Optimizing autoinjector devices using physics-based simulations and Gaussian processes.

Autoinjectors are becoming a primary drug delivery option to the subcutaneous space. These devices need to work robustly and autonomously to maximize drug bio-availability. However, current designs ignore the coupling between autoinjector dynamics and tissue biomechanics. Here we present a Bayesian framework for optimization of autoinjector devices that can account for the coupled autoinjector-tissue biomechanics and uncertainty in tissue mechanical behavior. The framework relies on replacing the high fidelity model of tissue insertion with a Gaussian process (GP). The GP model is accurate yet computationally affordable, enabling a thorough sensitivity analysis that identified tissue properties, which are not part of the autoinjector design space, as important variables for the injection process. Higher fracture toughness decreases the crack depth, while tissue shear modulus has the opposite effect. The sensitivity analysis also shows that drug viscosity and spring force, which are part of the design space, affect the location and timing of drug delivery. Low viscosity could lead to premature delivery, but can be prevented with smaller spring forces, while higher viscosity could prevent premature delivery while demanding larger spring forces and increasing the time of injection. Increasing the spring force guarantees penetration to the desired depth, but it can result in undesirably high accelerations. The Bayesian optimization framework tackles the challenge of designing devices with performance metrics coupled to uncertain tissue properties. This work is important for the design of other medical devices for which optimization in the presence of material behavior uncertainty is needed.

Modeling large-volume subcutaneous injection of monoclonal antibodies with anisotropic porohyperelastic models and data-driven tissue layer geometries.

Subcutaneous injection of therapeutic monoclonal antibodies (mAbs) has become one of the fastest-growing fields in the pharmaceutical industry. The transport and mechanical processes behind large volume injections are poorly understood. Here, we leverage a large-deformation poroelastic model to study high-dose, high-speed subcutaneous injection. We account for the anisotropy of subcutaneous tissue using of a fibril-reinforced porohyperelastic model. We also incorporate the multi-layer structure of the skin tissue, generating data-driven geometrical models of the tissue layers using histological data. We analyze the impact of handheld autoinjectors on the injection dynamics for different patient forces. Our simulations show the importance of considering the large deformation approach to model large injection volumes. This work opens opportunities to better understand the mechanics and transport processes that occur in large-volume subcutaneous injections of mAbs.

A framework to optimize spring-driven autoinjectors.

The major challenges in the optimization of autoinjectors lie in developing an accurate model and meeting competing requirements. We have developed a computational model for spring-driven autoinjectors, which can accurately predict the kinematics of the syringe barrel, needle displacement (travel distance) at the start of drug delivery, and injection time. This paper focuses on proposing a framework to optimize the single-design of autoinjectors, which deliver multiple drugs with different viscosity. We replace the computational model for spring-driven autoinjectors with a surrogate model, i.e., a deep neural network, which improves computational efficiency 1,000 times. Using this surrogate, we perform Sobol sensitivity analysis to understand the effect of each model input on the quantities of interest. Additionally, we pose the design problem within a multi-objective optimization framework. We use our surrogate to discover the corresponding Pareto optimal designs via Pymoo, an open source library for multi-objective optimization. After these steps, we evaluate the robustness of these solutions and finally identify two promising candidates. This framework can be effectively used for device design optimization as the computation is not demanding, and decision-makers can easily incorporate their preferences into this framework.

Improving reconstructive surgery design using Gaussian process surrogates to capture material behavior uncertainty.

To produce functional, aesthetically natural results, reconstructive surgeries must be planned to minimize stress as excessive loads near wounds have been shown to produce pathological scarring and other complications (Gurtner et al., 2011). Presently, stress cannot easily be measured in the operating room. Consequently, surgeons rely on intuition and experience (Paul et al., 2016; Buchanan et al., 2016). Predictive computational tools are ideal candidates for surgery planning. Finite element (FE) simulations have shown promise in predicting stress fields on large skin patches and in complex cases, helping to identify potential regions of complication. Unfortunately, these simulations are computationally expensive and deterministic (Lee et al., 2018a). However, running a few, well selected FE simulations allows us to create Gaussian process (GP) surrogate models of local cutaneous flaps that are computationally efficient and able to predict stress and strain for arbitrary material parameters. Here, we create GP surrogates for the advancement, rotation, and transposition flaps. We then use the predictive capability of these surrogates to perform a global sensitivity analysis, ultimately showing that fiber direction has the most significant impact on strain field variations. We then perform an optimization to determine the optimal fiber direction for each flap for three different objectives driven by clinical guidelines (Leedy et al., 2005; Rohrer and Bhatia, 2005). While material properties are not controlled by the surgeon and are actually a source of uncertainty, the surgeon can in fact control the orientation of the flap with respect to the skin's relaxed tension lines, which are associated with the underlying fiber orientation (Borges, 1984). Therefore, fiber direction is the only material parameter that can be optimized clinically. The optimization task relies on the efficiency of the GP surrogates to calculate the expected cost of different strategies when the uncertainty of other material parameters is included. We propose optimal flap orientations for the three cost functions and that can help in reducing stress resulting from the surgery and ultimately reduce complications associated with excessive mechanical loading near wounds.

Prediction of Energetic Material Properties from Electronic Structure Using 3D Convolutional Neural Networks.

We develop a convolutional neural network capable of directly parsing the 3D electronic structure of a molecule described by spatial point data for charge density and electrostatic potential represented as a 4D tensor. This method effectively bypasses the need to construct complex representations, or descriptors, of a molecule. This is beneficial because the accuracy of a machine learned model depends on the input representation. Ideally, input descriptors encode the essential physics and chemistry that influence the target property. Thousands of molecular descriptors have been proposed, and proper selection of features requires considerable domain expertise or exhaustive and careful statistical downselection. In contrast, deep learning networks are capable of learning rich data representations. This provides a compelling motivation to use deep learning networks to learn molecular structure-property relations from "raw" data. The convolutional neural network model is jointly trained on over 20,000 molecules that are potentially energetic materials (explosives) to predict dipole moment, total electronic energy, Chapman-Jouguet (C-J) detonation velocity, C-J pressure, C-J temperature, crystal density, HOMO-LUMO gap, and solid phase heat of formation. This work demonstrates the first use of complete 3D electronic structure for machine learning of molecular properties.

Propagation of uncertainty in the mechanical and biological response of growing tissues using multi-fidelity Gaussian process regression.

A key feature of living tissues is their capacity to remodel and grow in response to environmental cues. Within continuum mechanics, this process can be captured with the multiplicative split of the deformation gradient into growth and elastic contributions. The mechanical and biological response during tissue adaptation is characterized by inherent variability. Accounting for this uncertainty is critical to better understand tissue mechanobiology, and, moreover, it is of practical importance if we aim to develop predictive models for clinical use. However, the current gold standard in computational models of growth and remodeling remains the use of deterministic finite element (FE) simulations. Here we focus on tissue expansion, a popular technique in which skin is stretched by a balloon-like device inducing its growth. We construct FE models of tissue expansion with various levels of detail, and show that a sufficiently broad set of FE simulations from these models can be used to train an accurate and efficient multi-fidelity Gaussian process (GP) surrogate. The approach is not limited to simulation data, rather, it can fuse different kinds of data, including from experiments. The main appeal of the framework relies on the common experience that highly detailed models (or experiments) are more accurate but also more costly, while simpler models (or experiments) can be easily evaluated but are bound to have some error. In these situations, doing uncertainty analysis tasks with the high fidelity models alone is not feasible and, conversely, relying solely on low fidelity approximations is also undesirable. We show that a multi-fidelity GP outperforms the high fidelity GP and low fidelity GP when tested against the most detailed FE model. In turn, having trained the multi-fidelity GP model, we showcase the propagation of uncertainty from the mechanical and biological response parameters to the spatio-temporal growth outcomes. We expect that the methods and applications in this paper will enable future research in parameter calibration under uncertainty and uncertainty propagation in real clinical scenarios involving tissue growth and remodeling.

Automated Indoor Image Localization to Support a Post-Event Building Assessment.

Image data remains an important tool for post-event building assessment and documentation. After each natural hazard event, significant efforts are made by teams of engineers to visit the affected regions and collect useful image data. In general, a global positioning system (GPS) can provide useful spatial information for localizing image data. However, it is challenging to collect such information when images are captured in places where GPS signals are weak or interrupted, such as the indoor spaces of buildings. The inability to document the images' locations hinders the analysis, organization, and documentation of these images as they lack sufficient spatial context. In this work, we develop a methodology to localize images and link them to locations on a structural drawing. A stream of images can readily be gathered along the path taken through a building using a compact camera. These images may be used to compute a relative location of each image in a 3D point cloud model, which is reconstructed using a visual odometry algorithm. The images may also be used to create local 3D textured models for building-components-of-interest using a structure-from-motion algorithm. A parallel set of images that are collected for building assessment is linked to the image stream using time information. By projecting the point cloud model to the structural drawing, the images can be overlaid onto the drawing, providing clear context information necessary to make use of those images. Additionally, components- or damage-of-interest captured in these images can be reconstructed in 3D, enabling detailed assessments having sufficient geospatial context. The technique is demonstrated by emulating post-event building assessment and data collection in a real building.

Propagation of material behavior uncertainty in a nonlinear finite element model of reconstructive surgery.

Excessive mechanical stress following surgery can lead to delayed healing, hypertrophic scars, and even skin necrosis. Measuring stress directly in the operating room over large skin areas is not feasible, and nonlinear finite element simulations have become an appealing alternative to predict stress contours on arbitrary geometries. However, this approach has been limited to generic cases, when in reality each patient geometry and procedure are unique, and material properties change from one person to another. In this manuscript, we use multi-view stereo to capture the patient-specific geometry of a 7-year-old female undergoing cranioplasty and complex tissue rearrangement. The geometry is used to setup a nonlinear finite element simulation of the reconstructive procedure. A key contribution of this work is incorporation of material behavior uncertainty. The finite element simulation is computationally expensive, and it is not suitable for uncertainty propagation which would require many such simulations. Instead, we run only a few expensive simulations in order to build a surrogate model by Gaussian process regression of the principal components of the stress fields computed with these few samples. The inexpensive surrogate is then used to compute the statistics of the stress distribution in this patient-specific scenario.

A stochastic optimization approach to coarse-graining using a relative-entropy framework.

Relative entropy has been shown to provide a principled framework for the selection of coarse-grained potentials. Despite the intellectual appeal of it, its application has been limited by the fact that it requires the solution of an optimization problem with noisy gradients. When using deterministic optimization schemes, one is forced to either decrease the noise by adequate sampling or to resolve to ad hoc modifications in order to avoid instabilities. The former increases the computational demand of the method while the latter is of questionable validity. In order to address these issues and make relative entropy widely applicable, we propose alternative schemes for the solution of the optimization problem using stochastic algorithms.