Scaffolds have been broadly applied within tissue engineering and regenerative medicine to regenerate, replace, or augment diseased or damaged tissue. For a scaffold to perform optimally, several design considerations must be addressed, with an eye toward the eventual form, function, and tissue site. The chemical and mechanical properties of the scaffold must be tuned to optimize the interaction with cells and surrounding tissues. For complex tissue engineering, mass transport limitations, vascularization, and host tissue integration are important considerations. As the tissue architecture to be replaced becomes more complex and hierarchical, scaffold design must also match this complexity to recapitulate a functioning tissue. We outline these design constraints and highlight creative and emerging strategies to overcome limitations and modulate scaffold properties for optimal regeneration. We also highlight some of the most advanced strategies that have seen clinical application and discuss the hurdles that must be overcome for clinical use and commercialization of tissue engineering technologies. Finally, we provide a perspective on the future of scaffolds as a functional contributor to advancing tissue engineering and regenerative medicine.

/pdf/a-perspective-on-the-clinical-translation-of-scaffolds-for-1n2hyrubhk.pdf

A Perspective on the Clinical Translation of Scaffolds for Tissue Engineering

Finite element modeling of soft tissues: material models, tissue interaction and challenges.

Computational mechanics has been advanced in every area of orthopedic biomechanics. The objective of this paper is to provide a general review of the computational models used in the analysis of the mechanical function of the knee joint in different loading and pathological conditions. Major review articles published in related areas are summarized first. The constitutive models for soft tissues of the knee are briefly discussed to facilitate understanding the joint modeling. A detailed review of the tibiofemoral joint models is presented thereafter. The geometry reconstruction procedures as well as some critical issues in finite element modeling are also discussed. Computational modeling can be a reliable and effective method for the study of mechanical behavior of the knee joint, if the model is constructed correctly. Single-phase material models have been used to predict the instantaneous load response for the healthy knees and repaired joints, such as total and partial meniscectomies, ACL and PCL reconstructions, and joint replacements. Recently, poromechanical models accounting for fluid pressurization in soft tissues have been proposed to study the viscoelastic response of the healthy and impaired knee joints. While the constitutive modeling has been considerably advanced at the tissue level, many challenges still exist in applying a good material model to three-dimensional joint simulations. A complete model validation at the joint level seems impossible presently, because only simple data can be obtained experimentally. Therefore, model validation may be concentrated on the constitutive laws using multiple mechanical tests of the tissues. Extensive model verifications at the joint level are still crucial for the accuracy of the modeling.

/pdf/recent-advances-in-computational-mechanics-of-the-human-knee-392rvv5vep.pdf

Recent Advances in Computational Mechanics of the Human Knee Joint

Meniscal cartilage tears are common and predispose to osteoarthritis (OA). Most occur in the avascular portion of the meniscus where current repair techniques usually fail. We described previously the use of undifferentiated autologous mesenchymal stem cells (MSCs) seeded onto a collagen scaffold (MSC/collagen-scaffold) to integrate meniscal tissues in vitro. Our objective was to translate this method into a cell therapy for patients with torn meniscus, with the long-term goal of delaying or preventing the onset of OA. After in vitro optimization, we tested an ovine-MSC/collagen-scaffold in a sheep meniscal cartilage tear model with promising results after 13 weeks, although repair was not sustained over 6 months. We then conducted a single center, prospective, open-label first-in-human safety study of patients with an avascular meniscal tear. Autologous MSCs were isolated from an iliac crest bone marrow biopsy, expanded and seeded into the collagen scaffold. The resulting human-MSC/collagen-scaffold implant was placed into the meniscal tear prior to repair with vertical mattress sutures and the patients were followed for 2 years. Five patients were treated and there was significant clinical improvement on repeated measures analysis. Three were asymptomatic at 24 months with no magnetic resonance imaging evidence of recurrent tear and clinical improvement in knee function scores. Two required subsequent meniscectomy due to retear or nonhealing of the meniscal tear at approximately 15 months after implantation. No other adverse events occurred. We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Registration: EU Clinical Trials Register, 2010-024162-22. Stem Cells Translational Medicine 2017;6:1237-1248.

/pdf/repair-of-torn-avascular-meniscal-cartilage-using-28e139yfbw.pdf

Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study.

Biotribology: Recent progresses and future perspectives

The mechanical functions of the menisci may be partially performed through the fluid pressurization in articular cartilages and menisci. This creep behavior has not been investigated in whole knee joint modeling. A three-dimensional finite element knee model was employed in the present study to explore the fluid-flow dependent creep behaviors of normal and meniscectomy knees. The model included distal femur, tibia, fibula, articular cartilages, menisci and four major ligaments. Articular cartilage or meniscus was modeled as a fluid-saturated solid matrix reinforced by a nonlinear orthotropic and site-specific collagen network. A 300 N compressive force, equal to half of body weight, was applied to the knee in full extension followed by creep. The results showed that the fluid pressurization played a substantial role in joint contact mechanics. Menisci bore more loading as creep developed, leading to decreased stresses in cartilages. The removal of menisci not only changed the stresses in the cartilages, which was in agreement with published studies, but also altered the distribution and the rate of dissipation of fluid pressure in the cartilages. The high fluid pressures in the femoral cartilage moved from anterior to more central regions of the condyles after total meniscectomy. For both intact and meniscectomy joints, the fluid pressure level remained considerably high for thousands of seconds during creep, which lasted even longer after meniscectomy. For the femoral cartilage, the maximum principal stress was generally in agreement with the fiber direction, which indicated the essential role of fibers in load support of the tissue.

Creep behavior of the intact and meniscectomy knee joints.

A viscoelastic poromechanical model of the knee joint in large compression

Partial meniscectomy is believed to change the biomechanics of the knee joint through alterations in the contact of articular cartilages and menisci. Although fluid pressure plays an important role in the load support mechanism of the knee, the fluid pressurization in the cartilages and menisci has been ignored in the finite element studies of the mechanics of meniscectomy. In the present study, a 3D fibril-reinforced poromechanical model of the knee joint was used to explore the fluid flow dependent changes in articular cartilage following partial medial and lateral meniscectomies. Six partial longitudinal meniscectomies were considered under relaxation, simple creep, and combined creep loading conditions. In comparison to the intact knee, partial meniscectomy not only caused a substantial increase in the maximum fluid pressure but also shifted the location of this pressure in the femoral cartilage. Furthermore, these changes were positively correlated to the size of meniscal resection. While in the intact joint, the location of the maximum fluid pressure was dependent on the loading conditions, in the meniscectomized joint the location was predominantly determined by the site of meniscal resection. The partial meniscectomy also reduced the rate of the pressure dissipation, resulting in even larger difference between creep and relaxation times as compared to the case of the intact knee. The knee joint became stiffer after meniscectomy because of higher fluid pressure at knee compression followed by slower pressure dissipation. The present study indicated the role of fluid pressurization in the altered mechanics of meniscectomized knees.

Partial meniscectomy changes fluid pressurization in articular cartilage in human knees.

An inverse method to identify the location and time history of a single elastic impact load based on the time dependent structural responses is presented. At first, the unknown impact location is found through an inverse analysis without any information about the time history of the load. Two different methods are presented for the location identification. In both methods, an objective function expressing relationship between pairs of structural responses is minimized to find the optimal impact location. In the first method, the steepest descent technique is used to find the impact location precisely. In the second method, a zero-order search technique is developed for fast, but a little less accurate, identification of the impact location. After determining the location, the time dependent value of the impact load is reconstructed using the least-squares method. In-plane strain and its time integrals at sampling points are used to find the location and history of the impact load. In case of high strain fluctuation, time integration of strain removes fluctuations without introducing any additional error. This significantly simplifies the time history determination of the impact load. Two examples are presented to show the validity and effectiveness of the proposed method.

An Efficient Inverse Method for Identification of the Location and Time History of an Elastic Impact Load

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