On the Relative Relevance of Subject-Specific Geometries and Degeneration-Specific Mechanical Properties for the Study of Cell Death in Human Intervertebral Disk Models

Capturing patient- or condition-specific intervertebral disk (IVD) properties in finite element models is outmost important in order to explore how biomechanical and biophysical processes may interact in spine diseases. However, disk degenerative changes are often modeled through equations similar to those employed for healthy organs, which might not be valid. As for the simulated effects of degenerative changes, they likely depend on specific disk geometries. Accordingly, we explored the ability of continuum tissue models to simulate disk degenerative changes. We further used the results in order to assess the interplay between these simulated changes and particular IVD morphologies, in relation to disk cell nutrition, a potentially important factor in disk tissue regulation. A protocol to derive patient-specific computational models from clinical images was applied to different spine specimens. In vitro, IVD creep tests were used to optimize poro-hyperelastic input material parameters in these models, in function of the IVD degeneration grade. The use of condition-specific tissue model parameters in the specimen-specific geometrical models was validated against independent kinematic measurements in vitro. Then, models were coupled to a transport-cell viability model in order to assess the respective effects of tissue degeneration and disk geometry on cell viability. While classic disk poro-mechanical models failed in representing known degenerative changes, additional simulation of tissue damage allowed model validation and gave degeneration-dependent material properties related to osmotic pressure and water loss, and to increased fibrosis. Surprisingly, nutrition-induced cell death was independent of the grade-dependent material properties, but was favored by increased diffusion distances in large IVDs. Our results suggest that in situ geometrical screening of IVD morphology might help to anticipate particular mechanisms of disk degeneration

Computational pharmacokinetics of solute penetration into human intervertebral discs-Effects of endplate permeability, solute molecular weight and disc size

A finite element model is developed to predict the penetration time-history of three different solutes into the human lumbar disc following intravenous injection. Antibiotics are routinely administered intravenously in spinal surgery to prevent disc infection. Successful prophylaxis requires antibiotics to reach adequate inhibitory levels. Here, the transient diffusion of cephazolin is investigated over 10. h post-injection in a human disc model subject to reported concentrations in the blood stream as the prescribed boundary sources. Post-injection variation of cephazolin concentrations in the disc adjacent to supply sources closely followed the decay curve in the blood stream and fell sharply with time. Much lower concentrations were computed in the inner annulus and nucleus; much of the disc (80% at 1. h and 49% at 4. h) experienced concentrations below required inhibitory level of 1. mg/L in agreement with measurements. Changes in endplate permeability, disc size, and solute molecular weight had profound effects on concentration profiles at all times and regions, especially in the disc centre, demonstrating their crucial roles on the adequate delivery of drugs. Larger solutes markedly slow transport into the disc. The failure to reach critical therapeutic levels in the central disc regions, especially when endplates calcify and in larger discs, raises concerns and calls for caution in attempts to extrapolate findings of studies on animals with much smaller and non degenerate discs to the human discs. The current study also demonstrates the capability of computational models in predicting the transport of intravenously injected solutes into the disc. © 2012 Elsevier Ltd

Disc size markedly influences concentration profiles of intravenously administered solutes in the intervertebral disc: a computational study on glucosamine as a model solute

Purpose: Tests on animals of different species with large differences in intervertebral disc size are commonly used to investigate the therapeutic efficacy of intravenously injected solutes in the disc. We hypothesize that disc size markedly affects outcome. Methods: Here, using a small non-metabolized molecule, glucosamine (GL) as a model solute, we calculate the influence of disc size on transport of GL into rat, rabbit, dog and human discs for 10 h post intravenous-injection. We used transient finite element models and considered an identical GL supply for all animals. Results: Huge effects of disc size on GL concentration profiles were found. Post-injection GL concentration in the rat disc reached 70 % blood concentration within 15 min but remained below 10 % in the human disc nucleus throughout. The GL rapidly penetrated post-injection into smaller discs resulting in homogeneous concentrations. In contrast, GL concentration, albeit at much lower levels, increased with time in the human disc with a small outward flux at the annulus periphery at longer periods. Conclusions: Changes in the disc size hugely influenced GL concentrations throughout the disc at all regions and times. Increases in administered dose can neither remedy the very low concentration levels in the disc center in larger human disc at early post-injection hours nor alter the substantial differences in concentration profiles estimated among various species. The size effect will only be exacerbated as molecular weight of the solute increases and as the endplate calcifies. Extrapolation of findings from animal to human discs on the efficacy of intravenously administered solutes must proceed with great caution. © 2013 Springer-Verlag Berlin Heidelberg

Computational investigation of sulphate diffusion into the dog disc

We proposed a model to investigate the transient diffusion of drug (sulphate) into the intervertebral disc. Using finite element method, drug diffusion was simulated and the concentration of diffused drug in each region of disc including Nucleus pulpous (NP), Inner annulus fibroses (IA), and Outer annulus fibroses (OA) was measured. In addition, to investigate the role of CEP permeability on the amount of diffused drug, model was simulated with different cartilage endplate (CEP) permeability. Having obtained concentration distribution for different cases, it was clearly shown that the amount of diffused drug is affected by the endplate permeability and the more permeable CEP, the more diffused drug into the disc specifically at the center of the disc. © 2011 IEEE

Developing Bioreactors to Host Joint-Derived Tissues That Require Mechanical Stimulation

Demographics of the Western Societies points toward an elderly population in need of research on replacement parts for joints and their components, such as the meniscus, cartilage, ligaments, tendons, and intervertebral discs. There is a lack of basic research to predict treatment options before degeneration or inflammation has progressed, and at late stages, when regeneration might not be an option anymore. Thus, to achieve a better understanding of the current specific problems in orthopedic research, there is a need for clinically relevant mechanobiological models. Animal experiments, especially those on large animals, are costly and, in some cases, doubtful as regards clinical translation. Ex vivo bioreactors that allow biomechanical loading are aimed to mimic the in vivo situation of critical joints that are prone to failure. These tissues often require unique adaptations prior and during organ culture as these are often under mechanical forces in situ. On the one hand, ex vivo organ cultures are limited in regarding the size and cell numbers that can be kept alive and the duration of experiments. However, a strong asset of these cultures is the use of primary human material, which is a chance to provide more translational relevant results. Within this book chapter, we give a brief history of general concepts for bioreactor constructions in the field of orthopedic research and give some recent examples for tendons, the knee joint and the intervertebral disc. We offer a summary of the current state of the art, pitfalls and limitations in the design and the future challenges