibrous scaffolds were analyzed for morphology and fiber size using scanning electron microscopy. Increased fiber stability and decreased beading was found with higher concentrations of nor-CA for each solvent system. TFA appeared to be the most versatile as it was able to form fibers without beads at concentrations of 15%, 18%, and 21% nor-CA, with the most stable and uniform fibers at 21% nor-CA. This solvent had a conductivity measurement of 0.98 mS. DMAc/acetone had a much higher conductivity measurement and increased beading at lower concentrations of nor-CA.

Date Created
2022-05
Agent

Biologics in Treating Tendinopathies: Perception Versus Truth in the Eyes of College-Level Athletes

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Description
Biological therapies are substances made from living organisms used to treat disease or injury. Common biologic therapies today include platelet rich plasma injections (PRP), stem cell therapy, and growth factor therapy. Ever since their emergence just over a decade ago,…

Biological therapies are substances made from living organisms used to treat disease or injury. Common biologic therapies today include platelet rich plasma injections (PRP), stem cell therapy, and growth factor therapy. Ever since their emergence just over a decade ago, biological treatments have been used to treat a variety of conditions including tendonitis. Tendonitis commonly affects athletes of all levels and is the inflammation or irritation of a tendon that leads to pain and tenderness. Despite the potential promise of biological treatments in treating persistent injuries like tendonitis, there is not a consensus in the scientific community on their effectiveness in treating non-surgical injuries. However, many athletes still seek these forms of treatment. Currently, there are many unknowns regarding how up and coming high-level athletes perceive biologics, if they understand what biologics are, how they’re learning about biologics, and what type of injuries they believe should warrant biologics treatment. Here we show that the majority of high-level collegiate athletes at Arizona State University (ASU) know what biological therapies are, but do not possess accurate information about their effectiveness and medical use. We found through a survey sent out to the student athletes at ASU that while athletes are familiar with PRP and stem cell injections, they are primarily learning about them from potentially unreliable sources such as social media, friends, and family. Further, student athletes falsely perceive biologics are commonly used in physician treatment protocols for persistent tendonitis and are recommended to athletes months earlier than in reality. Our results demonstrate that high-level collegiate athletes do have a misperception on the effectiveness of biological treatments and that further education is needed for athletes about the truth and myths of biologics.
Date Created
2022-05
Agent

Characterization of Hyaluronic Acid Shear Thinning Hydrogels Towards Neural Cell Applications

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Description

Traumatic brain injury (TBI) is a widespread health issue that affects approximately 1.7 million lives per year. The effects of TBI go past the incident of primary injury, as chronic damage can follow for years and cause irreversible neurodegeneration. A…

Traumatic brain injury (TBI) is a widespread health issue that affects approximately 1.7 million lives per year. The effects of TBI go past the incident of primary injury, as chronic damage can follow for years and cause irreversible neurodegeneration. A potential strategy for repair that has been studied is cell transplantation, as neural stem cells improve neurological function. While promising, neural stem cell transplantation presents challenges due to a relatively low survival rate post-implantation and issues with determining the optimal method of transplantation. Shear-thinning hydrogels are a type of hydrogel whose linkages break when under shear stress, exhibiting viscous flow, but reform and recover upon relaxation. Such properties allow them to be easily injected for minimally invasive delivery, while also shielding encapsulated cells from high shear forces, which would normally degrade the function and viability of such cells. As such, it is salient to research whether shear-thinning hydrogels are feasible candidates in neural cell transplantation applications for neuroregenerative medicine. In this honors thesis, shear-thinning hydrogels were formed through guest-host interactions of adamantane modified HA (guest ad-HA) and beta-cyclodextrin modified HA (host CD-HA). The purpose of the study was to characterize the injection force profile of different weight percentages of the HA shear-thinning hydrogel. The break force and average glide force were also compared between the differing weight percentages. By understanding the force exerted on the hydrogel when being injected, we could characterize how neural cells may respond to encapsulation and injection within HA shear-thinning hydrogels. We identified that 5% weight HA hydrogel required greater injection force than 4% weight HA hydrogel to be fully delivered. Such contexts are valuable, as this implies that higher weight percentage gels impart higher shear forces on encapsulated cells than lower weight gels. Further study is required to optimize our injection force system’s sensitivity and to investigate if cell encapsulation increases the force required for injection.

Date Created
2021-05
Agent

Electrospun Pretreatment Membranes

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Description
Managing water resources has become one of the most pressing concerns of scientists both in academia and industry. The reverse osmosis (RO) water treatment process is a well-researched technology among the pressure driven processes to produce potable water. RO is…

Managing water resources has become one of the most pressing concerns of scientists both in academia and industry. The reverse osmosis (RO) water treatment process is a well-researched technology among the pressure driven processes to produce potable water. RO is an energy intensive process and often RO membranes are susceptible to fouling and scaling that drives up operational cost and hinder the efficiency. To increase the performance of RO membranes the feed water is pretreated to remove pollutants before desalination. This work aims to fabricate pretreatment membranes to prevent the effects of fouling and scaling by introducing hydrophilic character to membrane. This work explores electrospinning, a cost-effective and scalable technique, to blend two polymers into a nonwoven membrane comprised of fibers ~100 nm - 10 µm in diameter.

A rotary drum collector holding the mat was used to simultaneously collect the electrospun hydrophobic poly(vinyl chloride) (PVC) and hydrophilic poly(vinyl alcohol) (PVA) fibers from two separate solutions. The hydrophilicity of the resulting membrane was tuned by controlling the relative deposition rate of PVA onto the co-spun mat. Fiber diameter and morphologies were characterized by scanning electron microscopy, and Fourier-transform infrared spectroscopy and Confocal fluorescence microscopy further confirmed the presence of both polymers. Moreover, a rigorous analysis to map the PVA/PVC concentration was established to accurately report the relative concentrations of the two polymers on the co-spun mat. After electrospinning, the PVA in the co-spun mats were cross-linked with poly(ethylene glycol) diacid to impart mechanical strength and tune the porosity.

EDS analysis revealed inconsistencies in the mass deposition of both polymers suggesting an improvement in the current experimental design to establish a meaningful relationship between PVA concentration and hydrophilicity. However, tensile test revealed that co-spun mats with high mass flow ratios of PVA possessed high mechanical strength showing a significant improvement in the Young’s Modulus. Furthermore, the co-spun mats were challenged with filtration experiments expecting a positive correlation of flux with PVA concentration. But it was found that with increased concentration, crosslinked PVA constricted PVC fibers minimizing the pores causing a lower flux and a dense membrane structure suitable for filtration.
Date Created
2020
Agent

Reflections on Engineering School from Practicing Engineers

Description
This study was conducted to look for ways to improve engineering school in order to maximize student benefit. The results of the survey showed that additional communication and professional interaction lessons as well as more emphasis on software and…

This study was conducted to look for ways to improve engineering school in order to maximize student benefit. The results of the survey showed that additional communication and professional interaction lessons as well as more emphasis on software and programming languages would help prepare engineers for their careers. There was unanimous support of communication materials from survey respondents, with constructive confrontation and career path discussion receiving the most positive feedback. Due to the unanimous support of communications material, and the fact that short communications lessons could drive home key points without adding too much work to engineering students’ already busy schedules, two short lesson outlines for constructive confrontation and career path discussion were produced for this study.
Date Created
2020-12
Agent

Multifunctional Soft Materials: Design, Development and Applications

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Description
Soft materials are matters that can easily deform from their original shapes and structures under thermal or mechanical stresses, and they range across various groups of materials including liquids, foams, gels, colloids, polymers, and biological substances. Although soft materials already…

Soft materials are matters that can easily deform from their original shapes and structures under thermal or mechanical stresses, and they range across various groups of materials including liquids, foams, gels, colloids, polymers, and biological substances. Although soft materials already have numerous applications with each of their unique characteristics, integrating materials to achieve complementary functionalities is still a growing need for designing advanced applications of complex requirements. This dissertation explores a unique approach of utilizing intermolecular interactions to accomplish not only the multifunctionality from combined materials but also their tailored properties designed for specific tasks. In this work, multifunctional soft materials are explored in two particular directions, ionic liquids (ILs)-based mixtures and interpenetrating polymer network (IPN).

First, ILs-based mixtures were studied to develop liquid electrolytes for molecular electronic transducers (MET) in planetary exploration. For space missions, it is challenging to operate any liquid electrolytes in an extremely low-temperature environment. By tuning intermolecular interactions, the results demonstrated a facile method that has successfully overcome the thermal and transport barriers of ILs-based mixtures at extremely low temperatures. Incorporation of both aqueous and organic solvents in ILs-based electrolyte systems with varying types of intermolecular interactions are investigated, respectively, to yield optimized material properties supporting not only MET sensors but also other electrochemical devices with iodide/triiodide redox couple targeting low temperatures.

Second, an environmentally responsive hydrogel was synthesized via interpenetrating two crosslinked polymer networks. The intermolecular interactions facilitated by such an IPN structure enables not only an upper critical solution temperature (UCST) transition but also a mechanical enhancement of the hydrogel. The incorporation of functional units validates a positive swelling response to visible light and also further improves the mechanical properties. This studied IPN system can serve as a promising route in developing “smart” hydrogels utilizing visible light as a simple, inexpensive, and remotely controllable stimulus.

Over two directions across from ILs to polymeric networks, this work demonstrates an effective strategy of utilizing intermolecular interactions to not only develop multifunctional soft materials for advanced applications but also discover new properties beyond their original boundaries.
Date Created
2020
Agent

Controlling the Electrospun Scaffold Profile at the Interface between Varying Fiber Alignment

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Description
Musculoskeletal heterogenous tissues are crucial for dissipating mechanical load during physical activity. Modern procedures to repair these tissues have proven inadequate to restore full functionality, thus there is a need for alternative reconstructive methods. Consequently, tissue engineered scaffolds can mimic…

Musculoskeletal heterogenous tissues are crucial for dissipating mechanical load during physical activity. Modern procedures to repair these tissues have proven inadequate to restore full functionality, thus there is a need for alternative reconstructive methods. Consequently, tissue engineered scaffolds can mimic the native structure of tissues and trigger a healing response. Heterogenous tissues like the tendon-bone junction consist of an interdigitated fiber alignment gradient from the tendon to the bone. It has been shown that electrospun fiber alignment gradients can be fabricated from the incorporation of magnetic fields. In this study, manipulating electrostatic and magnetic interactions from various electrospinning collector arrangements were investigated for creating an interdigitated fiber alignment gradient. The collector arrangement consisting of a magnet overlaid with razor cut aluminum foil proved to provide increased control over the interfacial shape. The rapid transition at the interfacial region was verified with brightfield microscopy revealing an interdigitated gradient from highly aligned fibers to unaligned fibers.
Date Created
2020-05
Agent

Controlling Calcium Binding on NorHA Scaffolds using a Biomineralization Peptide

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Description
The tendon-bone junction is essential for allowing humans to transfer mechanical loads during activities. When injury does occur to this important area, current surgical techniques improperly bypass important physical and chemical gradients and do not restore proper function. It is…

The tendon-bone junction is essential for allowing humans to transfer mechanical loads during activities. When injury does occur to this important area, current surgical techniques improperly bypass important physical and chemical gradients and do not restore proper function. It is essential to create tissue engineered scaffolds that create proper models for the region and induce healing responses for repair. To advance research into these scaffolds, electrospinning fibers and hydrogels made of norbornene functionalized hyaluronic acid (NorHA) were used to promote bone growth by adhering calcium to the material. To further improve calcium adherence, which is indicative of bone regions, a mineralization peptide was allowed to soak through the fibers. NorHA proved to be a suitable material for biomineralization experiments, showing slow calcium adherence within the first hour before accelerating in adherence over 24 hours in both fibers and hydrogels. When the mineralization peptide was implemented calcium adherence on fibers increased nearly eight times within the first 15 minutes of experimentation.
Date Created
2020-05
Agent

Laser-Activated Nanomaterials for Tissue Repair

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Description
Tissue approximation and repair have been performed with sutures and staples for centuries, but these means are inherently traumatic. Tissue repair using laser-responsive nanomaterials can lead to rapid tissue sealing and repair and is an attractive alternative to existing clinical…

Tissue approximation and repair have been performed with sutures and staples for centuries, but these means are inherently traumatic. Tissue repair using laser-responsive nanomaterials can lead to rapid tissue sealing and repair and is an attractive alternative to existing clinical methods. Laser tissue welding is a sutureless technique for sealing incised or wounded tissue, where chromophores convert laser light to heat to induce in tissue sealing. Introducing chromophores that absorb near-infrared light creates differential laser absorption and allows for laser wavelengths that minimizes tissue damage.

In this work, plasmonic nanocomposites have been synthesized and used in laser tissue welding for ruptured porcine intestine ex vivo and incised murine skin in vivo. These laser-responsive nanocomposites improved tissue strength and healing, respectively. Additionally, a spatiotemporal model has been developed for laser tissue welding of porcine and mouse cadaver intestine sections using near-infrared laser irradiation. This mathematical model can be employed to identify optimal conditions for minimizing healthy cell death while still achieving a strong seal of the ruptured tissue using laser welding. Finally, in a model of surgical site infection, laser-responsive nanomaterials were shown to be efficacious in inhibiting bacterial growth. By incorporating an anti-microbial functionality to laser-responsive nanocomposites, these materials will serve as a treatment modality in sealing tissue, healing tissue, and protecting tissue in surgery.
Date Created
2019
Agent
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