PRISM :: Browsing by Author "Sen, Arindom"

Browsing by Author "Sen, Arindom"

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Allogeneic Adipose-Derived Mesenchymal Stem Cells as an Adjunct to Endovascular Treatment of Intracranial Aneurysms
(2023-06) Belanger, Brooke Lynnae; Mitha, Alim; Sen, Arindom; Liao, Shan; Ungrin, Mark
Intracranial aneurysms are a condition characterized by the weakening of blood vessels in the brain, affecting approximately 1 in 5 individuals. Rupture of these fragile blood vessels can result significant brain bleeding, also known as subarachnoid hemorrhage, leading to a stroke that can cause severe neurological deficits or death. Current treatment approaches involve either endovascular or open surgery. One of the most common treatments is endovascular surgery, a minimally invasive procedure that entails inserting a small catheter through the femoral or radial artery and navigating it to the location of the aneurysm in the brain. Depending on the anatomical features, the aneurysm sac is filled with small platinum coils, or a mesh metal stent which is placed to cover the aneurysm opening. The objective in both cases is to redirect blood flow and eliminate the risk of stroke. However, recurrent aneurysms occur in up to 30% of these procedures, necessitating multiple surgeries. Recent advancements have introduced novel endovascular devices such as bioresorbable stents to enhance the outcomes of aneurysm treatment. Additionally, allogeneic adult mesenchymal stem cells have shown promise in improving healing processes. This dissertation aims to expand our understanding of the impact of stem cells on aneurysm healing and how they can be effectively utilized to improve the outcomes of brain aneurysm treatments, including endovascular coiling and stenting.
Open Access
Biomaterials for intervertebral disc repair
(2012-07-24) Lee, Haeyeon; Sen, Arindom
Each intervertebral disc (IVD) in the spine has an inner gel-like nucleus pulposus (NP) surrounded by an outer annulus fibrosus (AF). IVD degeneration has been linked to low back pain, a medical condition that affects millions of people and has significant socioeconomic consequences. The goal of this study was to assess the properties of different biomaterials to determine their utility in IVD repair strategies. Different compositions of gellan gum were investigated for NP repair. Through optimization of gellan gum properties, it was found that 2% (w/v) low acyl gellan gum had the best mechanical properties while having a suitable gelling temperature for cell encapsulation. When gellan gum, fibrin, and chitosan/gelatin/glycerol phosphate hydrogels were compared for sealing defects in the AF, it was found none could withstand pressures as high as intact IVDs. Therefore, a triphasic prototype construct composed of Kryptonite bone cement, gellan gum, and reinforcing fibre was evaluated to determine if it could contribute to AF repair. Whereas, it was found that constructs with sutures had better tensile properties than those with electrospun fibres, overall the current generation of constructs was not sufficient for AF repair. This thesis represents an important step in understanding the use of biomaterials for IVD repair.
Open Access
Bioprocessing of human bone marrow mesecnchymal stem cells for the treatment of intervertebral disc degeneration
(2012) Yuan, Yifan; Kallos, Michael S.; Sen, Arindom
Lower back pain is a major medical problem in North America. From the biological point of view, the degeneration of intervertebral disc may be the main cause for lower back pain. The current study focused on using stem cell to differentiation into large number of healthy intervertebral disc cells. Human bone marrow mesenchymal stem cells (hBMMSCs) were used. This project has been divided into two parts: I. hBM-MSCs expansion, 2. hBM-MSCs differentiation. Experiments were carried out manipulating culture medium components ( oxygen tension, calcium, serum, pH) and agitation to improve the expansion of hBM-MSCs in bioreactors. After 33 days of culture under the developed protocol, approximately I 03 fold increase over the inoculation density had been obtained in suspension bioreactor culture. The differentiation of MSCs to nucleus pulposus-like cells was performed by using multiple growth factor cocktails and notochordal conditioned medium. There was higher expression of genes and proteins specific for nucleus pulposus cells, after exposure of MSCs to conditioned medium over 21 days than in basal medium.
Open Access
Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics
(2018-09-12) Phelps, Jolene; Sanati-Nezhad, Amir; Ungrin, Mark; Duncan, Neil A.; Sen, Arindom
Mesenchymal stem cells (MSCs) have attracted tremendous research interest due to their ability to repair tissues and reduce inflammation when implanted into a damaged or diseased site. These therapeutic effects have been largely attributed to the collection of biomolecules they secrete (i.e., their secretome). Recent studies have provided evidence that similar effects may be produced by utilizing only the secretome fraction containing extracellular vesicles (EVs). EVs are cell-derived, membrane-bound vesicles that contain various biomolecules. Due to their small size and relative mobility, they provide a stable mechanism to deliver biomolecules (i.e., biological signals) throughout an organism. The use of the MSC secretome, or its components, has advantages over the implantation of the MSCs themselves: (i) signals can be bioengineered and scaled to specific dosages, and (ii) the nonliving nature of the secretome enables it to be efficiently stored and transported. However, since the composition and therapeutic benefit of the secretome can be influenced by cell source, culture conditions, isolation methods, and storage conditions, there is a need for standardization of bioprocessing parameters. This review focuses on key parameters within the MSC culture environment that affect the nature and functionality of the secretome. This information is pertinent to the development of bioprocesses aimed at scaling up the production of secretome-derived products for their use as therapeutics.
Open Access
Bioreactor protocols for the long-term expansion of mammalian neural stem cells in suspension culture
(2003) Sen, Arindom; Behie, Leo A.
Open Access
Can Mesenchymal Stem Cells Inhibit the Formation of Saccular Aneurysms?
(2017) Avery, Michael B; Sen, Arindom; Mitha, Alim P.; Rinker, Kristina; Eesa, Muneer
Intracranial saccular aneurysms are pathological dilations of cerebral blood vessels that can spontaneously rupture leading to significant morbidity and mortality. Our current understanding of saccular aneurysm pathogenesis involves a complex interplay of predisposing factors and inflammatory cascades, leading to an outpouching at the site of a vessel bifurcation. While several treatments exist today, none are aimed at preventing aneurysm formation. Mesenchymal stem cells are pluripotent cells that have interesting immunomodulatory properties and have been studied in the context of many inflammatory diseases. Few studies have addressed aneurysms and suggest that these cells have the potential to be adjuvants to current treatment modalities in treating fully formed aneurysms. This thesis details the first studies investigating the use of mesenchymal stem cells in preventing the formation of saccular aneurysms. A pre- clinical trial was conducted, as well as an in vivo localization experiment to determine the potential mechanism of action.
Open Access
Cellular Therapy for Saccular Intracranial Aneurysms: A Proof-of-Concept Study
(2015-09-23) Adibi, Mohammad Amin; Sen, Arindom; Mitha, Alim
Intracranial aneurysms are pathological dilations of arteries in the brain. Rupture of an aneurysm would be catastrophic, resulting in death in half of the cases and permanent neu- rological deficits in half of the survivors. The current standard-of-care for treating aneurysms is endovascular coiling, a procedure that involves packing the aneurysm with soft platinum- made coils that cause the blood within the aneurysm to clot, consequently slowing the flow of blood into the aneurysm. This is followed by a healing response that remodels the clot into fibrous tissue and regenerates a neointima layer that covers the neck of the aneurysm and isolates it from the parent vessel. Lack of proper healing in about one-fifth of the patients results in recurrence of the aneurysm. Building on a growing body of literature, this project evaluated the potential therapeutic effects of mesenchymal stem/stromal cells (MSCs) on the healing of coiled aneurysms in a rabbit model.
Open Access
Characterization of Proteoglycan 4 Supramolecular Structure and its Effect on Lubricating Function
(2018-09-14) Martens, Kayla; Schmidt, Tannin; MacCallum, Justin; Derksen, Darren; Sen, Arindom
Proteoglycan 4 (PRG4) is a mucin-like glycoprotein that is a key synovial fluid constituent, functioning as a cartilage boundary lubricant. PRG4 has been suggested to exist as a supramolecular structure. The objectives of this thesis were to (1) characterize the supramolecular structure of recombinant human PRG4 (rhPRG4) and its dependency on concentration, (2) elucidate the molecular forces underlying the formation of the supramolecular structure, and (3) assess the lubricating ability of the supramolecular structure. rhPRG4’s ability to form a supramolecular structure and reduce friction was concentration dependent. Arginine (0.2M) disrupted the formation of the supramolecular structure of rhPRG4 and diminished its lubricating ability. Conversely, 20 mM calcium enhanced the formation of rhPRG4 supramolecular structure and enhanced its lubricating ability. These results suggest non-covalent interactions mediate rhPRG4’s supramolecular structure, shown here to exist for the first time, which in turn is a functionally (lubrication) determinant property.
Open Access
Development of culture protocols for the production of synovium-derived precursor cells
(2010) Dry, Helen C.; Sen, Arindom
Open Access
Development of suspension culture protocols to expand populations of adult human stem cells from synovial fluid
(2012) Jorgenson, Kristen; Sen, Arindom
Synovial fluid (SF) contains a population of mesenchymal stem cells (MSCs) with the capacity to generate cartilage, and as such may play a role is new treatment approaches for cartilage disorders. However, it is necessary to generate clinically-relevant numbers of these cells in a scalable and reproducible culture system. This study used three donors to evaluate microcarrier technology to expand populations of adult human SFÂderived MSCs. Inoculation and growth protocols developed showed that an increase in cell to microcarrier ratio and using a fed batch culture system had the greatest impact in increasing the final cell yield. With the improved suspension culture protocol, a maximum cell density of 1.89 x 105 cells/ml was achieved compared with 1.12 x 105 cells/ml obtained in static culture. Additionally, serial propagation in microcarrier suspension bioreactors achieved a 21.3 cell fold increase after 18 days in culture. Characterization of SF-derived MSCs showed that the cells maintained their defining characteristics.
Open Access
Enzymatic degradation of carboxymethyl cellulose – A biotechnological approach for hydraulic fracturing operations
(2019-12-19) Scheffer, Gabrielle; Gieg, Lisa Marie; Ng, Kenneth Kai Sing; Sen, Arindom
Carboxymethyl cellulose (CMC) is a polymer used in different industrial sectors. In the oil and gas industry, CMC is often used during hydraulic fracturing (fracking) operations as a thickening agent helping for proppant delivery. Accumulations of CMC at fracture faces (filter cakes) can impede oil and gas recovery. Although chemical oxidizers are added to disrupt these accumulations, there is industrial interest in developing alternative, enzyme-based treatments. Little is known about whether CMC can be biodegraded under fracking conditions. Here, we enriched a methanogenic CMC-degrading culture, and demonstrated its ability to express extracellular enzymes able to utilize CMC under various conditions that typify oil fields. Finally, isolation and purification of the enzymes allowed for complete degradation of the polymer within 3 h, and allowed for the identification of putative purified cellulases. This study demonstrates that enzyme technology holds great promise as a viable approach to treating CMC filter cakes under field conditions.
Open Access
Evaluating the capacity of adult human mesenchymal stem cells to differentiate into insulin-producing cells in vitro
(2008) Ratanshi, Imran; Sen, Arindom
Open Access
Gaseous BTEX Biofiltration: Experimental and Numerical Study of Dynamics, Substrate Interaction and Multiple Steady States
(2018-01) Süß, Michael; De Visscher, Alex; Sen, Arindom; Siegler, Hector; Gieg, Lisa
Air pollution has a global impact on the environment and human health. In recent decades growing consciousness of air pollutants has led to a substantial decline in hazardous emissions. Nevertheless, air quality problems persist. A group of pollutants of particular concern are benzene, toluene, ethylbenzene and xylene, commonly referred to as BTEX. BTEX are known for their adverse effects on human health such as the carcinogenicity of benzene among others. Continuous development, improvement and exploring of new innovative control technologies are of great importance and striven for by researchers and industry. Biological methods such as biofilters are considered to be a sustainable and environmentally friendly technology. Hence, the present dissertation investigated the employment of a promising microorganism, Nocardia sp., to treat BTEX in a biofilter as well as the experimental and computational study of different steady states. At an empty-bed residence time (EBRT) of 1.5 min and an inlet concentration between 0.05 – 0.14 g m- 3 single benzene, toluene, ethylbenzene and m-xylene were removed with an efficiency of 100%, 93%, 96% and 87% respectively. With increasing inlet concentration, the removal efficiency (RE) declined, however an increase of EBRT generally resulted in higher RE. A similar trend was observed when BTEX were treated as a mixture and highest RE were achieved at low concentrations. In addition, the determination of kinetic parameters of the microorganism were carried out and the threshold substrate concentration for benzene and m-xylene were estimated. The exploration of a possible jump of steady states were numerically examined by considering only the biofilm. Therefore, two independent computer simulations were developed, which includes diffusion limitation and substrate degradation following Haldane kinetics. Results clearly indicate a jump of steady states in a very small range of inlet concentration and a distortion of prevailing Haldane kinetics. A further development of one model was carried out and aforementioned determined kinetic parameters were applied. This model correctly described the jump of steady states in an actual biofilter at a concentration change of 0.272 g m-3. Obtained results are supported by experimental validation.
Open Access
Generation of Tissue-Engineered Cartilage Constructs in Stirred Suspension Bioreactors
(2016) Allen, Leah Marie; Sen, Arindom; Hart, David; Matyas, John; Ungrin, Mark; Schmidt, Tannin; Ramirez-Serrano, Alejandro
Traumatic injuries to articulating joints, such as the knee and hip, can result in the formation of defects within the articular cartilage contained therein. These defects do not heal spontaneously and can initiate a degenerative process, eventually resulting in osteoarthritis (OA). Current cartilage repair options are limited and do not result in the regeneration of durable cartilage. Mesenchymal stem cells (MSCs) isolated from the synovial fluid within joints have an inherent ability to differentiate towards a chondrogenic lineage. Tissue engineered cartilage constructs (TECs) formed from MSCs have been shown to contribute to cartilage repair when implanted into a defect site, thereby providing a potential approach to prevent the onset or the progression of OA. TECs have traditionally been formed in the wells of static culture plates and serum-containing medium. Unfortunately, TECs made in this manner can exhibit variable characteristics which are likely exacerbated by the use of animal-sourced serum in the medium. Therefore, a need still exists to better optimize the generation of uniform TECs to enhance the clinical translatability of this otherwise promising technology. This work investigated the aggregation and culture of human MSCs within suspension bioreactors and serum-free culture conditions for eventual use in filling articular cartilage defects. It also investigated the impact of low-oxygen tension and chondrogenic medium to enhance the MSC differentiation into a chondrogenic phenotype. Expanding on a body of knowledge, this work demonstrated the ability of suspension bioreactors to create a population of aggregates using serum-free culture conditions and non-osteoarthritic human SF-MSCs. Additionally, it demonstrated that the application of low-oxygen tension and chondrogenic growth factors to the suspension bioreactor system is simple. The culture of MSC aggregates in suspension bioreactors under low-oxygen tension resulted in up-regulated gene expression for aggrecan, significantly more collagen/DNA production, and less necrosis on the inside of the aggregates as compared to ambient oxygen tension. The application of chondrogenic medium to the aggregates in the suspension bioreactors resulted in enhanced collagen type-II gene expression and deposition as compared to the static TECs. Although, the overall amount of ECM quantified and staining for glycosaminoglycans was more prominent in the static TECs.
Open Access
High temperature utilization of PAM and HPAM by microbial communities enriched from oilfield produced water and activated sludge
(2019-04-09) Berdugo-Clavijo, Carolina; Sen, Arindom; Seyyedi, Mojtaba; Quintero, Harvey; O’Neil, Bill; Gieg, Lisa M
Abstract Non-hydrolyzed polyacrylamide (PAM) and partially hydrolyzed polyacrylamide (HPAM) are commonly used polymers in various industrial applications, including in oil and gas production operations. Understanding the microbial utilization of such polymers can contribute to improved recovery processes and help to develop technologies for polymer remediation. Microbial communities enriched from oilfield produced water (PW) and activated sludge from Alberta, Canada were assessed for their ability to utilize PAM and HPAM as nitrogen and carbon sources at 50 °C. Microbial growth was determined by measuring CO2 production, and viscosity changes and amide concentrations were used to determine microbial utilization of the polymers. The highest CO2 production was observed in incubations wherein HPAM was added as a nitrogen source for sludge-derived enrichments. Our results showed that partial deamination of PAM and HPAM occurred in both PW and sludge microbial cultures after 34 days of incubation. Whereas viscosity changes were not observed in cultures when HPAM or PAM was provided as the only carbon source, sludge enrichment cultures amended with HPAM and glucose showed significant decreases in viscosity. 16S rRNA gene sequencing analysis indicated that microbial members from the family Xanthomonadaceae were enriched in both PW and sludge cultures amended with HPAM or PAM as a nitrogen source, suggesting the importance of this microbial taxon in the bio-utilization of these polymers. Overall, our results demonstrate that PAM and HPAM can serve as nitrogen sources for microbial communities under the thermophilic conditions commonly found in environments such as oil and gas reservoirs.
Open Access
Hip Derived Synovial Mesenchymal Progenitor Cell Surface Markers In Situ as Indicators for Differentiation Potential
(2016) Affan, Asmaa; Krawetz, Roman; Sen, Arindom; Powell, Jim
The degeneration of articular cartilage observed in patients with osteoarthritic (OA) joints coupled with the lack of regenerative abilities of cartilage play a major role in causing disability in OA patients. The synovial membrane within the joints is home to synovial mesenchymal progenitor cell (sMPC) populations that have the ability to undergo chondrogenesis (in vivo and in vitro). However, it remains unknown if these sMPCs express any markers in vivo/in situ that give information as to which of the specific MPC sub-populations have pro-chondrogenic capacity. In the patient cohort examined in this study, the most common cell surface marker profile on MPCs was determined to be CD90+/CD44+/CD73+, and though it included cells that had chondrogenic capacity, it also included cells that did not. Additional markers are therefore required to further discriminate the heterogeneous populations of MPCs and identify synovial MPCs that are enriched for chondrogenic capacity.
Open Access
Improving Algae Growth Kinetics in Suspension Bioreactors for the Production of Recombinant Proteins
(2016) Clark, Brendan Robert; Sen, Arindom; Alcantara, Joenel; Hollenberg, Morley; De la Hoz Siegler, Hector; Gates, Ian; Tay, Andrew
Millions of individuals rely on recombinant proteins such as essential biopharmaceuticals. Recently, genetically engineered microalgae have been identified as a potentially inexpensive and fast growing host organism for recombinant protein production. Using Chlamydomonas reinhardtii, a species of unicellular green microalgae, the goal was to improve algal cell growth kinetics, genetically engineer the cells and develop a bioprocess to analyze recombinant protein production. C. reinhardtii growth kinetics were improved under mixotrophic growth conditions using acetate in small scale 10 mL cultures. This process was scaled-up to 500 mL spinner flask suspension bioreactors and through the use of a fed-batch acetate feeding strategy, cell growth rates and maximum cell concentrations were improved. A genetic construct was designed, manufactured, isolated and used to genetically transform C. reinhardtii. A bioprocess was then developed to isolate and analyze protein production rates from these cells. Results indicated product concentrations of 8.44 mg/L of culture.
Open Access
Influence of ground effects on body forces for bi-copter UAV
(2017) Norton, Daniel; Ramirez-Serrano, Alejandro; Martinuzzi, Robert; Hugo, Ronald J.; Wood, David Howe; Sen, Arindom
The Navig8 are a family of dimensionally similar Unmanned Aerial Vehicles (UAVs) designed for high-speed autonomous flight in confined spaces. The Navig8 UAVs generate their lift through the use of dual shrouded fans, and are capable of controlling the pitch of their bodies while hovering. The use of shrouded fans increases the efficiency of the Navig8, which allows the UAV's design to have smaller fans while simultaneously decreasing its power usage. The autonomous control of a Navig8 UAV requires an understanding of the forces acting on its body while operating in close proximity to the ground, which is known as the ground effects region, as well as the forces acting on their fans and shrouds. Computational Fluid Dynamics (CFD) simulations were used to determine the forces acting on the Navig8 UAV's body, fans, and shrouds as a function of height and dihedral angle using a dimensionally-similar model. Heights were defined as the distance from the bottom of the shroud to the ground, and dihedral angles were defined as the difference between the fan's axis of rotation and vertical. Positive dihedral angles direct flow away from the UAV's body. Heights ranged from a maximum of 7.0 fan diameters to a minimum of 0.75 fan diameters. Dihedral angles ranged from a maximum of 8 degrees to a minimum of 0 degrees. The simulated results were compared to the results calculated from existing methods to estimate body and fan forces while operating in the ground effects region. Recommendations were made to the design and operation of the Navig8 based upon the results. The simulated forces acting on the Navig8's body were found to have two primary competing sources: 1) fountain forces and 2) suck-down forces. Fountain forces are caused by the flow from the two fans impacting the ground and creating wall jets. These wall jets intersecting each other beneath the UAV's body then fountain into the body which results in an upwards force. Suck-down forces are caused by a vortex forming between the downwards flow from the fan and the upwards fountain flow. This results in a general downwards force on the body. Suck-down forces are primarily important at altitudes below 1.5 fan diameters, where the gradient of body lift with respect to height is positive, which results in unstable operation. Body lift peaks at approximately 25% of the combined fan and shroud lift out of ground effects at an altitude between 1.1 and 1.5 fan diameters. The body forces decrease from their peak with increasing altitude and drop below 5% by an altitude of 3.8 fan diameters. Increasing the dihedral angle of the fans increases the maximum altitude for which body forces are significant, but has no noticeable impact on the maximum body forces. The change in fan lift varied by less than 2% and the change in shroud lift varied by less than 3% within the experimental range of heights and dihedral angles. The simulated body forces did not agree with those calculated from available estimation methods. Simulated body forces were higher in magnitude than the estimated body forces from available methods, and these methods were unable to properly account for the dominance of suck-down forces at elevations below 1.5 fan diameters.
Open Access
Interactions between Biofilm Growth and Fluid Flow in Porous Media
(2013-07-16) Bozorg, Ali; Sen, Arindom; Gates, Ian
Many engineered and natural systems are influenced by biofilms, which are surface attached communities of microorganisms embedded in a matrix composed of microbially produced extracellular polymeric substances. In porous media, biofilms can progressively accumulate within pore spaces, making it increasingly difficult for fluids to flow through the pore network. Therefore, biofilms are often considered to be detrimental in processes relying on fluid flow in porous media. Engineering biofilm development in porous structures, however, can maximize the beneficial aspects of biofilms while minimizing their detrimental effects. Due to an inadequate understanding of interactions between flow properties and biofilm development, field scale applications of biofilm based processes are still unpredictable. This study was divided to two main parts. The first part focused on a theoretical investigation of biofilm growth in porous media. By treating biofilm as an evolving viscous fluid that shares void spaces with a separate aqueous phase in porous media, a novel macroscopic approach was developed to simulate biofilm growth in porous media. Modelling results revealed that relative permeability functions can be used to link flow of water to biofilm saturation. However, this modelling approach was complex, and certain model parameters needed to be experimentally determined. Therefore, in the second part of the study, by using a bioluminescent bacterium, a noninvasive imaging method was developed to visualize biofilm evolution within porous media. Detected bioluminescence intensities were used to nondestructively quantify biofilm and porous media characteristics. The imaging technique was also used to study bacterial transport in porous media with different hydraulic properties. Results indicated that biofilm formation can significantly improve bacterial sticking efficiency in porous media by modifying hydrophobicity of solid surfaces. Finally, the developed imaging technique was used to monitor biofilm development under a constant pressure gradient in a two-dimensional flow field. Results revealed that in porous media with small pore sizes and low permeabilities, biofilm grows predominantly in upstream regions toward the nutrient source and against the fluid flow, whereas in porous media with coarse pore sizes and elevated permeabilities, biofilm primarily disperses in the downstream direction, in the same direction as the fluid flow, but away from the nutrient source. Observed differences in growth patterns could be explained by considering the pore size distribution in a given medium.
Open Access
Intercellular Gap Junction Communication in the Bovine Annulus Fibrosus
(2019-02-21) McWhae, Russell; Duncan, Neil A.; Matyas, John Robert; Sen, Arindom; Li, Leping; Salo, Paul T.
The intervertebral disc has a complex, anisotropic structure. The annulus fibrosus, the fibrous outer layer of the intervertebral disc, consists of fifteen to twenty-five concentric layers of collagen fibers at alternating orientations. Cells inside and between these lamellae are known to communicate with each other through gap junctions, protein channels that directly couple the membranes of adjacent cells and form interconnected networks that may be used to coordinate a response to mechanical stimuli. These fibroblastic cells fall into three distinct morphologies: spindle-shaped lamellar cells, round lamellar cells, and interlamellar cells. With confocal microscopy methods, gap-junctional intercellular signal propagation between groups of interconnected cells was examined. While the anisotropic microenvironment of the outer annulus was hypothesized to manifest in non-homogenous signal-propagation patterns, it was demonstrated that no clear directional biases or non-homogenous behavior existed among different cell morphologies and orientations; instead, intercellular signal propagation appears to be primarily proximity based.