Yoed Rabin

Is intracellular hyperthermia superior to extracellular hyperthermia in the thermal sense

More than 20 years ago, it was hypothesized that intracellular hyperthermia is superior to extracellular hyperthermia. It was further hypothesized that even a single biological cell containing magnetic nanoparticles can be treated for hyperthermia by an AC magnetic field, independent of its surrounding cells. Since experimental investigation of the thermal effects of intracellular hyperthermia is not feasible, these hypotheses have been studied theoretically. The current report shows that nano-scale heating effects are negligible. This study further shows that intracellular heat generation is sufficient to create the necessary conditions for hyperthermia only in a large group of cells loaded with nanoparticles, having an overall diameter of at least 1mm. It is argued in this report that there is no reason to believe that intracellular hyperthermia is superior to extracellular hyperthermia in the thermal sense.

An experimental investigation on thermal exposure during bone drilling

This study presents an experimental investigation of the effects of spindle speed, feed rate, and depth of drilling on the temperature distribution during drilling of the cortical section of the bovine femur. In an effort to reduce measurement uncertainties, a new approach for temperature measurements during bone drilling is presented in this study. The new approach is based on a setup for precise positioning of multiple thermocouples, automated data logging system, and a computer numerically controlled (CNC) machining system. A battery of experiments that has been performed to assess the uncertainty and repeatability of the new approach displayed adequate results. Subsequently, a parametric study was conducted to determine the effects of spindle speed, feed rate, hole depth, and thermocouple location on the measured bone temperature. This study suggests that the exposure time during bone drilling far exceeds the commonly accepted threshold for thermal injury, which may prevail at significant distances from the drilled hole. Results of this study suggest that the correlation of the thermal exposure threshold for bone injury and viability should be further explored.

A new thermal model for bone drilling with applications to orthopaedic surgery

This paper presents a new thermal model for bone drilling with applications to orthopaedic surgery. The new model combines a unique heat-balance equation for the system of the drill bit and the chip stream, an ordinary heat diffusion equation for the bone, and heat generation at the drill tip, arising from the cutting process and friction. Modeling of the drill bit-chip stream system assumes an axial temperature distribution and a lumped heat capacity effect in the transverse cross-section. The new model is solved numerically using a tailor-made finite-difference scheme for the drill bit-chip stream system, coupled with a classic finite-difference method for the bone. The theoretical investigation addresses the significance of heat transfer between the drill bit and the bone, heat convection from the drill bit to the surroundings, and the effect of the initial temperature of the drill bit on the developing thermal field. Using the new model, a parametric study on the effects of machining conditions and drill-bit geometries on the resulting temperature field in the bone and the drill bit is presented. Results of this study indicate that: (1) the maximum temperature in the bone decreases with increased chip flow; (2) the transient temperature distribution is strongly influenced by the initial temperature; (3) the continued cooling (irrigation) of the drill bit reduces the maximum temperature even when the tip is distant from the cooled portion of the drill bit; and (4) the maximum temperature increases with increasing spindle speed, increasing feed rate, decreasing drill-bit diameter, increasing point angle, and decreasing helix angle. The model is expected to be useful in determination of optimum drilling conditions and drill-bit geometries.

Computerized planning for multiprobe cryosurgery using a force-field analogy.

Cryosurgery is the destruction of undesired biological tissues by freezing. For internal organs, multiple cryoprobes are inserted into the tissue with the goal of maximizing cryoinjury within a predefined target region, while minimizing cryoinjury to the surrounding tissues. The objective of this study is to develop a computerized planning tool to determine the best locations to insert the cryoprobes, based on bioheat transfer simulations. This tool is general and suitable for all available cooling techniques and hardware. The planning procedure employs a novel iterative optimization technique based on a force-field analogy. In each iteration, a single transient bioheat transfer simulation of the cryoprocedure is computed. At the end of the simulation, regions of tissue that would have undesired temperatures apply “forces” to the cryoprobes directly moving them to better locations. This method is more efficient than traditional numerical optimization techniques, because it requires significantly fewer bioheat transfer simulations for each iteration of planning. For demonstration purposes, 2D examples on cross sections typical of prostate cryosurgery are given.

Thermal expansion measurements of frozen biological tissues at cryogenic temperatures.

Thermal expansion data are essential for analyses of cryodestruction associated with thermal stresses during cryopreservation protocols as well as during cryosurgery. The present study tests a commonly used hypothesis that the thermal expansion of frozen tissues is similar to that of pure water ice crystals. This study further provides insight into the potential effect of the presence of cryoprotectants on thermal expansion. A new apparatus for thermal strain measurements of frozen biological tissues within a cryogenic temperature range is presented. Results are presented for fresh tissue samples taken from beef muscle, chicken muscle, rabbit muscle, rabbit bone, and pig liver. Pilot studies of the effect of cryoprotectants on thermal expansion are further presented for rabbit muscle immersed in dimethyl sulphoxide (2 mols/l) and glycerol (2 mols/l), and for pig liver perfused with dimethyl sulphoxide (2 mols/l). Thermal expansion of frozen soft biological tissues was found to be similar to that of water ice crystals in the absence of cryoprotectant. Thermal expansion of the rabbit bone was found to be about one half of that of frozen soft tissues. A significant reduction in the thermal expansion at higher temperatures was observed in the presence of cryoprotectants. A rapid change of thermal strain near -100 degrees C was also observed, which is likely to be associated with the glass transition process of the cryoprotectant solutions.

Computerized Planning of Cryosurgery Using Cryoprobes and Cryoheaters

In a typical minimally invasive cryoprocedure, multiple cryoprobes are inserted into the tissue with the goal of maximizing cryoinjury within a predefined target region, while minimizing cryoinjury to the surrounding tissues. A temperature-controlled electrical heater has been developed recently by this research team, in order to assist in limiting the cryoinjury to the target region. The new device has been termed a ‘cryoheater,’ and it can work with any cryosurgical cooling technique. A prototype computerized planning tool has been presented recently by this research team, which helps to determine the best locations in which to insert the cryoprobes. This prototype was designed for cryoprobes only. The planning procedure utilized a novel iterative optimization technique, based on a force-field analogy. The combination of cryoheaters with computerized planning is the subject matter of this report. The current report includes a review of cryoheater development, and presents an improved cryosurgery planning tool which incorporates cryoheaters.

The promise of organ and tissue preservation to transform medicine

The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.

Experimental verification of numerical simulations of cryosurgery with application to computerized planning.

As a part of an ongoing effort to develop computerized planning tools for cryosurgery, an experimental study has been conducted to verify a recently developed numerical technique for bioheat transfer simulations. Experiments were performed on gelatin solution as a phantom material, using proprietary liquid-nitrogen cryoprobes. Urethral warming was simulated with the application of a cryoheater, which is a proprietary temperature-controlled electrical heater. The experimental design was aimed at creating a 2D heat transfer problem. Analysis of experimental results was based on reconstruction of the frozen region from video recordings, using a region-growing segmentation algorithm. Results of this study show an average disagreement of 2.9% in the size of the frozen region, between experimental data and numerical simulation of the same experiment, which validates both the recently developed algorithm for numerical simulations and the newly developed algorithm for segmentation from video recordings.

Improved tissue cryopreservation using inductive heating of magnetic nanoparticles

A scalable technology using iron oxide nanoparticles and inductive radiofrequency heating rapidly and uniformly rewarms vitrified tissues. Improved tissue cryopreservation with nanowarming Organ transplantation is limited by the availability of viable donor organs. Although storage at very low temperatures (cryopreservation) could extend the time between organ harvest and transplant, the current gold standard for rewarming (convection) leads to cracking and crystallization in samples larger than a few milliliters. Manuchehrabadi et al. demonstrate the rewarming of cells and tissues by radiofrequency inductive heating using magnetic nanoparticles suspended in a cryoprotectant solution. This nanowarming technique rapidly and uniformly rewarmed cryopreserved fibroblasts, porcine arteries, and porcine heart tissues in systems up to 50 ml in volume, yielding tissues with higher viability than convective rewarming. Vitrification, a kinetic process of liquid solidification into glass, poses many potential benefits for tissue cryopreservation including indefinite storage, banking, and facilitation of tissue matching for transplantation. To date, however, successful rewarming of tissues vitrified in VS55, a cryoprotectant solution, can only be achieved by convective warming of small volumes on the order of 1 ml. Successful rewarming requires both uniform and fast rates to reduce thermal mechanical stress and cracks, and to prevent rewarming phase crystallization. We present a scalable nanowarming technology for 1- to 80-ml samples using radiofrequency-excited mesoporous silica–coated iron oxide nanoparticles in VS55. Advanced imaging including sweep imaging with Fourier transform and microcomputed tomography was used to verify loading and unloading of VS55 and nanoparticles and successful vitrification of porcine arteries. Nanowarming was then used to demonstrate uniform and rapid rewarming at >130°C/min in both physical (1 to 80 ml) and biological systems including human dermal fibroblast cells, porcine arteries and porcine aortic heart valve leaflet tissues (1 to 50 ml). Nanowarming yielded viability that matched control and/or exceeded gold standard convective warming in 1- to 50-ml systems, and improved viability compared to slow-warmed (crystallized) samples. Last, biomechanical testing displayed no significant biomechanical property changes in blood vessel length or elastic modulus after nanowarming compared to untreated fresh control porcine arteries. In aggregate, these results demonstrate new physical and biological evidence that nanowarming can improve the outcome of vitrified cryogenic storage of tissues in larger sample volumes.

The Grand Challenges of Organ Banking: Proceedings from the first global summit on complex tissue cryopreservation.

The first Organ Banking Summit was convened from Feb. 27 - March 1, 2015 in Palo Alto, CA, with events at Stanford University, NASA Research Park, and Lawrence Berkeley National Labs. Experts at the summit outlined the potential public health impact of organ banking, discussed the major remaining scientific challenges that need to be overcome in order to bank organs, and identified key opportunities to accelerate progress toward this goal. Many areas of public health could be revolutionized by the banking of organs and other complex tissues, including transplantation, oncofertility, tissue engineering, trauma medicine and emergency preparedness, basic biomedical research and drug discovery - and even space travel. Key remaining scientific sub-challenges were discussed including ice nucleation and growth, cryoprotectant and osmotic toxicities, chilling injury, thermo-mechanical stress, the need for rapid and uniform rewarming, and ischemia/reperfusion injury. A variety of opportunities to overcome these challenge areas were discussed, i.e. preconditioning for enhanced stress tolerance, nanoparticle rewarming, cyroprotectant screening strategies, and the use of cryoprotectant cocktails including ice binding agents.