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This study investigates thermomechanical stress in cryopreservation by vitrification of the heart, while exploring the effects of nanowarming-assisted recovery from cryogenic storage. This study expands upon a recently published study, combining experimental investigation and thermal analysis of cryopreservation on a rat heart model. Specifically, this study focuses on scenarios with variable concentrations of silica-coated iron-oxide nanoparticles (sIONPs), while accounting for loading limitations associated with the heart physiology, as well as the properties of cryoprotective agent (CPA) solution and the geometry of the container. Results of this study suggest that variable sIONP concentration based on the heart physiology will elevate mechanical stresses when compared with the mathematically simplified, uniform distribution case. The most dangerous part of rewarming is below glass transition and at the onset of nanowarming past the glass transition temperature on the way for organ recovery from cryogenic storage. Throughout rewarming, regions that rewarm faster, such as the chambers of the heart (higher sIONP concentration), undergo compressive stresses, while the slower rewarming regions, such as the heart myocardium (low sIONP concentration), undergo tension. Being a brittle material, the vitrified organ is expected to fail under tension in lower stresses than in compression. Unfortunately, the location and magnitude of the maximum stress in the investigated cases varied, while general rules were not identified. This investigation demonstrates the need to tailor the thermal protocol of heart cryopreservation on a case-by-case basis, since the location, orientation, magnitude, and instant at which the maximum mechanical stress is found cannot be predicted a priori . While thermomechanical stress poses a significant risk to organ integrity, careful design of the thermal protocol can be instrumental in reducing the likelihood of structural damage, while taking full advantage of the benefits of nanowarming.

Advanced liver preservation strategies could revolutionize liver transplantation by extending preservation time, thereby allowing for broader availability and better matching of transplants. However, developing new cryopreservation protocols requires exploration of a complex design space, further complicated by the scarcity of real human livers to experiment upon. We aim to create computational models of the liver to aid in the development of new cryopreservation protocols. Towards this goal, we present an approach for generating 3D models of the liver vasculature by building upon the space colonization algorithm. Additionally, we introduce the concept of a super lobule which enables a computational abstraction of biological liver lobules. User-tunable parameters allow for vasculatures of varying depth and topology to be generated. In each model, we solve for a common lumped resistance value assigned to the super lobules, allowing the overall physiological blood pressure and flow rate through the liver to be preserved. We demonstrate our approach’s ability to maintain consistency between models of varying depth. Finally, we simulate steady state machine perfusion of the generated models and demonstrate how they can be used to quickly test the effect of different boundary conditions when designing organ preservation protocols.

A new mathematical model is proposed for the analysis of thermo-mechanics effects during isochoric cryopreservation. In that process, some ice crystallization in a fixed-volume container drives pressure elevation, which may be favorable to the preservation of biological material when it resides in the unfrozen portion of the same container. The proposed model is comprehensive, integrating for the first time concepts from the disparate fields of thermodynamics, heat transfer, fluid mechanics, and solid mechanics. The novelty in this study is in treating the cryopreserved material as having a pseudo-viscoelastic behavior over a very narrow temperature range, without affecting the mechanical behavior of the material in the rest of the domain. This unique approach permits treating the domain as a continuum, while avoiding the need to trace freezing fronts and sperate the analysis to liquid and solid subdomains. Consistent with the continuum approach, the heat transfer problem is solved using the enthalpy approach. The presented analysis focusses on isochoric cooling of pure water between standard atmospheric conditions and the triple point of liquid water, ice Ih, and ice III (-22°C and 207.4 MPa). The proposed model is also applicable to isochoric vitrification, by substituting the pseudo-viscoelastic material model with the real viscosity model of the vitrifying material. Results of this study display good agreement with phase-diagram data at steady state, and with experimental data from the literature. Furthermore, this study provides a venue to discussing experimentation aspects of isochoric cryopreservation. The proposed model is further demonstrated on a 3D problem, while discussing scale considerations, crystallization conditions, and transient effects. Notably, the new model can be used to bridge the gap between limited pressure and temperature measurements during cryopreservation and the analysis of the continuum. Arguably, this study presents the most advanced thermo-mechanics model to solve practical problems relating to isochoric cryopreservation.

This study presents a simplified thermal-fluids (TF) mathematical model to analyze large surface deformations in cryoprotective agents (CPA) during cryopreservation by vitrification. The CPA deforms during vitrification due to material flow caused by the combined effects of thermal gradients within the domain, thermal contraction due to temperature, and exponential increase in the viscosity of the CPA as it is cooled towards glass transition. While it is well understood that vitrification is associated with thermo-mechanical stress, which might lead to structural damage, those large deformations can lead to stress concentration, further intensifying the probability to structural failure. The results of the TF model are experimentally validated by means of cryomacroscopy on a cuvette containing 7.05M dimethyl sulfoxide (DMSO) as a representative CPA. The TF model presented in this study is a simplified version of a previously presented thermo-mechanics (TM) model, where the TM model is set to solve the coupled heat transfer, fluid mechanics and solid mechanics problems, while the TF model omits further deformations in the solid state. It is demonstrated in this study that the TF model alone is sufficient to capture large-body deformations during vitrification. However, the TF model alone cannot be used to estimate mechanical stresses, which become significant only when the deformation rates become so small that the deformed body practically behaves as an amorphous solid. This study demonstrates the high sensitivity of deformation predictions to variation in material properties, chief among which are the variations of density and viscosity with temperature. Finally, this study includes a discussion on the possibility of turning on and off the TF and TM models in respective parts of the domain, in order to solve the multiphysics problem in a computationally cost-effective manner.

The objective of this study is to provide thermal conductivity data for CPA-based nanofluids for the benefit of the analyses of cryopreservation by vitrification. Thermal conductivity measurements were conducted using a hot-wire technique on an experimentation platform of the cryomacroscope, to correlate measurements with observed physical effects such as crystallization and fracturing. Tested materials in this study include the CPA cocktails M22, VS55, DP6, and DP6+sucrose. Nanofluids in this study include the above CPA cocktails as base solutions, when mixed with either iron-oxide nanoparticles (IONP) or silica-coated iron-oxide nanoparticles (sIONP). Results of this study demonstrated the addition of sIONP to any of the CPA cocktails tested did not significantly affect its thermal conductivity, its tendency to vitrify or, conversely, its tendency to form rewarming phase crystallization (RPC). Fractures were observed with cryomacroscopy at the onset of rewarming for DP6+sIONP under carefully controlled rewarming conditions without RF activation, despite the inherent opacity of the sIONP solutions. It is likely that using RF heating in order to accelerate rewarming while unifying the temperature distribution would prevent fracture and RPC. However, sIONP were not activated in this study, as the RF heating mechanism would interfere with thermal conductivity measurements. The addition of IONP to DP6 appears to hinder the tendency of the CPA to vitrify, which is a detrimental effect. But it is unlikely that uncoated nanoparticle solutions will be used in practical applications.

This study presents experimental results and an analysis approach for polarized light effects associated with thermomechanical stress during cooling of glass promoting solutions, with applications to cryopreservation and tissue banking in a process known as vitrification. Polarized light means have been previously integrated into the cryomacroscope-a visualization device to detect physical effects associated with cryopreservation success, such as crystallization, fracture formation, and contamination. The experimental study concerns vitrification in a cuvette, which is a rectangular container. Polarized light modeling in the cuvette is based on subdividing the tridimensional (3D) domain into a series of planar (2D) problems, for which a mathematical solution is available in the literature. The current analysis is based on tracking the accumulated changes in light polarization and magnitude, as it passes through the sequence of planar problems. Results of this study show qualitative agreement in light intensity history and distribution between experimental data and simulated results. The simulated results help explaining differences between 2D and 3D effects in photoelasticity, most notably, the counterintuitive observation that high stress areas may correlate with low light intensity regions based on the particular experimental conditions. Finally, it is suggested that polarized-light analysis must always be accompanied by thermomechanical stress modeling in order to explain 3D effects.

This study presents an efficient computational technique for the simulation of ultrasound imaging artifacts associated with cryosurgery based on nonlinear ray tracing. This study is part of an ongoing effort to develop computerized training tools for cryosurgery, with prostate cryosurgery as a development model. The capability of performing virtual cryosurgical procedures on a variety of test cases is essential for effective surgical training. Simulated ultrasound imaging artifacts include reverberation and reflection of the cryoprobes in the unfrozen tissue, reflections caused by the freezing front, shadowing caused by the frozen region, and tissue property changes in repeated freeze–thaw cycles procedures. The simulated artifacts appear to preserve the key features observed in a clinical setting. This study displays an example of how training may benefit from toggling between the undisturbed ultrasound image, the simulated temperature field, the simulated imaging artifacts, and an augmented hybrid presentation of the temperature field superimposed on the ultrasound image. The proposed method is demonstrated on a graphic processing unit at 100 frames per second, on a mid-range personal workstation, at two orders of magnitude faster than a typical cryoprocedure. This performance is based on computation with C++ accelerated massive parallelism and its interoperability with the DirectX-rendering application programming interface.

This study focuses on the implementation of an efficient numerical technique for cryosurgery simulations on a graphics processing unit as an alternative means to accelerate runtime. This study is part of an ongoing effort to develop computerized training tools for cryosurgery, with prostate cryosurgery as a developmental model. The ability to perform rapid simulations of various test cases is critical to facilitate sound decision making associated with medical training. Consistent with clinical practice, the training tool aims at correlating the frozen region contour and the corresponding temperature field with the target region shape. The current study focuses on the feasibility of graphics processing unit-based computation using C++ accelerated massive parallelism, as one possible implementation. Benchmark results on a variety of computation platforms display between 3-fold acceleration (laptop) and 13-fold acceleration (gaming computer) of cryosurgery simulation, in comparison with the more common implementation on a multicore central processing unit. While the general concept of graphics processing unit-based simulations is not new, its application to phase-change problems, combined with the unique requirements for cryosurgery optimization, represents the core contribution of the current study.

The current study aims to explore possible relationships between various prostate shapes and the difficulty in creating a computer-based plan for cryosurgery. This research effort is a part of an ongoing study to develop computational means in order to improve cryosurgery training and education. This study uses a computerized planner—a key building block of a recently developed prototype for cryosurgery training. The quality of planning is measured by the overall defect volume, a proprietary concept which refers to undercooled areas internal to the target region and overcooled areas external to it. Results of this study numerically confirm that the overall defect volume decreases with an increasing number of cryoprobes, regardless of the geometry of the prostate. However, the number of cryoprobes required to achieve the smallest possible defect may be unrealistically high (<30). Results of this study also demonstrate that the optimal cryoprobe layout is associated with a smaller defect for symmetric prostate geometries and, independently, for prostate models that better resemble a sphere. Furthermore, a smaller defect is typically achieved when the urethra passes through the center of the prostate model. This study proposes to create a cryoprobe convex hull for the purpose of initial planning, which is a subdomain similar in shape to the prostate but at a reduced size. Parametric studies indicate that a cryoprobe convex hull contracted by 7 to 9 mm in all directions from the prostate capsule serves as a quasi-optimal initial condition for planning, that is, a preselected number of cryoprobes placed in the cryoprobe convex hull yields favorable results for optimization. The cryoprobe convex hull could accelerate computer-based planning, while also being adopted as a concept for traditional cryosurgery training, when computerized means are absent.

ObjectiveInterventional radiology methods have been adopted for intraoperative control of the surgical region of interest (ROI) in a wide range of minimally invasive procedures. One major obstacle that hinders the success of procedures using interventional radiology methods is the preoperative and intraoperative deformation of the ROI. While fiducial markers (FM) tracing has been shown to be promising in tracking such deformations, determining the optimal placement of the FM in the ROI remains a significant challenge. The current study proposes a computational framework to address this problem by preoperatively optimizing the layout of FM, thereby enabling an accurate tracking of the ROI deformations.MethodsThe proposed approach includes three main components: (1) creation of virtual deformation benchmarks, (2) method of predicting intraoperative tissue deformation based on FM registration, and (3) FM layout optimization. To account for the large variety of potential ROI deformations, virtual benchmarks are created by applying a multitude of random force fields on the tumor surface in physically based simulations. The ROI deformation prediction is carried out by solving the inverse problem of finding the smoothest force field that leads to the observed FM displacements. Based on this formulation, a simulated annealing approach is employed to optimize the FM layout that produces the best prediction accuracy.ResultsThe proposed approach is capable of finding an FM layout that outperforms the rationally chosen layouts by 40% in terms of ROI prediction accuracy. For a maximum induced displacement of 20 mm on the tumor surface, the average maximum error between the benchmarks and our FM-optimized predictions is about 1.72 mm, which falls within the typical resolution of ultrasound imaging.ConclusionsThe proposed framework can optimize FM layout to effectively reduce the errors in the intraoperative deformation prediction process, thus bridging the gap between preoperative imaging and intraoperative tissue deformation.