Cells, to carry out many important functions, employ an elaborate transport network with bio-molecular components forming roadways as well as vehicles. The transport is achieved with remarkable robustness under a very uncertain environment. The main goal of this proposal is to understand how biology achieves such functionality and leveraging the knowledge toward realizing effective engineered transport mechanisms for micron sized cargo. The realization of a robust infrastructure that enables simultaneous transport of many micron and smaller sized particles will have a transformative impact on a vast range of areas such as medicine, drug development, electronics, and bio-materials. A key challenge here is to probe the mechanisms often at the nanometer scale as the bio-molecular components are at tens of nanometer scale. The main tools for addressing these challenges come from an engineering perspective that is guided by existing insights from biology. The proposal will bring together researchers from engineering and biology and it provides an integrated environment for students. Moreover, it is known that an impaired transport mechanism can underlie many neurodegenerative maladies, and as the research here pertains to studying intracellular transport, discoveries hold the potential for shedding light on what causes the impaired transport. Robust infrastructure that enables simultaneous transport of many micron and smaller sized particles will have a transformative impact on a vast range of areas such as medicine, drug development, electronics, and bio-materials. Daunting challenges from the underlying highly uncertain and complex environments impede enabling robust and efficient transport systems at micro-scale. Motivated by transport in biological cells, this work proposes a robust and efficient engineered infrastructure for transporting micron/molecular scale cargo using biological constructs. For probing and manipulating the transport network, the proposal envisions strategies for coarse and fine resolution objectives at the global and local scales respectively. At the fine scale of monitoring and control, scarce and expensive physical resources such as high resolution sensors have to be shared for interrogation/control of multiple carriers. In this proposal, the principles for joint control, sensor allocation and scheduling of resources to achieve enhanced performance objectives of a high resolution probing tool, will be developed. A modern control perspective forms an essential strategy for managing multiple objectives. At the global scale, entire traffic will be monitored to arrive at real-time and off-line inferences on traffic modalities. Associated principles for dynamically identifying and tracking clusters of carriers and their importance will be built. This categorization of physical elements and their importance will determine the dynamic allocation of computational resources. Associated study of trade-offs will guide a combined strategy for allocation of computational resources and gathering of information on physical elements. Methods based on the reconstruction of graph topologies for reaching inferences that are suited to dynamically related time trajectories for the transportation infrastructure will be developed. The research proposed is transformative as it will enable a new transport paradigm at the cellular scale, which will also provide unique insights into intracellular transport where it will be possible to investigate multiple factors under the same experimental conditions.

The timely and accurate in-service identification of faults in mechanical structures, such as airplanes, can play a vitally important role in avoiding catastrophes. One major challenge, however, is that the sensing system relies on high frequency signals, the coordination of which is difficult to achieve throughout a large structure. To tackle this fundamental issue, the research team will take advantage of 3D printing technology to fabricate integrated sensor-structure components. Specifically, the team plans to innovate a novel printing scheme that can embed piezoelectric transducers (namely, sensor/actuator coupled elements) into layered composites. As the transducers are densely distributed throughout the entire structure, they function like a nerve system embedded into the structure. Such a sensor nerve system, when combined with new control and command systems and advanced data and signal processing capability, can fully unleash the latest computing power to pinpoint the fault location. The new framework of utilizing emerging additive manufacturing technology to produce a structural system with integrated, densely distributed active sensing elements will potentially lead to paradigm-shifting progress in structural self-diagnosis. This advancement may allow the acquisition of high-quality, active interrogation data throughout the entire structure, which can then be used to facilitate highly accurate and robust decision-making. It will lead to intellectual contributions including: 1) development of a new sensing modality with mechanical-electrical dual-field adaptivity, that yields rich and high-quality data throughout the structure; 2) design of an additive manufacturing scheme that inserts piezoelectric micro transducer arrays throughout the structure to enable active interrogation; and 3) formulation of new data analytics and inverse analysis that can accurately identify the fault location/severity and guide the fine-tuning of the sensor system.

Epilepsy is one of the most common neurological disorders, affecting between 0.4% and 1% of the world's population. While seizures can be controlled in approximately two thirds of newly diagnosed patients through the use of one or more antiepileptic drugs (AEDs), the remainder experience seizures even on multiple medications. The primary impacts of the chronic condition of epilepsy on a patient are a lower quality of life, loss of productivity, comorbidities, and increased risk of death. Epilepsy is an intermittent brain disorder, and in localization-related epilepsy, which is the most common form of epilepsy, one or a few discrete brain areas (the seizure focus or seizure foci) are believed to be responsible for seizure initiation. More recent approaches with implantable electrical stimulation seizure control devices hold value as a therapeutic option for the control of seizures. These devices, directly or indirectly, target the seizure focus and seek to control its expression. In this project we will build a multichannel brain implantable device based on emerging cyber physical system (CPS) principles. This brain implantable CPS device will incorporate key design features to make the device dependable, scalable, composable, certifiable, and interoperable. The device will operate over the life of an animal, or a patient, and continuously record brain activity and stimulate the brain when seizure related activity is detected to abort an impending seizure. Episodic brain disorders such as epilepsy have a considerable impact on a patient's productivity and quality of life and may be life-threatening when seizures cannot be controlled with medications. The goal of this project is to create a second generation brain-implantable sensing and stimulating device (BISSD) based on emerging CPS principles and practice. The development of a BISSD as a exemplifies several defining aspects that inform and illustrate core CPS principles. First, to meet the important challenge of regulatory approval a composable, scalable and certifiable framework that supports testing in multiple species is proposed. Second, a BISSD must be wholly integrated with the patient and fully cognizant at every instant of brain state, including dynamic changes in both the normal and abnormal expression of brain physiology and therapeutic intervention. Thus, this project seeks a tight conjunction of the cyber solution that must monitor itself and monitor and stimulate the brain using implanted, adaptable, distributed, and networked electrodes, and the physical system which in this case is the intermittently failing human brain. Third, a BISSD must function for an extensive period of time, up to the life of the patient, because each surgery to place and retrieve a BISSD carries an attendant risk. This requirement necessitates a dependable solution, which this project seeks to reliably achieve through both an understanding of the brain's foreign body response and a unique hierarchical fault-tolerant design. Fourth, an advanced salient approaches to acquire, compress, and analyze sensor signals to achieve real-time monitoring and control of seizures is employed. This project should yield a powerful, scalable CPS framework for robust fault-tolerant implantable medical devices with real-time processing that can grow with advances in sensors, sensing modalities, time-series analysis, real-time computation, control, materials, power and knowledge of underlying biology. The USA has a competitive advantage in the control of seizures in medically refractory epilepsy. In the modern era, epilepsy surgery evolved in the USA in the 1970s and spread from here to other parts of the world. Similarly, the USA enjoys a competitive advantage in BISSDs, and success in this effort will enable the USA to build on and maintain this advantage. In addition to epilepsy, advances made here can be expected to benefit the treatment of other neurological and psychiatric brain disorders.

The timely and accurate in-service identification of faults in mechanical structures, such as airplanes, can play a vitally important role in avoiding catastrophes. One major challenge, however, is that the sensing system relies on high frequency signals, the coordination of which is difficult to achieve throughout a large structure. To tackle this fundamental issue, the research team will take advantage of 3D printing technology to fabricate integrated sensor-structure components. Specifically, the team plans to innovate a novel printing scheme that can embed piezoelectric transducers (namely, sensor/actuator coupled elements) into layered composites. As the transducers are densely distributed throughout the entire structure, they function like a nerve system embedded into the structure. Such a sensor nerve system, when combined with new control and command systems and advanced data and signal processing capability, can fully unleash the latest computing power to pinpoint the fault location. The new framework of utilizing emerging additive manufacturing technology to produce a structural system with integrated, densely distributed active sensing elements will potentially lead to paradigm-shifting progress in structural self-diagnosis. This advancement may allow the acquisition of high-quality, active interrogation data throughout the entire structure, which can then be used to facilitate highly accurate and robust decision-making. It will lead to intellectual contributions including: 1) development of a new sensing modality with mechanical-electrical dual-field adaptivity, that yields rich and high-quality data throughout the structure; 2) design of an additive manufacturing scheme that inserts piezoelectric micro transducer arrays throughout the structure to enable active interrogation; and 3) formulation of new data analytics and inverse analysis that can accurately identify the fault location/severity and guide the fine-tuning of the sensor system.