Cartilage thickness mismatches in patellar osteochondral allograft transplants affect local cartilage stresses.

Osteochondral allograft implantation is a form of cartilage transplant in which a cylindrical graft of cartilage and subchondral bone from a donor is implanted into a patient's prepared articular defect site. No standard exists for matching the cartilage thickness of the donor and recipient. The goal of this study was to use finite element (FE) analysis to identify the effect of cartilage thickness mismatches between donor and recipient cartilage on cartilage stresses in patellar transplants. Two types of FE models were used: patient-specific 3D models and simplified 2D models. 3D models highlighted which geometric features produced high-stress regions in the patellar cartilage and provided ranges for the parameter sweeps that were conducted with 2D models. 2D models revealed that larger thickness mismatches, thicker recipient cartilage, and a donor-to-recipient cartilage thickness ratio (DRCR) < 1 led to higher stresses at the interface between the donor and recipient cartilage. A surface angle between the donor-recipient cartilage interface and cartilage surface normal near the graft boundary increased stresses when DRCR > 1, with the largest increase observed for an angle of 15°. A surface angle decreased stresses when DRCR < 1. Clinical Significance: This study highlights a potential mechanism to explain the high rates of failure of patellar OCAs. Additionally, the relationship between geometric features and stresses explored in this study led to a hypothetical scoring system that indicates which transplanted patellar grafts may have a higher risk of failure.

The Role of the Non-Collagenous Extracellular Matrix in Tendon and Ligament Mechanical Behavior: A Review.

Tendon is a connective tissue that transmits loads from muscle to bone, while ligament is a similar tissue that stabilizes joint articulation by connecting bone to bone. The 70-90% of tendon and ligament's extracellular matrix (ECM) is composed of a hierarchical collagen structure that provides resistance to deformation primarily in the fiber direction, and the remaining fraction consists of a variety of non-collagenous proteins, proteoglycans, and glycosaminoglycans (GAGs) whose mechanical roles are not well characterized. ECM constituents such as elastin, the proteoglycans decorin, biglycan, lumican, fibromodulin, lubricin, and aggrecan and their associated GAGs, and cartilage oligomeric matrix protein (COMP) have been suggested to contribute to tendon and ligament's characteristic quasi-static and viscoelastic mechanical behavior in tension, shear, and compression. The purpose of this review is to summarize existing literature regarding the contribution of the non-collagenous ECM to tendon and ligament mechanics, and to highlight key gaps in knowledge that future studies may address. Using insights from theoretical mechanics and biology, we discuss the role of the non-collagenous ECM in quasi-static and viscoelastic tensile, compressive, and shear behavior in the fiber direction and orthogonal to the fiber direction. We also address the efficacy of tools that are commonly used to assess these relationships, including enzymatic degradation, mouse knockout models, and computational models. Further work in this field will foster a better understanding of tendon and ligament damage and healing as well as inform strategies for tissue repair and regeneration.

Fiber splay precludes the direct identification of ligament material properties: Implications for ACL graft selection.

Anterior cruciate ligament (ACL) injuries typically require surgical reconstruction to restore adequate knee stability. The middle third of an injured patient's patellar tendon (PT) is a commonly used graft for ACL reconstruction. However, many clinicians and researchers question whether it is the best option, as several studies have suggested that it is a stiffer material than the ACL. Still, there is little to no consensus on even the most basic material property of ligaments/tendons: the tangent modulus in the fiber direction, or slope of the linear portion of the uniaxial stress-strain curve. In this study, we investigate the effect of fiber splay (the tendency of collagen fibers to spread out near the enthesis) on the apparent tangent modulus. Using a simplified theoretical model, we establish a quantity we call the splay ratio, which describes the relationship between splay geometry and the apparent tangent modulus. We then more rigorously investigate the effect of the splay ratio on the apparent tangent modulus of the ovine PT and anteromedial and posterolateral regions of the ACL using experimental and computational methods. Both approaches confirmed that splay geometry significantly affects the apparent material behavior. Because true material properties are independent of geometry, we conclude that the macroscopic response of ligaments and tendons is not sufficient for the characterization of their material properties, but rather is reflective of both material and structural properties. We further conclude that the PT is probably not a stiffer material than ACL, but that the PT graft is likely a stiffer structure than either ACL region.

The Influence of Anterior Cruciate Ligament Matrix Mechanical Properties on Simulated Whole-Knee Biomechanics.

Knee finite element (FE) models are used to study tissue deformation in response to complex loads. Typically, ligaments are modeled using transversely isotropic, hyperelastic material models fitted to tension data along the predominant fiber direction (longitudinal) and, less commonly, to tension data orthogonal to the fiber direction (transverse). Currently, the shear and bulk responses of the anterior cruciate ligament (ACL) are not fitted to experimental data. In this study, a newly proposed material model was fitted to longitudinal tension, transverse tension, and shear experimental data. The matrix transverse tensile, shear, and bulk stiffnesses were then varied independently to determine the impact of each property on knee kinematics and tissue deformation in a whole-knee FE model. The range of values for each parameter was chosen based on published FE studies of the knee. For a knee at full extension under 134 N anterior tibial force (ATF), increasing matrix transverse tensile stiffness, shear stiffness, or bulk stiffness decreased anterior tibial translation (ATT), ACL longitudinal strain, and ACL shear strain. For a knee under 134 N ATF and 1600 N compression, changing the ACL matrix mechanical properties caused variations in ATT and thus changed cartilage deformation contours by changing the point of contact between the femoral and the tibial cartilage. These findings indicate that material models for the ACL must describe matrix material properties to best predict the in vivo response to applied loads.

Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design.

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body's principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems. Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission. Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males. In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR). These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases. Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%). These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission.

A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome.

A key component in the body's stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions. Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses. Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

Microsecond folding dynamics of apomyoglobin at acidic pH.

Apomyolgobin (apoMb) is an important model for understanding the folding mechanism of helical proteins. This study focuses on a partially structured state of sperm whale apoMb populated at pH 4.2 (M-state), which structurally resembles a late kinetic intermediate in the formation of the native state (N) at higher pH. The thermodynamics and cooperativity of apoMb folding at pH 4.2 and 6.2 were studied by global analysis of the urea-induced unfolding transitions monitored by tryptophan fluorescence and circular dichroism. The kinetics of folding and unfolding of apoMb at pH 4.2 was measured over a time window from 40 to 850 µs, using fluorescence-detected continuous-flow measurements. Our observation of biphasic kinetics provides clear evidence for rapid (<100 µs) accumulation of previously unresolved intermediate states in both refolding and unfolding experiments. Quantitative kinetic modeling of the results, using a four-state mechanism with two intermediates on a direct route between the unfolded and folded states (U↔I↔L↔M), gave new insight into the conformational states and barriers that precede the rate-limiting step in the formation of the N-state of apoMb.

Dual functional polyelectrolyte multilayer coatings for implants: permanent microbicidal base with controlled release of therapeutic agents.

Here we present a new bifunctional layer-by-layer (LbL) construct made by combining a permanent microbicidal polyelectrolyte multilayered (PEM) base film with a hydrolytically degradable PEM top film that offers controlled and localized delivery of therapeutics. Two degradable film architectures are presented: (1) bolus release of an antibiotic (gentamicin) to eradicate initial infection at the implant site, or (2) sustained delivery of an anti-inflammatory drug (diclofenac) to cope with inflammation at the site of implantation due to tissue injury. Each degradable film was built on top of a permanent base film that imparts the implantable device surface with microbicidal functionality that prevents the formation of biofilms. Controlled-delivery of gentamicin was demonstrated over hours and that of diclofenac over days. Both drugs retained their efficacy upon release. The permanent microbicidal base film was biocompatible with A549 epithelial cancer cells and MC3T3-E1 osteoprogenitor cells, while also preventing bacteria attachment from turbid media for the entire duration of the two weeks studied. The microbicidal base film retains its functionality after the biodegradable films have completely degraded. The versatility of these PEM films and their ability to prevent biofilm formation make them attractive as coatings for implantable devices.