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A high-performance public-domain Monte Carlo optical simulator is highly desirable to solve complex heterogeneous optical problems in biomedical engineering. Recently, we developed a Tetrahedron-based Inhomogeneous Monte- Carlo Optical Simulator (TIM-OS) pubware, which addresses this challenge efficiently and accurately based on the tetrahedral mesh.

Fluorescent protein biosensors are typically implemented via genetic encoding which makes the examination of scarce cell samples impractical. By directly delivering the protein form of the biosensor into cells using electroporation, we detected intracellular molecular activity with the sample size down to ~100 cells with high spatiotemporal resolution. Virginia Tech. Institute for Critical Technology and Applied Science National Science Foundation (U.S.) - Grant 1016547 National Science Foundation (U.S.) - Grant 0967069 National Science Foundation (U.S.) - Grant 1344298 Supplementary information is included in a separate file

Genetic analysis starting with cell samples often requires multi-step processing including cell lysis, DNA isolation/purification, and polymerase chain reaction (PCR) based assays. When conducted on a microfluidic platform, the compatibility among various steps often demands a complicated procedure and a complex device structure. Here we present a microfluidic device that permits a “one-pot” strategy for multi-step PCR analysis starting from cells. Taking advantage of the diffusivity difference, we replace the smaller molecules in the reaction chamber by diffusion while retaining DNA molecules inside. This simple scheme effectively removes reagents from the previous step to avoid interference and thus permits multi-step processing in the same reaction chamber. Our approach shows high efficiency for PCR and potential for a wide range of genetic analysis including assays based on single cells. Virginia Tech. Institute for Critical Technology and Applied Science. NanoBio Trust National Science Foundation (U.S.). Chemical, Bioengineering, Environmental and Transport Systems - Grant 1016547 National Science Foundation (U.S.). Chemical, Bioengineering, Environmental and Transport Systems - Grant 0967069 National Institutes of Health. National Cancer Institute - R21CA174577 Supplementary information is included in a separate file

Blood-perfused tissue models are joining the emerging field of tumor engineering because they provide new avenues for modulation of the tumor microenvironment and preclinical evaluation of the therapeutic potential of new treatments. The characterization of fluid flow parameters in such in-vitro perfused tissue models is a critical step towards better understanding and manipulating the tumor microenvironment. However, traditional optical flow measurement methods are inapplicable because of the opacity of blood and the thickness of the tissue sample. In order to overcome the limitations of optical method we demonstrate the feasibility of using phase-contrast x-ray imaging to perform microscale particle image velocimetry (PIV) measurements of flow in blood perfused hydrated tissue-representative microvessels. However, phase contrast x-ray images significantly depart from the traditional PIV image paradigm, as they have high intensity background, very low signal-to-noise ratio, and volume integration effects. Hence, in order to achieve accurate measurements special attention must be paid to the image processing and PIV cross-correlation methodologies. Therefore we develop and demonstrate a methodology that incorporates image preprocessing as well as advanced PIV cross-correlation methods to result in measured velocities within experimental uncertainty. Henry Luce Foundation Virginia Polytechnic Institute and State University Virginia Space Grant Consortium Virginia Polytechnic Institute and State University. Institute of Critical Technology and Applied Sciences U.S. Department of Energy Basic Energy Sciences Clare Booth Luce Graduate Fellowship Virginia Space Grant Consortium Graduate STEM Research Fellowship

Thermal loading effects in flow-through electroporation microfluidic devices have been systematically investigated by using dye-based ratiometric luminescence thermometry. Fluorescence measurements have revealed the crucial role played by both the applied electric field and flow rate on the induced temperature increments at the electroporation sections of the devices. It has been found that Joule heating could raise the intra-channel temperature up to cytotoxic levels (>45 °C) only when conditions of low flow rates and high applied voltages are applied. Nevertheless, when flow rates and electric fields are set to those used in real electroporation experiments we have found that local heating is not larger than a few degrees, i.e. temperature is kept within the safe range (, This work has been supported by NSF (CBET 1016547, 1041834, 0967069), the Universidad Autónoma de Madrid and Comunidad Autónoma de Madrid (Project S2009/MAT-1756), and the Spanish Ministerio de Educación y Ciencia (MAT2010-16161). Blanca del Rosal thanks Universidad Autónoma de Madrid for financial support (FPI-UAM grant)

Currently, conventional cancer treatment regimens often rely upon highly toxic chemotherapeutics or target oncogenes that are variably expressed within the heterogeneous cell population of tumors. These challenges highlight the need for novel treatment strategies that (1) are non-toxic yet able to at least partially reverse the aggressive phenotype of the disease to a benign or very slow-growing state, and (2) act on the cells independently of variably expressed biomarkers. Using a label-independent rapid microfluidic cell manipulation strategy known as contactless dielectrophoresis (cDEP), we investigated the effect of non-toxic concentrations of two bioactive sphingolipidmetabolites, sphingosine (So), with potential anti-tumor properties, and sphingosine-1-phosphate (S1P), a tumor-promoting metabolite, on the intrinsic electrical properties of early and late stages of mouse ovarian surface epithelial (MOSE) cancer cells. Previously, we demonstrated that electrical properties change as cells progress from a benign early stage to late malignant stages. Here, we demonstrate an association between So treatment and a shift in the bioelectrical characteristics of late stage MOSE (MOSE-L) cells towards a profile similar to that of benign MOSE-E cells. Particularly, the specific membrane capacitance of MOSE-L cells shifted toward that of MOSE-E cells, decreasing from 23.94 ± 2.75 to 16.46 ± 0.62 mF m_2 after So treatment, associated with a decrease in membrane protrusions. In contrast, S1P did not reverse the electrical properties of MOSE-L cells. This work is the first to indicate that treatment with non-toxic doses of So correlates with changes in the electrical properties and surface roughness of cells. It also demonstrates the potential of cDEP to be used as a new, rapid technique for drug efficacy studies, and for eventually designing more personalized treatment regimens. National Institutes of Health - 1R21 CA173092-01 National Institutes of Health -RO1 CA118846 National Science Foundation (U.S.) - Grant no. EFRI 0938047 Virginia Tech. Institute for Critical Technology and Applied Science

Maximum image resolution with commercial spiral CT scanners is inadequate to define clearly the anatomical features and electrode positions within this intricate, 3D space. The objective of this research was to develop theory, algorithms and equipment to increase spiral CT image resolution for temporal bone imaging, especially in cochlear implantation. Summary: Spiral CT with overlapping reconstruction allows better 3D resolution than conventional CT, and is important for temporal bone imaging • Spiral CT image deblurring achieves a 40% resolution gain without significant noise and ringing artifacts • Implant unwrapping measures the array insertion length with 0.3 mm mean accuracy, and facilitates electrode localization • Sub-mm scanning improves high-contrast resolution and suppresses stair-step artifacts. However, 0.5 mm collimation introduced more than doubled image noise

In [1-4], I. M. Gel'fand and M. I. Graev proposed inversion formulas for x-ray transforms in different spaces. In particular, Gel’fand-Graev’s inversion formula [1] is a fundamental relationship linking projection data to the Hilbert transform of an image to be reconstructed. This finding was re-discovered in the CT field; see [5-9]. It has wide applications, including local reconstruction [10-11], backprojection filtration (BPF) [12], interior tomography [13-17], and limited-angle tomography [18]. For a survey, see [19, 20]. Despite its high information density, Gel’fand-Graev’s inversion formula [1] was cast in high dimensions and specialized terms, and difficult to follow for a well-trained engineer. In this poster, we represent this formula and its proof for the 1D x-ray transform in a 3D real space for easy access and further extension. National Institute of Biomedical Imaging and Bioengineering (U.S.) - Grant EB011785 National Science Foundation (U.S.). Division of Civil, Mechanical and Manufacturing Innovation - Grant 0923297

Cardiovascular diseases are pervasive with high mortality and morbidity at tremendous social and healthcare costs. There are urgent needs for significantly higher fidelity cardiac CT with substantially lower radiation dose, which is currently not possible because of technical limitations. Although cardiac CT technology has improved significantly from 16 to 320 detector rows and from single to dual source, there remain technical challenges in terms of temporal resolution, spatial resolution, radiation dose, and so on. Based on an ideal academic-industrial partnership between Virginia Tech and the GE Global Research Center (GEGR), we are motivated to advance the state-of-the-art in cardiac CT. The overall goal of this project is to develop novel cardiac CT architectures and the associated reconstruction algorithms, and define the next-generation cardiac CT system. The specific aims are to (1) design, analyze and compare novel cardiac CT architectures with novel sources and scanning trajectories; (2) develop analytic and iterative cardiac CT reconstruction algorithms for ROI-oriented scanning and dynamic imaging for the proposed cardiac CT architectures; and (3) evaluate and validate the proposed architectures and algorithms in theoretical studies, numerical simulations, phantom experiments and observer studies. On completion of this project, we will have singled out the most promising cardiac CT architectures and algorithms to achieve 16cm coverage, 50ms temporal resolution, 20lp/cm spatial resolution, 10HU noise level, and 1mSv effective dose simultaneously for the entire examination, with detailed specifications and performance evaluation, setting the stage for prototyping a next-generation cardiac CT system in a Phase-II project. This project will enable significantly better diagnostic performance and bring major therapeutic benefits that affect over 60 million Americans. National Institute of Biomedical Imaging and Bioengineering (U.S.) - Grant EB011785

While clinical CT scanners are available at our medical school, for preclinical imaging we have a Scanco micro-CT scanner, an Xradia micro-CT scanner and an Xradia nano-CT scanner. With all these scanners, we can cover image resolution and sample size over six orders of magnitude. The Scanco scanner has resolution 16 µm and FOV 20-38 mm. The Xradia micro-CT scanner, purchased using an NIH SIG grant in 2008, is the highest resolution micro-CT system on the market. It produces 0.5 µm resolution and handle samples of up to 100 mm diameter. The Xradia nano-CT scanner, purchased using an NSF-MRI grant in 2009, has 50 nm resolution and represents the state-of-the-art. It allows tomographic imaging in either the attenuation or Zernike phase contrast mode. For the high-resolution performance of the micro-/nano-CT systems, special housing is vital to ensuring technical development and biomedical applications. We have a dedicated space for these systems in the Institute for Critical Technologies and Applied Sciences (ICTAS; http://www.ictas.vt.edu) Building A, adjacent to the Nanoscale Characterization and Fabrication Lab (NCFL; http://www.ictas.vt.edu/NCFL) at Virginia Tech, which hosts most other cutting-edge imaging systems under one roof. National Center for Research Resources (U.S.) - Grant RR025667 National Science Foundation (U.S.). Division of Civil, Mechanical and Manufacturing Innovation - Grant 0923297

Conventional tomography allows excellent reconstruction of an object from non-truncated projections. The long-standing interior problem is to reconstruct an interior ROI accurately only from local projection segments. Interior tomography solves the interior problem with practical knowledge such as a known sub-region or a sparsity model using compressive sensing. Advantages of interior tomography include radiation dose reduction (no x-rays go outside an ROI), scattering artifact suppression (no cross-talk from radiation outside the ROI), image quality improvement (with the novel reconstruction approach), large object handling (measurement can be truncated in any direction), and ultrafast imaging performance (with multiple source detector chains tightly integrated targeting the ROI). National Institute of Biomedical Imaging and Bioengineering (U.S.) - Grant EB002667 National Institute of Biomedical Imaging and Bioengineering (U.S.) - Grant EB004287 National Institute of Biomedical Imaging and Bioengineering (U.S.) - Grant EB007288

Cardiovascular diseases are pervasive at tremendous social and healthcare costs. There are urgent needs for higher fidelity cardiac CT with lower radiation dose. Based on the academic-industrial partnership between Virginia Tech and the GE Global Research Center (GEGR), we are defining a next generation cardiac CT architecture and the associated algorithms, which will achieve 16cm coverage, 50ms temporal resolution, 20lp/cm spatial resolution, 10HU noise level, and 5mSv effective dose simultaneously for the entire examination, with detailed specifications and performance evaluation. This project will set the stage for prototyping the next-generation cardiac CT system in a Phase-II project.

Past research results include the following: • Modern CT scanners that use spiral-beam scanning and perform >100-million scans annually in the USA • Construction of the only 500nm resolution micro-CT system on the East Coast and the only 50nm nano-CT system with the interior tomography capability in the world from inside the walls of SAM-CT x-ray imaging facility • With further promise to handle large objects, reduce radiation dose, and improve temporal resolution, Interior tomography has already been extended to SPECT, MRI and other imaging modalities • A 3D analysis of the underlying molecular/cellular activities is taken from a mouse subject with an embedded bioluminescent source after an imaging model is built, linking the bioluminescent measurement and the source distribution.

Demonstrations of anatomical systems computationally extracted from spiral CT images and then unraveled onto a plane in vivo to ultimately conceive 3D individualized models.

The radiative transfer equation (RTE) well describes the photon propagation but its high computational cost is prohibitive for tomographic imaging. The diffusion approximation (DA) to RTE is the most popular but it only works well in weakly absorbing and highly scattering media, and breaks down near sources and across boundaries. In 2007, we derived the phase approximation (PA) model from RTE based on the generalized Delta-Eddington phase function. The generalized phase function is a linear combination of isotropic scattering and strongly peaked forward scattering with anisotropy weight as a free coefficient. PA is highly accurate over a broad range of coefficients with a computational complexity comparable to that of DA.

There are many imaging systems. Their performance characterization is important for all applications. Various definitions are introduced for quantification of image resolution, which is the ability of an imaging system to separate two localized signals. In the nonnegative space, we postulated a set of axioms that a good image resolution measure should satisfy, obtained such an image resolution measure, applied our finding in comparing medical CT scanners, and won a 2004 Herbert M. Stauffer Award. We believe that imaging theory can be unified using the axiomatic approach.

Current x-ray imaging is of critical for clinical and pre-clinical applications but it is fundamentally restricted by the attenuation mechanism. X-ray grating-based imaging represents outstanding opportunities and major challenges, especially for tomography utilizing the wave nature of x-rays for superior tissue contrast at minimal radiation dose. Our general hypothesis is that 2D grating-based imaging can be developed to produce better projective/ and tomographic images of biomedical interest than 1D grating-based techniques. The overall goal is to develop the first of its kind 2D-grating-based imaging system for mouse and breast imaging.

Intravenous injection of contrast media is required to enhance conspicuity of the vasculature, organs and tumors in CT angiography (CTA) for diagnosis of cardiovascular structures, peripheral vessels and solid organs. The overall goal of this project is to develop boluschasing CTA for a wide class of diagnostic applications. This will be achieved by instantaneously reconstructing CT images, dynamically predicting bolus propagation, and adaptively varying scanning pitch from the aortic arch to the feet to allow real-time correction of any significant deviation from the prediction. *Complimentary film demonstrates the solution to resonating the bolus peak and imaging aperture of the CTA angiography function, that is, via real-time peak bolus identification and prediction as well as adaptively moving the patient table. Includes video file

While the conventional wisdom states that the interior problem - to reconstruct a region of interest (ROI) only from projection data through the ROI - does not have a unique solution, in June 2007 we published the first paper on interior tomography to solve the interior problem exactly and stably, aided by the prior knowledge on a subregion in the ROI. We underline that interior tomography is potentially a powerful, even indispensable tool to handle large objects, reduce radiation dose, suppress scattering artifacts, refine image quality, decrease engineering cost, increase system functionalities, and boost scanner throughput in many biomedical and other applications. Interior tomography can be extended to other similar tomography modalities including MRI, ultrasound tomography, SPECT and PET.

Bioluminescence tomography (BLT) is a molecular imaging modality, which derives a bioluminescent source distribution inside a small animal from external bioluminescent signals. We published the first paper on BLT in 2004 using the modality fusion approach. The introduction of BLT can be compared to the development of x-ray CT based on radiography. Without BLT, bioluminescent imaging is basically qualitative. With BLT, quantitative and 3D analyses become feasible inside a living mouse, which reveal important molecular and cellular information for numerous preclinical applications. *Complimentary film demonstrates 3D analysis of a living mouse with bioluminescent source Includes video file

Dr. Cui's group at Wake Forest has been investigating a newly discovered innate anticancer immunity in a colony of cancer resistant mice, and already demonstrated that the anticancer activity in the mice stems from the innate immune system, specifically from the granulocytes and macrophages. In 2007, they confirmed in vitro that the human granulocytes are capable of killing cancers effectively, suggesting a novel approach for cancer treatment. The FDA has approved this granulocyte infusion therapy (GIFT) for a phase II clinical trial. In collaboration with Dr. Cui's group, our main hypothesis is that optical molecular imaging of the granulocyte infiltration and cancer-killing activities in a mouse-based test-bed would identify potential donors and optimize outcomes in the clinical trial. The overall goal of this project is to develop a unique fluorescence tomography system that quantifies the leukocyte infiltration and cancer-killing abilities on prostate cancer sites in the murine model to evaluate the cancer-killing mechanisms and guide the GIFT trial.

X-ray computed tomography (CT) is instrumental in medicine, industry and homeland security, which depicts internal structures of an object from its shadows projected in a fan-beam or cone-beam from an x-ray source along a appropriate trajectory. We published the first paper on spiral conebeam CT in 1991 to solve the long object problem. Now, spiral conebeam scanning has been widely used in modern CT scanners, in which conebeam rotation and table translation are simultaneously performed, and spiral cone-beam CT remains a major area in CT research and development.

Parallel computing has been used to solve large-scale problems in many fields. While CT is being developed towards high-resolution, volumetric, dynamic and spectral imaging, datasets become increasingly large, and reconstruction speeds are often too slow. To meet this challenge, in 2004 Drs. Wang and Ni co-found a High performance Computing Lab, and have been working in this area ever since. In 2006, we designed and implemented the first parallel Katsevich algorithm. We have also parallelized EM, OS-EM, SART and OS-SART algorithms, respectively.

International audience; We proposed a novel method called HARP-I, which enhances the estimation of motion from tagged Magnetic Resonance Imaging (MRI). The harmonic phase of the images is unwrapped and treated as noisy measurements of reference coordinates on a deformed domain, obtaining motion with high accuracy using Radial Basis Functions interpolations. Results were compared against Shortest Path HARP Refinement (SP-HR) and Sine-wave Modeling (SinMod), two harmonic image-based techniques for motion estimation from tagged images. HARP-I showed a favorable similarity with both methods under noise-free conditions, whereas a more robust performance was found in the presence of noise. Cardiac strain was better estimated using HARP-I at almost any motion level, giving strain maps with less artifacts. Additionally, HARP-I showed better temporal consistency as a new method was developed to fix phase jumps between frames. In conclusion, HARP-I showed to be a robust method for the estimation of motion and strain under ideal and non-ideal conditions.

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. National Institutes of Health - National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [K25CA204599, P30CA012197]; Wake Forest Baptist Medical Center Comprehensive Cancer Center Signaling and Biotechnology Program Pilot Grant National Institutes of Health - National Cancer Institute K25CA204599 and P30CA012197. Wake Forest Baptist Medical Center Comprehensive Cancer Center Signaling and Biotechnology Program Pilot Grant.

M.S. The InsulPatch is a slim, powerless device (“patch-pump”) that can be used to deliver drugs through the skin, especially designed for drugs that are difficult to deliver orally. The patch technology is a promising replacement for conventional injection using syringes and bulky battery-powered pumps. At this stage, the primary drug that our device aims to deliver is insulin, which generally needs to be delivered through the skin. In this thesis, we demonstrate how our patch-pump is made and how its performance is tested. The patch-pump has two parts: the microfluidic pump and the microneedle array. The microfluidic pump is fabricated using a technique called photolithography, in which a photosensitive polymer is selectively cured by UV light, and replica molding, in which the precursor of another polymer is poured on a mold and cured. The microneedle array is made using 3D printing and designed in such a way so that it can be readily connected to the microfluidic pump. The microfluidic pump is used to drive the fluid flow powered by the user’s pulse, and the microneedle array is used to inject the fluid through the skin painlessly. Through testing the flow across the microfluidic pump prototypes using pressurized air, we characterized the correlation between the flow rate of fluid across the device and parameters including the actuation pressure and frequency of the pressurized air as well as the width of the flow channel. Future directions of the study include testing the devices in human subjects to characterize pulse-driven flow across the devices, computational modeling of the devices, and further changes of the device design to optimize the performance of the device. We will also optimize the device design computationally to tailor the device design to specific diabetic patients. Finally, we will incorporate a 3D-printed insulin reservoir into our system for the storage of insulin solution. Withhold all access to the ETD for 1 year patent I hereby certify that, if appropriate, I have obtained and submitted with my ETD a written permission statement from the ower(s) of each third part copyrighted matter to be included in my thesis or dissertation, allowing distribution as specified above. I certify that the version I submitted is the same as that approved by my advisory committee.

Purpose To investigate the safety and clinical efficacy of bipolar radiofrequency ablation (b-RFA) with increased (> 70 °C) target temperature for the treatment of spine metastases with the intent of achieving pain relief or local tumor control. Materials and methods Thirty-one patients with a total of 37 metastases who were treated with b-RFA with increased temperature and vertebroplasty from January 2016 to May 2019 were retrospectively included. There were 20 women and 11 men with a mean age of 62.4 ± 10.5 (SD) years (range: 40–78 years). Patients and metastases characteristics, procedure details and clinical outcomes were analyzed. Results Metastases were predominantly located in lumbar (22/37; 59.5%) or thoracic spine (13/37; 35.1%). Mean target temperature was 88.4 ± 3.5 (SD) °C (range: 70–90 °C). Technical success was 100% (37/37 metastases). One (1/37; 2.7%) major complication unrelated to b-RFA was reported. One (1/37; 2.7%) metastasis was lost to follow-up. Favorable outcome was noted in patients receiving b-RFA for pain management (16/20 metastases; 80%; mean follow-up, 3.4 ± 2.9 [SD] months) or with oligometastatic/oligoprogressive disease (6/6 metastases; 100%; mean follow-up, 5.0 ± 4.6 [SD] months). In patients receiving b-RFA to prevent complications, favorable outcome was noted in 6/10 metastases (60%; mean follow-up, 3.8 ± 4.8 [SD] months). Conclusions B-RFA with increased target temperature has an excellent safety profile and results in high rates of pain relief and local metastasis control in patients with oligometastatic/oligoprogressive disease. Suboptimal results are achieved in patients receiving b-RFA to prevent complications related to the growth of the index tumor.

Recent studies have begun to highlight the diverse and tumor-specific microbiomes across multiple cancer types. We believe this work raises the important question of whether the classical “Hallmarks of Cancer” should be expanded to include tumor microbiomes. To answer this question, the causal relationships and co-evolution of these microbiotic tumor ecosystems must be better understood. Because host-microbe interactions should be studied in a physiologically relevant context, animal models have been preferred. Yet these models are often poor mimics of human tumors and are difficult to interrogate at high spatiotemporal resolution. We believe that in vitro tissue engineered platforms could provide a powerful alternative approach that combines the high-resolution of in vitro studies with a high degree of physiological relevance. This review will focus on tissue engineered approaches to study host-microbe interactions and to establish their role as an emerging hallmark of cancer with potential as a therapeutic target. Published version

International audience; During general anesthesia (GA), direct analysis of arterial pressure or aortic flow waveforms may be inconclusive in complex situations. Patient-specific biomechanical models, based on data obtained during GA and capable to perform fast simulations of cardiac cycles, have the potential to augment hemodynamic monitoring. Such models allow to simulate Pressure-Volume (PV) loops and estimate functional indicators of cardiovascular (CV) system, e.g. ventricular-arterial coupling (Vva), cardiac efficiency (CE) or myocardial contractility, evolving throughout GA. In this prospective observational study, we created patient-specific biomechanical models of heart and vasculature of a reduced geometric complexity for n=45 patients undergoing GA, while using transthoracic echocardiography and aortic pressure and flow signals acquired in the beginning of GA (baseline condition). If intraoperative hypotension (IOH) appeared, diluted norepinephrine (NOR) was administered and the model readjusted according to the measured aortic pressure and flow signals. Such patients were a posteriori assigned into a so-called hypotensive group. The accuracy of simulated mean aortic pressure (MAP) and stroke volume (SV) at baseline were in accordance with the guidelines for the validation of new devices or reference measurement methods in all patients. After NOR administration in the hypotensive group, the percentage of concordance with 10% exclusion zone between measurement and simulation was > 95% for both MAP and SV. The modeling results showed a decreased Vva (0.64±0.37 vs 0.88±0.43; p=0.039) and an increased CE (0.8±0.1 vs 0.73±0.11; p=0.042) in hypotensive vs normotensive patients. Furthermore, Vva increased by 92±101%, CE decreased by 13±11% (p < 0.001 for both) and contractility increased by 14±11% (p = 0.002) in the hypotensive group post-NOR administration. In this work we demonstrated the application of fast-running patient-specific biophysical models to estimate PV loops and functional indicators of CV system using clinical data available during GA. The work paves the way for model-augmented hemodynamic monitoring at operating theatres or intensive care units to enhance the information on patient-specific physiology.

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. Published version

Purpose To improve the precision of a free-breathing 3D saturation-recovery-based myocardial T1 mapping sequence using a post-processing 3D denoising technique. Methods A T1 phantom and 15 healthy subjects were scanned on a 1.5 T MRI scanner using 3D saturation-recovery single-shot acquisition (SASHA) for myocardial T1 mapping. A 3D denoising technique was applied to the native T1-weighted images before pixel-wise T1 fitting. The denoising technique imposes edge-preserving regularity and exploits the co-occurrence of 3D spatial gradients in the native T1-weighted images by incorporating a multi-contrast Beltrami regularization. Additionally, 2D modified Look-Locker inversion recovery (MOLLI) acquisitions were performed for comparison purposes. Accuracy and precision were measured in the myocardial septum of 2D MOLLI and 3D SASHA T1 maps and then compared. Furthermore, the accuracy and precision of the proposed approach were evaluated in a standardized phantom in comparison to an inversion-recovery spin-echo sequence (IRSE). Results For the phantom study, Bland–Altman plots showed good agreement in terms of accuracy between IRSE and 3D SASHA, both on non-denoised and denoised T1 maps (mean difference −1.4 ± 18.9 ms and −4.4 ± 21.2 ms, respectively), while 2D MOLLI generally underestimated the T1 values (69.4 ± 48.4 ms). For the in vivo study, there was a statistical difference between the precision measured on 2D MOLLI and on non-denoised 3D SASHA T1 maps (P = 0.005), while there was no statistical difference after denoising (P = 0.95). Conclusion The precision of 3D SASHA myocardial T1 mapping was substantially improved using a 3D Beltrami regularization based denoising technique and was similar to that of 2D MOLLI T1 mapping, while preserving the higher accuracy and whole-heart coverage of 3D SASHA. Electronic supplementary material The online version of this article (10.1007/s10334-018-0703-y) contains supplementary material, which is available to authorized users.

Ventricular volumetric ejection fraction (VV EF) is often normal in patients with single ventricle circulations despite them experiencing symptoms related to circulatory failure. We sought to determine if kinetic energy (KE) could be a better marker of ventricular performance. KE was prospectively quantified using four-dimensional flow MRI in 41 patients with a single ventricle circulation (aged 0.5–28 yr) and compared with 43 healthy volunteers (aged 1.5–62 yr) and 14 patients with left ventricular (LV) dysfunction (aged 28–79 yr). Intraventricular end-diastolic blood was tracked through systole and divided into ejected and residual blood components. Two ejection fraction (EF) metrics were devised based on the KE of the ejected component over the total of both the ejected and residual components using 1) instantaneous peak KE to assess KE EF or 2) summating individual peak particle energy (PE) to assess PE EF. KE EF and PE EF had a smaller range than VV EF in healthy subjects (97.9 ± 0.8 vs. 97.3 ± 0.8 vs. 60.1 ± 5.2%). LV dysfunction caused a fall in KE EF ( P = 0.01) and PE EF ( P = 0.0001). VV EF in healthy LVs and single ventricle hearts was equivalent; however, KE EF and PE EF were lower ( P < 0.001) with a wider range indicating a spectrum of severity. Those reporting the greatest symptomatic impairment (New York Heart Association II) had lower PE EF than asymptomatic subjects ( P = 0.0067). KE metrics are markers of healthy cardiac function. PE EF may be useful in grading dysfunction. NEW & NOTEWORTHY Kinetic energy (KE) represents the useful work of the heart in ejecting blood. This article details the utilization of KE indexes to assess cardiac function in health and a variety of pathophysiological conditions. KE ejection fraction and particle energy ejection fraction (PE EF) showed a narrow range in health and a lower wider range in disease representing a spectrum of severity. PE EF was altered by functional status potentially offering the opportunity to grade dysfunction.

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. Wake Forest Clinical and Translational Science Institute [UL1 TR001420]; Army; Navy; NIH; Air Force; VA; Health Affairs [W81XWH-14-2-0004]; U.S. Army Medical Research Acquisition Activity, Fort Detrick MD [21702-5014]; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science, and Technology [2012R1A6A3A03040684] We thank H. S. Kim, J. S. Lee, and T. Bledsoe for a surgical procedure, Regenerative Medicine Clinical Center (RMCC) for hMPCs isolation, M. Devarasetty for imaging, and Y. M. Ju for technical assistance. The authors thank K. Klein at the Wake Forest Clinical and Translational Science Institute (UL1 TR001420) for editorial assistance. This work was supported by the Army, Navy, NIH, Air Force, VA and Health Affairs to support the AFIRM II effort under Award No. W81XWH-14-2-0004. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. J.H.K. was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2012R1A6A3A03040684).

Hyaluronan (or hyaluronic acid, HA) is a ubiquitous molecule that plays critical roles in numerous physiological functions in vivo, including tissue hydration, inflammation, and joint lubrication. Both the abundance and size distribution of HA in biological fluids are recognized as robust indicators of various pathologies and disease progressions. However, such analyses remain challenging because conventional methods are not sufficiently sensitive, have limited dynamic range, and/or are only semi-quantitative. Here we demonstrate label-free detection and molecular weight discrimination of HA with a solid-state nanopore sensor. We first employ synthetic HA polymers to validate the measurement approach and then use the platform to determine the size distribution of as little as 10 ng of HA extracted directly from synovial fluid in an equine model of osteoarthritis. Our results establish a quantitative method for assessment of a significant molecular biomarker that bridges a gap in the current state of the art., Involved in various diseases, hyaluronic acid is an important indicator of pathophysiology. Here, the authors report on a solid-state nanopore for the detection of the molecular weight and abundance of hyaluronic acid and demonstrate the system by studying an equine model of osteoarthritis

Variability in patient response to anti-cancer drugs is currently addressed by relating genetic mutations to chemotherapy through precision medicine. However, practical benefits of precision medicine to therapy design are less clear. Even after identification of mutations, oncologists are often left with several drug options, and for some patients there is no definitive treatment solution. There is a need for model systems to help predict personalized responses to chemotherapeutics. We have microengineered 3D tumor organoids directly from fresh tumor biopsies to provide patient-specific models with which treatment optimization can be performed before initiation of therapy. We demonstrate the initial implementation of this platform using tumor biospecimens surgically removed from two mesothelioma patients. First, we show the ability to biofabricate and maintain viable 3D tumor constructs within a tumor-on-a-chip microfluidic device. Second, we demonstrate that results of on-chip chemotherapy screening mimic those observed in subjects themselves. Finally, we demonstrate mutation-specific drug testing by considering the results of precision medicine genetic screening and confirming the effectiveness of the non-standard compound 3-deazaneplanocin A for an identified mutation. This patient-derived tumor organoid strategy is adaptable to a wide variety of cancers and may provide a framework with which to improve efforts in precision medicine oncology. Wake Forest Baptist Medical Center Clinical and Translational Science Institute Open Pilot Program; Wake Forest University School of Medicine; Comprehensive Cancer Center at Wake Forest Baptist Medical Center's NCI Cancer Center Support Grant [P30CA012197]; Defense Threat Reduction Agency (DTRA) under Space and Naval Warfare Systems Center Pacific (SSC PACIFIC) [N6601-13-C-2027] AS acknowledges funds from the Wake Forest Baptist Medical Center Clinical and Translational Science Institute Open Pilot Program. ARH acknowledges start-up funds from Wake Forest University School of Medicine. AS and ARH acknowledge services from the Wake Forest Cellular Imaging Shared Resource supported by the Comprehensive Cancer Center at Wake Forest Baptist Medical Center's NCI Cancer Center Support Grant P30CA012197. AS and ARH acknowledge funding by the Defense Threat Reduction Agency (DTRA) under Space and Naval Warfare Systems Center Pacific (SSC PACIFIC) Contract No. N6601-13-C-2027. The publication of this material does not constitute approval by the government of the findings or conclusions herein. The authors gratefully acknowledge Dr. Frank Marini for access to the confocal microscopy equipment employed in the studies.

International audience

International audience; Understanding (patho)physiological phenomena and mechanisms of failure in patients with Fontan circulation-a surgically established circulation for patients born with a functionally single ventricle-remains challenging due to the complex hemodynamics and high inter-patient variations in anatomy and function. In this work, we present a biomechanical model of the heart and circulation to augment the diagnostic evaluation of Fontan patients with early-stage heart failure. The proposed framework employs a reduced-order model of heart coupled with a simplified circulation including venous return, creating a closed-loop system. We deploy this framework to augment the information from data obtained during combined cardiac catheterization and magnetic resonance exams (XMR), performed at rest and during dobutamine stress in 9 children with Fontan circulation and 2 biventricular controls. We demonstrate that our modeling framework enables patient-specific investigation of myocardial stiffness, contractility at rest, contractile reserve during stress and changes in vascular resistance. Hereby, the model allows to identify key factors underlying the pathophysiological response to stress in these patients. In addition, the rapid personalization of the model to patient data and fast simulation of cardiac cycles make our framework directly applicable in a clinical workflow. We conclude that the proposed modeling framework is a valuable addition to the current clinical diagnostic XMR exam that helps to explain patient-specific stress hemodynamics and can identify potential mechanisms of failure in patients with Fontan circulation.

International audience; In this paper we propose a method for locally adjusted optical flow-based registration of multimodal images, which uses the segmentation of the object of interest and its representation by the signed-distance function (OF dist method). We deal with non-rigid registration of the image series acquired by the Modiffied Look-Locker Inversion Recovery (MOLLI) magnetic resonance imaging sequence, which is used for a pixel-wise estimation of T 1 relaxation time. The spatial registration of the images within the series is necessary to compensate the patient's imperfect breath-holding. The evolution of intensities and a large variation of image contrast within the MOLLI image series, together with the myocardium of left ventricle (the object of interest) typically not being the most distinct object in the scene, makes the registration challenging. The paper describes all components of the proposed OF dist method and their implementation. The method is then compared to the performance of a standard mutual information maximization-based registration method, applied either to the original image (MIM) or to the signed-distance function (MIM dist). Several experiments with synthetic and real MOLLI images are carried out. On synthetic image with a single object, MIM performed the best, while OF dist and MIM dist provided better results on synthetic images with more than one object and on real images. When applied to signed-distance function of two objects of interest, MIM dist provided a larger registration error (but more homogeneously distributed) compared to OF dist. For the real MOLLI image series with left ventricle pre-segmented using a level-set method, the proposed OF dist registration performed the best, as is demonstrated visually and by measuring the increase of mutual information in the object of interest and its neighborhood.

Immunotherapies have demonstrated limited efficacy in pancreatic ductal adenocarcinoma (PDAC) patients despite their success in treating other tumor types. This limitation is largely due to the relatively immunosuppressive environment surrounding the tumor. A focal ablative technique called irreversible electroporation (IRE) has been shown to modulate this environment, enhancing the efficacy of immunotherapy. One enhancing factor related to improved prognosis is a decrease in regulatory T cells (T-reg). This decrease has been previously unpredictable for clinicians using IRE, who currently have limited real-time metrics for determining the activation of the patient's immune response. Here, we report that larger overall changes in output current are correlated with larger decreases in T cell populations 24 hours post-treatment. This result suggests that clinicians can make real-time decisions regarding optimal follow-up therapy based on the range of output current delivered during treatment. This capability could maximize the immunomodulating effect of IRE in synergy with follow-up immunotherapy. Additionally, these results suggest that feedback from a preliminary IRE treatment of the local tumor may help inform clinicians regarding the timing and choice of subsequent therapies, such as resection, immunotherapy, chemotherapy, or follow-up thermal or non-thermal ablation. Cures Within Reach (PUJFSANY); PanCAN [16-65-IANN]; Bradley Fellowship; Department of Electrical and Computer Engineering at Virginia Tech This work was supported by Cures Within Reach (PUJFSANY). R.D. would also like to acknowledge PanCAN (16-65-IANN) for general support of his research. N.B. acknowledges the Bradley Fellowship and the Department of Electrical and Computer Engineering at Virginia Tech for financial support. The authors would also like to thank Timothy O'Brien for assistance with the data extraction, and Kenneth N. Aycock for input on the manuscript.

International audience; Objective: The accuracy of phase-contrast magnetic resonance imaging (PC-MRI) measurement is investigated using a computational fluid dynamics (CFD) model with the objective to determine the magnitude of the flow underestimation due to turbulence behind a narrowed valve in a phantom experiment. Materials and Methods: An acrylic stationary flow phantom is used with three insertable plates mimicking aortic valvular stenoses of varying degrees. Positive and negative horizontal fluxes are measured at equidistant slices using standard PC-MRI sequences by 1.5T and 3T systems. The CFD model is based on the 3D lattice Boltzmann method (LBM). The experimental and simulated data are compared using the Bland-Altman-derived limits of agreement. Based on the LBM results, the turbulence is quantified and confronted with the level of flow underestimation. Results: LBM gives comparable results to PC-MRI for valves up to moderate stenosis on both field strengths. The flow magnitude through a severely stenotic valve was underestimated due to signal void in the regions of turbulent flow behind the valve, consistently with the level of quantified turbulence intensity.Discussion: Flow measured by PC-MRI is affected by noise and turbulence. LBM can simulate turbulent flow efficiently and accurately, it has therefore the potential to improve clinical interpretation of PC-MRI.

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. National Science Foundation USANational Science Foundation (NSF) [NSF:CBET-1510920] National Science Foundation USA, Grant/Award Number: NSF:CBET-1510920

The end-systolic elastance (\(E_{\text {es}}\)) – the slope of the end-systolic pressure-volume relationship (ESPVR) at the end of ejection phase – has become a reliable indicator of myocardial functional state. The estimation of \(E_{\text {es}}\) by the original multiple-beat method is invasive, which limits its routine usage. By contrast, non-invasive single-beat estimation methods, based on the assumption of the linearity of ESPVR and the uniqueness of the normalised time-varying elastance curve \(E^N(t)\) across subjects and physiology states, have been applied in a number of clinical studies. It is however known that these two assumptions have a limited validity, as ESPVR can be approximated by a linear function only locally, and \(E^N(t)\) obtained from a multi-subject experiment includes a confidence interval around the mean function. Using datasets of 3 patients undergoing general anaesthesia (each containing aortic flow and pressure measurements at baseline and after introducing a vasopressor noradrenaline), we first study the sensitivity of two single-beat methods—by Sensaki et al. and by Chen et al.—to the uncertainty of \(E^N(t)\). Then, we propose a minimally-invasive method based on a patient-specific biophysical modelling to estimate the whole time-varying elastance curve \(E^{\text {model}}(t)\). We compare \(E^{\text {model}}_{\text {es}}\) with the two single-beat estimation methods, and the normalised varying elastance curve \(E^{N,\text {model}}(t)\) with \(E^{N}(t)\) from published physiological experiments.

International audience

International audience; The original version of this article unfortunately contained a mistake. The presentation of Equation was incorrect. The corrected equation is given below.

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. This work was supported by the National Cancer Institute of the National Institutes of Health through awards R21CA192042, R01CA213423, and P01CA207206 and by a National Science Foundation CAREER Award (CBET- 1652112).

Aligned and suspended fibers allow study of cell emergence, collective migration, and wound gap closure. Emergent leader and follower cells collectively migrate in streams and sheets. A physical fiber spacing of 375 μm, beyond which sheet advancement is hindered, is identified, thus enabling the engineering of closing and nonclosing gaps., 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 µm 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 early treatment and rapid closure of acute or chronic wounds is essential for normal healing and prevention of hypertrophic scarring. The use of split thickness autografts is often limited by the availability of a suitable area of healthy donor skin to harvest. Cellular and non-cellular biological skin-equivalents are commonly used as an alternative treatment option for these patients, however these treatments usually involve multiple surgical procedures and associated with high costs of production and repeated wound treatment. Here we describe a novel design and a proof-of-concept validation of a mobile skin bioprinting system that provides rapid on-site management of extensive wounds. Integrated imaging technology facilitated the precise delivery of either autologous or allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area, replicating the layered skin structure. Excisional wounds bioprinted with layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier showed rapid wound closure, reduced contraction and accelerated re-epithelialization. These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes. Telemedicine and Advanced Technology Research Center Armed Forces Institute for Regenerative Medicine We would like to thank the WFIRM surgical core facility, in particular Cara Clouse, Tammy Cockerham, Tiffany Bledsoe, Adam Wilson and Sandy Sink. We also thank Paul Robertson (Next Medical Design) and Kevin Rackers, the contract developers of the printer. This research was funded by the Telemedicine and Advanced Technology Research Center and the Armed Forces Institute for Regenerative Medicine.

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. National Science FoundationNational Science Foundation (NSF) [IIS-117519]; National Science Foundation (CAREER award)National Science Foundation (NSF) [CBET-1454226]; Institute for Critical Technology and Applied Science (ICTAS) at Virginia Tech The authors would like to thank our colleagues in the MicroN BASE laboratory at Virginia Tech, especially SeungBeum Suh and Ying Zhan. This project was partially supported by the National Science Foundation (Nos. IIS-117519 and CAREER award, CBET-1454226) and the Institute for Critical Technology and Applied Science (ICTAS) at Virginia Tech.