Publications by Type: Journal Article

Strain energy and kinetic energy in the human brain were estimated by magnetic resonance elastography (MRE) during harmonic excitation of the head, and compared to characterize the effect of loading direction and frequency on brain deformation. In brain MRE, shear waves are induced by external vibration of the skull and imaged by a modified MR imaging sequence; the resulting harmonic displacement fields are typically “inverted” to estimate mechanical properties, like stiffness or damping. However, measurements of tissue motion from MRE also illuminate key features of the response of the brain to skull loading. In this study, harmonic excitation was applied in two different directions and at five different frequencies from 20 to 90 Hz. Lateral loading induced primarily left-right head motion and rotation in the axial plane; occipital loading induced anterior-posterior head motion and rotation in the sagittal plane. The ratio of strain energy to kinetic energy (SE/KE) depended strongly on both direction and frequency. The ratio of SE/KE was approximately four times larger for lateral excitation than for occipital excitation and was largest at the lowest excitation frequencies studied. These results are consistent with clinical observations that suggest lateral impacts are more likely to cause injury than occipital or frontal impacts, and also with observations that the brain has low-frequency (∼10 Hz) natural modes of oscillation. The SE/KE ratio from brain MRE is potentially a simple and powerful dimensionless metric of brain vulnerability to deformation and injury.

We propose a relatively simple two-dimensional mathematical model for maladaptive inward remodeling of resistive arteries in hypertension in terms of vascular solid mechanics. The main premises are: (i) maladaptive inward remodeling manifests as a reduced increase in the arterial mass compared to the case of adaptive remodeling under equivalent hypertensive pressures and (ii) the pressure-induced circumferential stress in the arterial wall is restored to its basal target value as happens in the case of adaptive remodeling. The rationale for these assumptions is the experimental findings that elevated tone in association with sustained hypertensive pressure down-regulate the normal differentiation of vascular smooth muscle cells from contractile to synthetic phenotype and the data for the calculated hoop stress before and after completion of remodeling. Results from illustrative simulations show that as the hypertensive pressure increases, remodeling causes a nonmonotonic variation of arterial mass, a decrease in inner arterial diameter, and an increase in wall thickness. These findings and the model prediction that inward eutrophic remodeling is preceded by inward hypertrophic remodeling are supported by published observations. Limitations and perspectives for refining the mathematical model are discussed.

Human presence in space has uncovered several health concerns related to the space environment that need to be addressed for future space missions. The hostile space environment includes radiation and microgravity that cause various pathophysiological effects. Among them are conditions related to the cardiovascular system. The cardiovascular system shows a dysfunctional and deconditioning state, similar to ageing on Earth, once exposed to the space environment. As we aim for longer space missions to the Moon, Mars, and thus into deep space, better understanding, monitoring, and development of countermeasures for these accelerated ageing processes are necessary. Biomarkers and their integration into biosensors therefore become important tools to understand the underlying mechanisms, develop countermeasures and monitor accelerated cardiovascular ageing. In this review, we will provide a brief overview of the space environment and its effects on the human cardiovascular system. We list the known potential cardiovascular ageing biomarkers relevant to space along with our current knowledge of the underlying mechanisms of cardiovascular ageing. We also explore in more details about the various biosensors used, their specifications, and how lab-on-a-chip systems are crucial to the development of these biosensors for tracking cardiovascular ageing during upcoming space missions.

Drug-coated balloon (DCB) percutaneous interventional therapy allows for durable reopening of the narrowed lumen via physical tissue expansion and local anti-restenosis drug delivery, providing an alternative to traditional uncoated balloons or a permanent indwelling implant such as a conventional metallic drug-eluting stent. While DCB-based treatment of peripheral arterial disease (PAD) has been incorporated into clinical guidelines, DCB use has been recently curtailed due to reports that showed evidence of increased mortality risk in patients treated with paclitaxel (PTX)-coated balloons. Given the United States Food and Drug Administration's 2019 consequent warning regarding PTX-eluting DCBs and the subsequent marked reduction in clinical DCB use, there is now a critical need to better understand the compositional and mechanical factors underlying DCB efficacy and safety. Most work to date on DCB refinement has focused on designing both the enabling balloon catheter and alternate coatings composed of various drugs and excipients, followed by device evaluation in preclinical and clinical studies. We contend that improvement in DCB performance will require a better understanding of the biophysical factors operative during and following balloon deployment, and moreover that the elaboration and demonstrated control of these factors are needed to address current concerns with DCB use. This article provides a perspective on the biophysical interactions that govern DCB performance and offers new design strategies for the development of next-generation DCB devices.

Purpose

Premature coronary artery bypass graft (CABG) failure has been linked to geometric, mechanical, and compositional discrepancies between host and graft tissues. Acute hemodynamic disturbances and the introduction of wall stress gradients trigger a myriad of mechanobiological processes at the anastomosis that can be associated with restenosis and graft failure. Although the origins of coronary artery disease dictate the anastomotic target, an opportunity exists for graft-vessel optimization through rationale graft selection.

Methods

Here we explored the four distinct regions of the left (L) and right (R) ITA (1 = proximal, 2 = submuscular, 3 = middle, 4 = distal), and four common target vessels in the coronary circulation including the proximal and distal left anterior descending (PLAD & DLAD), right coronary (RCA), and left circumflex (LCX) arteries. Benchtop biaxial mechanical data was used to acquire constitutive model parameters of these tissues and enable vessel-specific computational models to elucidate the mechanical consequences of 32 unique graft-target combinations.

Results

Simulations revealed the maximum principal wall stresses for the PLAD, RCA, and LCX occurred when anastomosed with LITA₁, and the maximum flow-induced shear stress occurred with LITA₄. The DLAD, on the other hand, reached stress maximums when anastomosed to LITA₄. Using a normalized objective function of simulation output variables, we found LITA₂ to be the best graft choice for both LADs, RITA₃ for the RCA, and LITA₃ for the LCX.

Conclusion

Although mechanical compatibility is just one of many factors determining bypass graft outcomes, our data suggests improvements can be made to the grafting process through vessel-specific regional optimization.

Drug-coated balloon therapy is a minimally invasive endovascular approach to treat obstructive arterial disease, with increasing utilization in the peripheral circulation due to improved outcomes as compared to alternative interventional modalities. Broader clinical use of drug-coated balloons is limited by an incomplete understanding of device- and patient-specific determinants of treatment efficacy, including late outcomes that are mediated by postinterventional maladaptive inward arterial remodeling. To address this knowledge gap, we propose a predictive mathematical model of pressure-mediated femoral artery remodeling following drug-coated balloon deployment, with account of drug-based modulation of resident vascular cell phenotype and common patient comorbidities, namely, hypertension and endothelial cell dysfunction. Our results elucidate how postinterventional arterial remodeling outcomes are altered by the delivery of a traditional anti-proliferative drug, as well as by codelivery with an anti-contractile drug. Our findings suggest that codelivery of anti-proliferative and anti-contractile drugs could improve patient outcomes following drug-coated balloon therapy, motivating further consideration of novel payloads in next-generation devices.

Biotechnological innovations have vastly improved the capacity to perform large-scale protein studies, while the methods we have for identifying and quantifying individual proteins are still inadequate to perform protein sequencing at the single-molecule level. Nanopore-inspired systems devoted to understanding how single molecules behave have been extensively developed for applications in genome sequencing. These nanopore systems are emerging as prominent tools for protein identification, detection, and analysis, suggesting realistic prospects for novel protein sequencing. This review summarizes recent advances in biological nanopore sensors toward protein sequencing, from the identification of individual amino acids to the controlled translocation of peptides and proteins, with attention focused on device and algorithm development and the delineation of molecular mechanisms with the aid of simulations. Specifically, the review aims to offer recommendations for the advancement of nanopore-based protein sequencing from an engineering perspective, highlighting the need for collaborative efforts across multiple disciplines. These efforts should include chemical conjugation, protein engineering, molecular simulation, machine-learning-assisted identification, and electronic device fabrication to enable practical implementation in real-world scenarios.

Dementia refers to a particular group of symptoms characterized by difficulties with memory, language, problem-solving, and other thinking skills that affect a person’s ability to perform everyday activities. Alzheimer’s disease (AD) is the most common form of dementia, affecting about 6.2 million Americans aged 65 years and older. Likewise, cardiovascular diseases (CVDs) are a major cause of disability and premature death, impacting 126.9 million adults in the USA, a number that increases with age. Consequently, CVDs and cardiovascular risk factors are associated with an increased risk of AD and cognitive impairment. They share important age-related cardiometabolic and lifestyle risk factors, that make them among the leading causes of death. Additionally, there are several premises and hypotheses about the mechanisms underlying the association between AD and CVD. Although AD and CVD may be considered deleterious to health, the study of their combination constitutes a clinical challenge, and investigations to understand the mechanistic pathways for the cause-effect and/or shared pathology between these two disease constellations remains an active area of research. AD pathology is propagated by the amyloid β (Aβ) peptides. These peptides give rise to small, toxic, and soluble Aβ oligomers (SPOs) that are nonfibrillar, and it is their levels that show a robust correlation with the extent of cognitive impairment. This review will elucidate the interplay between the effects of accumulating SPOs in AD and CVDs, the resulting ER stress response, and their role in vascular dysfunction. We will also address the potential underlying mechanisms, including the possibility that SPOs are among the causes of vascular injury in CVD associated with cognitive decline. By revealing common mechanistic underpinnings of AD and CVD, we hope that novel experimental therapeutics can be designed to reduce the burden of these devastating diseases.

Cytomegalovirus (CMV) is a member of the β-herpesviruses and is ubiquitous, infecting 50%–99% of the human population depending on ethnic and socioeconomic conditions. CMV establishes lifelong, latent infections in their host. Spontaneous reactivation of CMV is usually asymptomatic, but reactivation events in immunocompromised or immunosuppressed individuals can lead to severe morbidity and mortality. Moreover, herpesvirus infections have been associated with several cardiovascular and post-transplant diseases (stroke, atherosclerosis, post-transplant vasculopathy, and hypertension). Herpesviruses, including CMV, encode viral G-protein-coupled receptors (vGPCRs) that alter the host cell by hijacking signaling pathways that play important roles in the viral life cycle and these cardiovascular diseases. In this brief review, we discuss the pharmacology and signaling properties of these vGPCRs, and their contribution to hypertension. Overall, these vGPCRs can be considered attractive targets moving forward in the development of novel hypertensive therapies.

We consider the thermal, mechanical, and chemical contact of two subsystems composed of ideal gases, both of which are not in the thermodynamic limit. After contact, the combined system is isolated, and the entropy is determined through the use of its standard connection to the phase space density (PSD), where only those microstates at a given energy value are counted. The various intensive properties of these small systems that follow from a derivative of the PSD, such as the temperature, pressure, and chemical potential (evaluated via a backward difference), while equal when the two subsystems are in equilibrium are nevertheless found not to behave in accordance with what is expected from macroscopic thermodynamics. Instead, it is the entropy, defined from its connection to the PSD, that still controls the behavior of these small (nonextensive) systems. We also analyze the contact of these two subsystems utilizing an alternative entropy definition, through its proposed connection to the phase space volume (PSV), where all microstates at or below a given energy value are counted. We show that certain key properties of these small systems obtained with the PSV either do not become equal or do not consistently describe the two subsystems when in contact, suggesting that the PSV should not be used for analyzing the behavior of small isolated systems.