Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: recommendations of the ORS spine section

Intervertebral disc degeneration is strongly associated with chronic low back pain, a leading cause of disability worldwide. Current back pain treatment approaches (both surgical and conservative) are limited to addressing symptoms, not necessarily the root cause. Not surprisingly therefore, long‐term efficacy of most approaches is poor. Cell‐based disc regeneration strategies have shown promise in preclinical studies, and represent a relatively low‐risk, low‐cost, and durable therapeutic approach suitable for a potentially large patient population, thus making them attractive from both clinical and commercial standpoints. Despite such promise, no such therapies have been broadly adopted clinically. In this perspective we highlight primary obstacles and provide recommendations to help accelerate successful clinical translation of cell‐based disc regeneration therapies. The key areas addressed include: (a) Optimizing cell sources and delivery techniques; (b) Minimizing potential risks to patients; (c) Selecting physiologically and clinically relevant efficacy metrics; (d) Maximizing commercial potential; and (e) Recognizing the importance of multidisciplinary collaborations and engaging with clinicians from inception through to clinical trials

Rapid Chondrocyte Isolation for Tissue Engineering Applications: The Effect of Enzyme Concentration and Temporal Exposure on the Matrix Forming Capacity of Nasal Derived Chondrocytes

Laboratory based processing and expansion to yield adequate cell numbers had been the standard in Autologous Disc Chondrocyte Transplantation (ADCT), Allogeneic Juvenile Chondrocyte Implantation (NuQu®), and Matrix-Induced Autologous Chondrocyte Implantation (MACI). Optimizing cell isolation is a key challenge in terms of obtaining adequate cell numbers while maintaining a vibrant cell population capable of subsequent proliferation and matrix elaboration. However, typical cell yields from a cartilage digest are highly variable between donors and based on user competency. The overall objective of this study was to optimize chondrocyte isolation from cartilaginous nasal tissue through modulation of enzyme concentration exposure (750 and 3000 U/ml) and incubation time (1 and 12 h), combined with physical agitation cycles, and to assess subsequent cell viability and matrix forming capacity. Overall, increasing enzyme exposure time was found to be more detrimental than collagenase concentration for subsequent viability, proliferation, and matrix forming capacity (sGAG and collagen) of these cells resulting in nonuniform cartilaginous matrix deposition. Taken together, consolidating a 3000 U/ml collagenase digest of 1 h at a ratio of 10 ml/g of cartilage tissue with physical agitation cycles can improve efficiency of chondrocyte isolation, yielding robust, more uniform matrix formation

Directional Hybrid FEM-MoM for Automotive System level Simulation

Electromagnetic compatibility (EMC) issues are becoming increasingly important for the automotive industry. An accurate system level analysis is required from an early design stage for optimal performance. The major difficulty encountered in automotive simulation is to deal with different geometric scales, ranging from fraction of wavelengths to multiple wavelengths. In many cases, a domain decomposition method using Finite Element Method (FEM) and Method of Moments (MoM) may be effective by computing each domain separately and stitching them together using equivalent boundary currents. However, when the problem size becomes larger, this method loses its efficacy as calculation of domain interactions become computationally costly. In this paper a new method is proposed for multi-domain problems in EMC radiation emission (RE) test, based on the fact that when two domains are electrically far apart, the back scattered field from the receiving antenna to DUT is quite minimal and can be neglected. The proposed method demonstrates a substantial reduction in memory requirements and computational time when compared to traditional multidomain hybrid FEM-MoM with acceptable accuracy

Extension of 2.5D PEEC for Coplanar Structures in Power Distribution Network Analysis

Power distribution network (PDN) of a multilayered printed circuit board is designed to supply low noise and stable power to ICs. Reduced voltage levels and increasing current-supply requirements accentuates the PDN design complexity. It therefore becomes necessary to have multiple design iterations to achieve an optimal impedance profile for the PDN. 3D full-wave electromagnetic solvers, like the Partial Element Equivalent Circuit (PEEC) method, are accurate but suffer from high compute time requirements, which prohibit its use in the early design phase iterations. On the other hand, pure 2.5D methods, like the non-orthogonal 2.5D PEEC approach, have lower time and memory requirements but fail to capture coplanar coupling due to the underlying TEM assumptions. This affects the accuracy of PDN modeling for coplanar power-ground or signal-power configurations. In this work, the non-orthogonal 2.5D PEEC formulation is extended to include coplanar mutual coupling. Numerical results using quadrilateral meshes demonstrate good accuracy reasonably close to 3D full-wave formulation for planar geometries

Non-orthogonal 2.5D PEEC for Power Integrity Analysis

Power distribution network (PDN) of a multilayered PCB is designed to supply low noise and stable power to ICs. Reduced voltage levels, increased current requirements make it challenging to attain the desired PDN impedance profile. It is therefore necessary to have multiple design iterations for optimal performance of the PDN. 3D full-wave electromagnetic solvers like the Partial Element Equivalent Circuit (PEEC) method are time constrained and therefore illsuited for early stage design. On the other hand, 2.5D tools have lower time and memory requirements and are reasonably accurate for planar power-ground structures. For example, Multilayered Finite Difference Method (MFDM) is a 2.5D formulation suitable for PDN analysis. However, present MFDM techniques are based on orthogonal meshes, such that power-ground planes with irregular shapes and holes require unnecessarily fine mesh at the boundary for a suitable staircase approximation. In this paper, a non-orthogonal 2.5D PEEC formulation is proposed to alleviate this problem. Numerical results using quadrilateral meshes demonstrate good accuracy as compared to 3D full-wave formulation for planar geometries

Mesh Interpolated Krylov Recycling Method to Expedite 3-D Full-Wave MoM Solution for Design Variants

Today's 3-D full-wave electromagnetic (EM) solvers follow the conventional model-mesh-solve workflow to analyze any EM structure. These solvers treat each model independently regardless of any similarity with a previously solved model and, therefore, sacrifice the possibility of accelerating a model solution from information harnessed from a prior solution of a similar model. This is a missed opportunity particularly in the solution of design variants, which involve multiple models with near-identical geometrical features. A Krylov recycling (KR) technique has been proposed in the past for the incremental solution of electrostatic problems. However, the technique is limited by the requirement of an unchanged mesh for the unmodified section of the model, which is difficult to achieve for a conformal mesh of a practical geometry. In this paper, a mesh-interpolated Krylov recycling (MIKR) technique is proposed to expedite the solution of 3-D full-wave surface-volume electric field integral equation-based system by reusing the Krylov subspace from the base design. The mesh interpolation mechanism is proposed to be able to handle mesh changes in the unmodified section of the model. The method is independent of the choice of fast solver compression methodology and the preconditioning strategy, and can be applied in unison with them. Numerical results demonstrate up to 5x speedup in convergence over a cutting-edge preconditioned linear complexity fast solver methodology

Nonorthogonal 2.5-D PEEC for Power Integrity Analysis of Package-Board Geometries

Design of the power ground layout of a multilayered printed circuit board (PCB) is crucial for low noise and stable power supply. 2.5-D tools are better suited for early stage power distribution network (PDN) analysis over 3-D full-wave electromagnetic solvers due to faster simulation times. For example, the multilayered finite difference method (MFDM), which is based on a 2.5-D formulation on an orthogonal mesh grid, can accurately model and analyze power planes. However, this method loses its advantage while analyzing planes with irregular shapes and holes, which require unnecessarily fine discretization at boundaries for a suitable staircase approximation in an orthogonal grid. In this paper, a nonorthogonal 2.5-D partial element equivalent circuit (PEEC) formulation is proposed, employing quadrilateral mesh elements for efficient simulation of the PDN. The individual stamps for resistance, inductance, capacitance, and conductance elements for a unit quadrilateral cell are derived. Further, the methodology is enhanced to capture coplanar coupling through the introduction of mutual inductance and capacitive terms between neighboring PEEC cell pairs. The numerical results demonstrate good accuracy compared with a 3-D full-wave commercial tool for layered PCB geometries. The efficiency of the proposed method is benchmarked against an orthogonal MFDM implementation and a commercial 2.5-D tool