Scholarly Works, School of Biomedical Engineering and Sciences

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3D Bioprinted Human Skeletal Muscle Constructs for Muscle Function Restoration
Kim, Ji Hyun; Seol, Young-Joon; Ko, In Kap; Kang, Hyun-Wook; Lee, Young Koo; Yoo, James J.; Atala, Anthony; Lee, Sang Jin (Springer Nature, 2018-08-17)
A bioengineered skeletal muscle tissue as an alternative for autologous tissue flaps, which mimics the structural and functional characteristics of the native tissue, is needed for reconstructive surgery. Rapid progress in the cell-based tissue engineering principle has enabled in vitro creation of cellularized muscle-like constructs; however, the current fabrication methods are still limited to build a three-dimensional (3D) muscle construct with a highly viable, organized cellular structure with the potential for a future human trial. Here, we applied 3D bioprinting strategy to fabricate an implantable, bioengineered skeletal muscle tissue composed of human primary muscle progenitor cells (hMPCs). The bioprinted skeletal muscle tissue showed a highly organized multi-layered muscle bundle made by viable, densely packed, and aligned myofiber-like structures. Our in vivo study presented that the bioprinted muscle constructs reached 82% of functional recovery in a rodent model of tibialis anterior (TA) muscle defect at 8 weeks of post-implantation. In addition, histological and immunohistological examinations indicated that the bioprinted muscle constructs were well integrated with host vascular and neural networks. We demonstrated the potential of the use of the 3D bioprinted skeletal muscle with a spatially organized structure that can reconstruct the extensive muscle defects.
Activation of bacterial channel MscL in mechanically stimulated droplet interface bilayers
Najem, Joseph S.; Dunlap, Myles D.; Rowe, Ian D.; Freeman, Eric C.; Grant, John Wallace; Sukharev, Sergei; Leo, Donald J. (Springer Nature, 2015-09-08)
MscL, a stretch-activated channel, saves bacteria experiencing hypo-osmotic shocks from lysis. Its high conductance and controllable activation makes it a strong candidate to serve as a transducer in stimuli-responsive biomolecular materials. Droplet interface bilayers (DIBs), flexible insulating scaffolds for such materials, can be used as a new platform for incorporation and activation of MscL. Here, we report the first reconstitution and activation of the low-threshold V23T mutant of MscL in a DIB as a response to axial compressions of the droplets. Gating occurs near maximum compression of both droplets where tension in the membrane is maximal. The observed 0.1-3 nS conductance levels correspond to the V23T-MscL sub-conductive and fully open states recorded in native bacterial membranes or liposomes. Geometrical analysis of droplets during compression indicates that both contact angle and total area of the water-oil interfaces contribute to the generation of tension in the bilayer. The measured expansion of the interfaces by 2.5% is predicted to generate a 4-6 mN/m tension in the bilayer, just sufficient for gating. This work clarifies the principles of interconversion between bulk and surface forces in the DIB, facilitates the measurements of fundamental membrane properties, and improves our understanding of MscL response to membrane tension.
Adsorbing/dissolving Lyoprotectant Matrix Technology for Non-cryogenic Storage of Archival Human Sera
Solivio, Morwena J.; Less, Rebekah; Rynes, Mathew L.; Kramer, Marcus; Aksan, Alptekin (Springer Nature, 2016-04-12)
Despite abundant research conducted on cancer biomarker discovery and validation, to date, less than two-dozen biomarkers have been approved by the FDA for clinical use. One main reason is attributed to inadvertent use of low quality biospecimens in biomarker research. Most proteinaceous biomarkers are extremely susceptible to pre-analytical factors such as collection, processing, and storage. For example, cryogenic storage imposes very harsh chemical, physical, and mechanical stresses on biospecimens, significantly compromising sample quality. In this communication, we report the development of an electrospun lyoprotectant matrix and isothermal vitrification methodology for non-cryogenic stabilization and storage of liquid biospecimens. The lyoprotectant matrix was mainly composed of trehalose and dextran (and various low concentration excipients targeting different mechanisms of damage), and it was engineered to minimize heterogeneity during vitrification. The technology was validated using five biomarkers; LDH, CRP, PSA, MMP-7, and C3a. Complete recovery of LDH, CRP, and PSA levels was achieved post-rehydration while more than 90% recovery was accomplished for MMP-7 and C3a, showing promise for isothermal vitrification as a safe, efficient, and low-cost alternative to cryogenic storage.
Aligned fibers direct collective cell migration to engineer closing and nonclosing wound gaps
Sharma, Puja; Ng, Colin; Jana, Aniket; Padhi, Abinash; Szymanski, Paige; Lee, Jerry S. H.; Behkam, Bahareh; Nain, Amrinder S. (2017-09-15)
Cell emergence onto damaged or organized fibrous extracellular matrix (ECM) is a crucial precursor to collective cell migration in wound closure and cancer metastasis, respectively. However, there is a fundamental gap in our quantitative understanding of the role of local ECM size and arrangement in cell emergence-based migration and local gap closure. Here, using ECM-mimicking nanofibers bridging cell monolayers, we describe a method to recapitulate and quantitatively describe these in vivo behaviors over multispatial (single cell to cell sheets) and temporal (minutes to weeks) scales. On fiber arrays with large interfiber spacing, cells emerge (invade) either singularly by breaking cell-cell junctions analogous to release of a stretched rubber band (recoil), or in groups of few cells (chains), whereas on closely spaced fibers, multiple chains emerge collectively. Advancing cells on fibers form cell streams, which support suspended cell sheets (SCS) of various sizes and curvatures. SCS converge to form local gaps that close based on both the gap size and shape. We document that cell stream spacing of 375 mu m and larger hinders SCS advancement, thus providing abilities to engineer closing and nonclosing gaps. Altogether we highlight the importance of studying cell-fiber interactions and matrix structural remodeling in fundamental and translational cell biology.
The assembly of integrated rat intestinal-hepatocyte cultures
Kothari, Anjaney; Rajagopalan, Padmavathy (2019-11)
The jejunum is the segment of the small intestine responsible for several metabolism and biotransformation functions. In this report, we have cultured rat jejunum explants in vitro and integrated them with hepatocyte cultures. We have also investigated the changes in jejunum function at different locations since spatial variations in intestinal functions have been reported previously. We divided the length of the rat jejunum into three distinct regions of approximately 9 cm each. We defined the regions as proximal (adjacent to the duodenum), medial, and distal (adjacent to the ileum). Spatiotemporal variations in functions were observed between these regions within the jejunum. Alkaline phosphatase activity (a marker of enterocyte function), decreased twofold between the proximal and distal regions at 4 hr. Lysozyme activity (a marker of Paneth cell function) increased from the proximal to the distal jejunum by 40% at 24 hr. Mucin-covered areas, a marker of goblet cell function, increased by twofold between the proximal and distal segments of the jejunum at 24 hr. When hepatocytes were integrated with proximal jejunum explants, statistically higher urea (similar to 2.4-fold) and mucin (57%) production were observed in the jejunum explants. The integrated intestine-liver cultures can be used as a platform for future investigations.
Binding Interactions of Keratin-Based Hair Fiber Extract to Gold, Keratin, and BMP-2
de Guzman, Roche C.; Tsuda, Shanel M.; Ton, Minh-Thi N.; Zhang, Xiao; Esker, Alan R.; Van Dyke, Mark E. (PLOS, 2015-08-28)
Hair-derived keratin biomaterials composed mostly of reduced keratin proteins (kerateines) have demonstrated their utility as carriers of biologics and drugs for tissue engineering. Electrostatic forces between negatively-charged keratins and biologic macromolecules allow for effective drug retention; attraction to positively-charged growth factors like bone morphogenetic protein 2 (BMP-2) has been used as a strategy for osteoinduction. In this study, the intermolecular surface and bulk interaction properties of kerateines were investigated. Thiol-rich kerateines were chemisorbed onto gold substrates to form an irreversible 2-nm rigid layer for surface plasmon resonance analysis. Kerateine-to-kerateine cohesion was observed in pH-neutral water with an equilibrium dissociation constant (KD) of 1.8 × 10⁻⁴ M, indicating that non-coulombic attractive forces (i.e. hydrophobic and van der Waals) were at work. The association of BMP-2 to kerateine was found to be greater (KD = 1.1 × 10−7 M), within the range of specific binding. Addition of salts (phosphate-buffered saline; PBS) shortened the Debye length or the electrostatic field influence which weakened the kerateine-BMP-2 binding (KD = 3.2 × 10⁻⁵ M). BMP-2 in bulk kerateine gels provided a limited release in PBS (~ 10% dissociation in 4 weeks), suggesting that electrostatic intermolecular attraction was significant to retain BMP-2 within the keratin matrix. Complete dissociation between kerateine and BMP-2 occurred when the PBS pH was lowered (to 4.5), below the keratin isoelectric point of 5.3. This phenomenon can be attributed to the protonation of keratin at a lower pH, leading to positive-positive repulsion. Therefore, the dynamics of kerateine-BMP-2 binding is highly dependent on pH and salt concentration, as well as on BMP-2 solubility at different pH and molarity. The study findings may contribute to our understanding of the release kinetics of drugs from keratin biomaterials and allow for the development of better, more clinically relevant BMP-2-conjugated systems for bone repair and regeneration..
Biomechanics of hair cell kinocilia: experimental measurement of kinocilium shaft stiffness and base rotational stiffness with Euler-Bernoulli and Timoshenko beam analysis
Spoon, Corrie E.; Grant, John Wallace (Company of Biologists, 2011-03-01)
Vestibular hair cell bundles in the inner ear contain a single kinocilium composed of a 9+2 microtubule structure. Kinocilia play a crucial role in transmitting movement of the overlying mass, otoconial membrane or cupula to the mechanotransducing portion of the hair cell bundle. Little is known regarding the mechanical deformation properties of the kinocilium. Using a force-deflection technique, we measured two important mechanical properties of kinocilia in the utricle of a turtle, Trachemys (Pseudemys) scripta elegans. First, we measured the stiffness of kinocilia with different heights. These kinocilia were assumed to be homogenous cylindrical rods and were modeled as both isotropic Euler-Bernoulli beams and transversely isotropic Timoshenko beams. Two mechanical properties of the kinocilia were derived from the beam analysis: flexural rigidity (El) and shear rigidity (kGA). The Timoshenko model produced a better fit to the experimental data, predicting El=10,400 pN mu m(2) and kGA=247 pN. Assuming a homogenous rod, the shear modulus (G=1.9 kPa) was four orders of magnitude less than Young's modulus (E=14.1 MPa), indicating that significant shear deformation occurs within deflected kinocilia. When analyzed as an Euler-Bernoulli beam, which neglects translational shear, El increased linearly with kinocilium height, giving underestimates of El for shorter kinocilia. Second, we measured the rotational stiffness of the kinocilium insertion (kappa) into the hair cell's apical surface. Following BAPTA treatment to break the kinocilial links, the kinocilia remained upright, and kappa was measured as 177 +/- 47 pN mu m rad(-1). The mechanical parameters we quantified are important for understanding how forces arising from head movement are transduced and encoded by hair cells.
Burst sine wave electroporation (B-SWE) for expansive blood–brain barrier disruption and controlled non-thermal tissue ablation for neurological disease
Campelo, Sabrina N.; Salameh, Zaid S.; Arroyo, Julio P.; May, James L.; Altreuter, Sara O.; Hinckley, Jonathan; Davalos, Rafael V.; Rossmeisl, John H. Jr. (AIP Publishing, 2024-05-30)
The blood–brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE’s transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond.
Bursts of Bipolar Microsecond Pulses Inhibit Tumor Growth
Sano, Michael B.; Arena, Christopher B.; Bittleman, Katelyn Rose; DeWitt, Matthew R.; Cho, Hyung J.; Szot, Cchristopher S.; Saur, Dieter; Cissell, James M.; Robertson, John L.; Lee, Yong Woo; Davalos, Rafael V. (Nature Publishing Group, 2015-10-13)
Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions. High-frequency IRE (H-FIRE), a new treatment modality which replaces the monopolar IRE pulses with a burst of bipolar pulses, has the potential to resolve these clinical challenges. We explored the pulse-duration space between 250 ns and 100 μs and determined the lethal electric field intensity for specific H-FIRE protocols using a 3D tumor mimic. Murine tumors were exposed to 120 bursts, each energized for 100 μs, containing individual pulses 1, 2, or 5 μs in duration. Tumor growth was significantly inhibited and all protocols were able to achieve complete regressions. The H-FIRE protocol substantially reduces muscle contractions and the therapy can be delivered without the need for a neuromuscular blockade. This work shows the potential for H-FIRE to be used as a focal therapy and merits its investigation in larger pre-clinical models.
Canine Cancer Screening Via Ultraviolet Absorbance And Fluorescence Spectroscopy Of Serum Proteins
Dickerson, Bryan Douglas; Geist, Brian L.; Spillman, William B. Jr.; Robertson, John L. (Optical Society of America, 2007-01-01)
A cost-effective optical cancer screening and monitoring technique was demonstrated in a pilot study of canine serum samples and was patented for commercialization. Compared to conventional blood chemistry analysis methods, more accurate estimations of the concentrations of albumin, globulins, and hemoglobin in serum were obtained by fitting the near UV absorbance and photoluminescence spectra of diluted serum as a linear combination of component reference spectra. Tracking these serum proteins over the course of treatment helped to monitor patient immune response to carcinoma and therapy. For cancer screening, 70% of dogs with clinical presentation of cancer displayed suppressed serum hemoglobin levels (below 20 mg/dL) in combination with atypical serum protein compositions, that is, albumin levels outside of a safe range (from 4 to 8 g/dL) and globulin levels above or below a more normal range (from 1.7 to 3.7 g/dL). Of the dogs that met these criteria, only 20% were given a false positive label by this cancer screening test. (C) 2007 Optical Society of America.
Characterization and structure-property relationships of an injectable thiol-Michael addition hydrogel toward compatibility with glioblastoma therapy
Khan, Zerin Mahzabin; Wilts, Emily; Vlaisavljevich, Eli; Long, Timothy E.; Verbridge, Scott S. (Elsevier, 2022-05-01)
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer and although patients undergo surgery and chemoradiotherapy, residual cancer cells still migrate to healthy brain tissue and lead to tumor relapse after treatment. New therapeutic strategies are therefore urgently needed to better mitigate this tumor recurrence. To address this need, we envision after surgical removal of the tumor, implantable biomaterials in the resection cavity can treat or collect residual GBM cells for their subsequent eradication. To this end, we systematically characterized a poly(ethylene glycol)-based injectable hydrogel crosslinked via a thiol-Michael addition reaction by tuning its hydration level and aqueous NaHCO3 concentration. The physical and chemical properties of the different formulations were investigated by assessing the strength and stability of the polymer networks and their swelling behavior. The hydrogel biocompatibility was assessed by performing in vitro cytotoxicity assays, immunoassays, and immunocytochemistry to monitor the reactivity of astrocytes cultured on the hydrogel surface over time. These characterization studies revealed key structure-property relationships. Furthermore, the results indicated hydrogels synthesized with 0.175 M NaHCO3 and 50 wt% water content swelled the least, possessed a storage modulus that can withstand high intracranial pressures while avoiding a mechanical mismatch, had a sufficiently crosslinked polymer network, and did not degrade rapidly. This formulation was not cytotoxic to astrocytes and produced minimal immunogenic responses in vitro. These properties suggest this hydrogel formulation is the most optimal for implantation in the resection cavity and compatible toward GBM therapy. Statement of significance: Survival times for glioblastoma patients have not improved significantly over the last several decades, as cancer cells remain after conventional therapies and form secondary tumors. We characterized a biodegradable, injectable hydrogel to reveal structure-property relationships that can be tuned to conform the hydrogel toward glioblastoma therapy. Nine formulations were systematically characterized to optimize the hydrogel based on physical, chemical, and biological compatibility with the glioblastoma microenvironment. This hydrogel can potentially be used for adjuvant therapy to glioblastoma treatment, such as by providing a source of molecular release for therapeutic agents, which will be investigated in future work. The optimized formulation will be developed further to capture and eradicate glioblastoma cells with chemical and physical stimuli in future research.
Characterization of Ablation Thresholds for 3D-Cultured Patient-Derived Glioma Stem Cells in Response to High-Frequency Irreversible Electroporation
Ivey, J. W.; Wasson, E. M.; Alinezhadbalalami, N.; Kanitkar, A.; Debinski, Waldemar; Sheng, Z.; Davalos, Rafael V.; Verbridge, Scott S. (American Association for the Advancement of Science, 2019-04-28)
High-frequency irreversible electroporation (H-FIRE) is a technique that uses pulsed electric fields that have been shown to ablate malignant cells. In order to evaluate the clinical potential of H-FIRE to treat glioblastoma (GBM), a primary brain tumor, we have studied the effects of high-frequency waveforms on therapy-resistant glioma stem-like cell (GSC) populations. We demonstrate that patient-derived GSCs are more susceptible to H-FIRE damage than primary normal astrocytes. This selectivity presents an opportunity for a degree of malignant cell targeting as bulk tumor cells and tumor stem cells are seen to exhibit similar lethal electric field thresholds, significantly lower than that of healthy astrocytes. However, neural stem cell (NSC) populations also exhibit a similar sensitivity to these pulses. This observation may suggest that different considerations be taken when applying these therapies in younger versus older patients, where the importance of preserving NSC populations may impose different restrictions on use.We also demonstrate variability in threshold among the three patient-derived GSC lines studied, suggesting the need for personalized cell-specific characterization in the development of potential clinical procedures. Future work may provide further useful insights regarding this patient-dependent variability observed that could inform targeted and personalized treatment.
Characterization of multicellular breast tumor spheroids using image data-driven biophysical mathematical modeling
Bowers, Haley J.; Fannin, Emily E.; Thomas, Alexandra; Weis, Jared A. (2020-07-14)
Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy. Here, we present a coupled experimental-computational framework to estimate phenotypic growth and biophysical tumor microenvironment properties. This novel framework utilizes standard microscopy imaging of MCTS systems to drive a biophysical mathematical model of MCTS growth and mechanical interactions. By extending our previous in vivo mechanically-coupled reaction-diffusion modeling framework we developed a microscopy image processing framework capable of mechanistic characterization of MCTS systems. Using MDA-MB-231 breast cancer MCTS, we estimated biophysical parameters of cellular diffusion, rate of cellular proliferation, and cellular tractions forces. We found significant differences in these model-based biophysical parameters throughout the treatment time course between untreated and treated MCTS systems, whereas traditional size-based morphometric parameters were inconclusive. The proposed experimental-computational framework estimates mechanistic MCTS growth and invasion parameters with significant potential to assist in better and more precise assessment of in vitro drug efficacy through the development of computational analysis methodologies for three-dimensional cell culture systems to improve the development and evaluation of antineoplastic drugs.
Composting Animal Carcasses Removed from Roads: An Analysis of Pathogen Destruction and Leachate Constituents in Deer Mortality Static Windrow Composting
Donaldson, B. M.; Smith, G. P.; Kweon, Y.; Sriranganathan, Nammalwar; Wilson, D.L. (Virginia Center for Transportation Innovation and Research, 2012-06-01)
More than 48,700 deer-vehicle collisions occurred in Virginia from 2010 through 2011, the fifth highest number in all U.S. states. The Virginia Department of Transportation (VDOT) is responsible for the removal and disposal of animal carcasses along the state road system. The predominant methods currently used (landfill and burial) have several costly disadvantages, including long travel distances to landfills, increasing landfill restrictions, and lack of viable burial areas. Other states have found static compost windrows to be an easy and cost-effective carcass management technique. Deer mortality static compost windrows were monitored for 1 year under conditions typical of a VDOT area maintenance headquarters facility. Windrows were analyzed for pathogen destruction and the degree to which underlying soil filtered leachate contaminants. In response to high windrow temperatures, indicator pathogens E. coli, Salmonella were reduced by 99.99% the first sampling day (Day 7) and ascarids were deemed non-viable by Day 77. Soil filtration of leachate was effective in reducing concentrations of ammonia, chloride, and total organic carbon. Nitrate, a contaminant of particular regulatory concern, had an estimated mass contaminant loss of 1.9 lb/acre, compared to the 8 to 45 lb/acre estimated loss from fertilizer application on agronomic crops in Virginia. Results from this study indicate that with properly constructed static compost windrows, (1) high temperatures destroy indicator pathogens; (2) the natural filtration of leachate through soil reduces deer mortality contaminant concentrations; and (3) the low volume of leachate from windrows results in nominal losses of nitrate and other contaminants. The study recommends that VDOT consider sharing these results with the Virginia Department of Environmental Quality to discuss options for a statewide composting program. This could provide VDOT with an additional carcass management option.
Compressed Sensing Inspired Image Reconstruction from Overlapped Projections
Yang, Lin; Lu, Yang; Wang, Ge (Hindawi, 2010-06-22)
The key idea discussed in this paper is to reconstruct an image from overlapped projections so that the data acquisition process can be shortened while the image quality remains essentially uncompromised. To perform image reconstruction from overlapped projections, the conventional reconstruction approach (e.g., filtered backprojection (FBP) algorithms) cannot be directly used because of two problems. First, overlapped projections represent an imaging system in terms of summed exponentials, which cannot be transformed into a linear form. Second, the overlapped measurement carries less information than the traditional line integrals. To meet these challenges, we propose a compressive sensing-(CS-) based iterative algorithm for reconstruction from overlapped data. This algorithm starts with a good initial guess, relies on adaptive linearization, and minimizes the total variation (TV). Then, we demonstrated the feasibility of this algorithm in numerical tests.
Computational and experimental study of chemotaxis of an ensemble of bacteria attached to a microbead
Traore, Mahama Aziz; Sahari, A.; Behkam, Bahareh (American Physical Society, 2011-12-12)
Micro-objects propelled by whole cell actuators, such as flagellated bacteria, are being increasingly studied and considered for a wide variety of applications. In this work we present theoretical and experimental investigations of chemotactic motility of a 10 mu m diameter microbead propelled by an ensemble of attached flagellated bacteria. The stochastic model presented here encompasses the behavior of each individual bacterium attached to the microbead in a spatiotemporally varying chemoattractant field. The computational model shows that in a chemotactic environment, the ensemble of bacteria, although constrained, propel the bead in a chemotactic manner with a 67% enhancement in displacement to distance ratio (defined as directionality) compared to nonchemotactic propulsion. The simulation results are validated experimentally. Close agreement between theory and experiments demonstrates the possibility of using the presented model as a predictive tool for other similar biohybrid systems.
Cone-Beam Composite-Circling Scan and Exact Image Reconstruction for a Quasi-Short Object
Yu, Hengyong; Wang, Ge (Hindawi, 2008-02-03)
Here we propose a cone-beam composite-circling mode to solve the quasi-short object problem, which is to reconstruct a short portion of a long object from longitudinally truncated cone-beam data involving the short object. In contrast to the saddle curve cone-beam scanning, the proposed scanning mode requires that the X-ray focal spot undergoes a circular motion in a plane facing the short object, while the X-ray source is rotated in the gantry main plane. Because of the symmetry of the proposed mechanical rotations and the compatibility with the physiological conditions, this new mode has significant advantages over the saddle curve from perspectives of both engineering implementation and clinical applications. As a feasibility study, a backprojection filtration (BPF) algorithm is developed to reconstruct images from data collected along a composite-circling trajectory. The initial simulation results demonstrate the correctness of the proposed exact reconstruction method and the merits of the proposed mode.
Connexin 43-Based Therapeutics for Dermal Wound Healing
Montgomery, Jade; Ghatnekar, Gautam S.; Grek, Christina L.; Moyer, Kurtis E.; Gourdie, Robert G. (MDPI, 2018-06-15)
The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local knockdown of Cx43 found improvements in wound closure rate and final scar appearance. Further preclinical work conducted using Cx43-based peptide therapeutics, including alpha connexin carboxyl terminus 1 (αCT1), a peptide mimetic of the Cx43 carboxyl terminus, reported similar improvements in wound healing and scar formation. Clinical trials and further study into the mode of action have since been conducted on αCT1, and Phase III testing for treatment of diabetic foot ulcers is currently underway. Therapeutics targeting connexin activity show promise in beneficially modulating the human body’s natural healing response for improved patient outcomes across a variety of injuries.
Cytoskeletal Disruption after Electroporation and Its Significance to Pulsed Electric Field Therapies
Graybill, Philip M.; Davalos, Rafael V. (MDPI, 2020-04-30)
Pulsed electric fields (PEFs) have become clinically important through the success of Irreversible Electroporation (IRE), Electrochemotherapy (ECT), and nanosecond PEFs (nsPEFs) for the treatment of tumors. PEFs increase the permeability of cell membranes, a phenomenon known as electroporation. In addition to well-known membrane effects, PEFs can cause profound cytoskeletal disruption. In this review, we summarize the current understanding of cytoskeletal disruption after PEFs. Compiling available studies, we describe PEF-induced cytoskeletal disruption and possible mechanisms of disruption. Additionally, we consider how cytoskeletal alterations contribute to cell–cell and cell–substrate disruption. We conclude with a discussion of cytoskeletal disruption-induced anti-vascular effects of PEFs and consider how a better understanding of cytoskeletal disruption after PEFs may lead to more effective therapies.
Data-driven statistical modeling of the emergent behavior of biohybrid microrobots
Leaman, Eric J.; Sahari, Ali; Traore, Mahama Aziz; Geuther, Brian Q.; Morrow, Carmen M.; Behkam, Bahareh (2020-03-01)
Multi-agent biohybrid microrobotic systems, owing to their small size and distributed nature, offer powerful solutions to challenges in biomedicine, bioremediation, and biosensing. Synthetic biology enables programmed emergent behaviors in the biotic component of biohybrid machines, expounding vast potential benefits for building biohybrid swarms with sophisticated control schemes. The design of synthetic genetic circuits tailored toward specific performance characteristics is an iterative process that relies on experimental characterization of spatially homogeneous engineered cell suspensions. However, biohybrid systems often distribute heterogeneously in complex environments, which will alter circuit performance. Thus, there is a critically unmet need for simple predictive models that describe emergent behaviors of biohybrid systems to inform synthetic gene circuit design. Here, we report a data-driven statistical model for computationally efficient recapitulation of the motility dynamics of two types of Escherichia coli bacteria-based biohybrid swarms-NanoBEADS and BacteriaBots. The statistical model was coupled with a computational model of cooperative gene expression, known as quorum sensing (QS). We determined differences in timescales for programmed emergent behavior in BacteriaBots and NanoBEADS swarms, using bacteria as a comparative baseline. We show that agent localization and genetic circuit sensitivity strongly influence the timeframe and the robustness of the emergent behavior in both systems. Finally, we use our model to design a QS-based decentralized control scheme wherein agents make independent decisions based on their interaction with other agents and the local environment. We show that synergistic integration of synthetic biology and predictive modeling is requisite for the efficient development of biohybrid systems with robust emergent behaviors.

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