Amir A. Al-Munajjed

The healing of bony defects by cell-free collagen-based scaffolds compared to stem cell-seeded tissue engineered constructs

One of the key challenges in tissue engineering is to understand the host response to scaffolds and engineered constructs. We present a study in which two collagen-based scaffolds developed for bone repair: a collagen-glycosaminoglycan (CG) and biomimetic collagen-calcium phosphate (CCP) scaffold, are evaluated in rat cranial defects, both cell-free and when cultured with MSCs prior to implantation. The results demonstrate that both cell-free scaffolds showed excellent healing relative to the empty defect controls and somewhat surprisingly, to the tissue engineered (MSC-seeded) constructs. Immunological analysis of the healing response showed higher M1 macrophage activity in the cell-seeded scaffolds. However, when the M2 macrophage response was analysed, both groups (MSC-seeded and non-seeded scaffolds) showed significant activity of these cells which are associated with an immunomodulatory and tissue remodelling response. Interestingly, the location of this response was confined to the construct periphery, where a capsule had formed, in the MSC-seeded groups as opposed to areas of new bone formation in the non-seeded groups. This suggests that matrix deposited by MSCs during in vitro culture may adversely affect healing by acting as a barrier to macrophage-led remodelling when implanted in vivo. This study thus improves our understanding of host response in bone tissue engineering.

Development of a biomimetic collagen-hydroxyapatite scaffold for bone tissue engineering using a SBF immersion technique.

The objective of this study was to develop a biomimetic, highly porous collagen-hydroxyapatite (HA) composite scaffold for bone tissue engineering (TE), combining the biological performance and the high porosity of a collagen scaffold with the high mechanical stiffness of a HA scaffold. Pure collagen scaffolds were produced using a lyophilization process and immersed in simulated body fluid (SBF) to provide a biomimetic coating. Pure collagen scaffolds served as a control. The mechanical, material, and structural properties of the scaffolds were analyzed and the biological performance of the scaffolds was evaluated by monitoring the cellular metabolic activity and cell number at 1, 2, and 7 days post seeding. The SBF-treated scaffolds exhibited a significantly increased stiffness compared to the pure collagen group (4-fold increase), while a highly interconnected structure (95%) was retained. FTIR indicated that the SBF coating exhibited similar characteristics to pure HA. Micro-CT showed a homogeneous distribution of HA. Scanning electron microscopy also indicated a mineralization of the collagen combined with a precipitation of HA onto the collagen. The excellent biological performance of the collagen scaffolds was maintained in the collagen-HA scaffolds as demonstrated from cellular metabolic activity and total cell number. This investigation has successfully developed a biomimetic collagen-HA composite scaffold. An increase in the mechanical properties combined with an excellent biological performance in vitro was observed, indicating the high potential of the scaffold for bone TE.

A Comparative Study of Shear Stresses in Collagen-Glycosaminoglycan and Calcium Phosphate Scaffolds in Bone Tissue-Engineering Bioreactors

The increasing demand for bone grafts, combined with their limited availability and potential risks, has led to much new research in bone tissue engineering. Current strategies of bone tissue engineering commonly use cell-seeded scaffolds and flow perfusion bioreactors to stimulate the cells to produce bone tissue suitable for implantation into the patients body. The aim of this study was to quantify and compare the wall shear stresses in two bone tissue engineering scaffold types (collagen-glycosaminoglycan (CG) and calcium phosphate) exposed to fluid flow in a perfusion bioreactor. Based on micro-computed tomography images, three-dimensional numerical computational fluid dynamics (CFD) models of the two scaffold types were developed to calculate the wall shear stresses within the scaffolds. For a given flow rate (normalized according to the cross-sectional area of the scaffolds), shear stress was 2.8 times as high in the CG as in the calcium-phosphate scaffold. This is due to the differences in scaffold geometry, particularly the pore size (CG pore size approximately 96 microm, calcium phosphate pore size approximately 350 microm). The numerically obtained results were compared with those from an analytical method that researchers use widely experimentalists to determine perfusion flow rates in bioreactors. Our CFD simulations revealed that the cells in both scaffold types were exposed to a wide range of wall shear stresses throughout the scaffolds and that the analytical method predicted shear stresses 12% to 21% greater than those predicted using the CFD method. This study demonstrated that the wall shear stresses in calcium phosphate scaffolds (745.2 mPa) are approximately 40 times as high as in CG scaffolds (19.4 mPa) when flow rates are applied that have been experimentally used to stimulate the release of prostaglandin E(2). These findings indicate the importance of using accurate computational models to estimate shear stress and determine experimental conditions in perfusion bioreactors for tissue engineering.

Deformation simulation of cells seeded on a collagen-GAG scaffold in a flow perfusion bioreactor using a sequential 3D CFD-elastostatics model.

Tissue-engineered bone shows promise in meeting the huge demand for bone grafts caused by up to 4 million bone replacement procedures per year, worldwide. State-of-the-art bone tissue engineering strategies use flow perfusion bioreactors to apply biophysical stimuli to cells seeded on scaffolds and to grow tissue suitable for implantation into the patients body. The aim of this study was to quantify the deformation of cells seeded on a collagen-GAG scaffold which was perfused by culture medium inside a flow perfusion bioreactor. Using a microCT scan of an unseeded collagen-GAG scaffold, a sequential 3D CFD-deformation model was developed. The wall shear stress and the hydrostatic wall pressure acting on the cells were computed through the use of a CFD simulation and fed into a linear elastostatics model in order to calculate the deformation of the cells. The model used numerically seeded cells of two common morphologies where cells are either attached flatly on the scaffold wall or bridging two struts of the scaffold. Our study showed that the displacement of the cells is primarily determined by the cell morphology. Although cells of both attachment profiles were subjected to the same mechanical load, cells bridging two struts experienced a deformation up to 500 times higher than cells only attached to one strut. As the scaffolds pore size determines both the mechanical load and the type of attachment, the design of an optimal scaffold must take into account the interplay of these two features and requires a design process that optimizes both parameters at the same time.

Influence of a novel calcium-phosphate coating on the mechanical properties of highly porous collagen scaffolds for bone repair.

Lyophilised collagen scaffolds have shown enormous potential in tissue engineering in a number of areas due to their excellent biological performance. However, they are limited for use in bone tissue engineering due to poor mechanical properties. This paper discusses the development of a calcium-phosphate coating for collagen scaffolds in order to improve their mechanical properties for bone tissue engineering. Pure collagen scaffolds produced in a lyophilization process were coated by immersing them in sodium ammonium hydrogen phosphate (NaNH(4)HPO(4)) followed by calcium chloride (CaCl(2)). The optimal immersing sequence, duration, as well as the optimal solution concentration which facilitated improved mechanical properties of the scaffolds was investigated. The influence of the coating on composition, structural and material properties was analysed. This investigation successfully developed a novel collagen/calcium-phosphate composite scaffold. An increase in the mechanical properties of the scaffolds from 0.3 kPa to up to 90 kPa was found relative to a pure collagen scaffold, while the porosity was maintained as high as 92%, indicating the potential of the scaffold for bone tissue engineering or as a bone graft substitute.

Influence of minimally invasive total hip replacement on hip reaction forces and their orientations

Minimally invasive surgery (MIS) is becoming increasingly popular. Supporters claim that the main advantages of MIS total hip replacement (THR) are less pain and a faster rehabilitation and recovery. Critics claim that safety and efficacy of MIS are yet to be determined. We focused on a biomechanical comparison between surgical standard and MIS approaches for THR during the early recovery of patients. A validated, parameterized musculoskeletal model was set to perform a squat of a 50th percentile healthy European male. A bilateral motion was chosen to investigate effects on the contralateral side. Surgical approaches were simulated by excluding the incised muscles from the computations. Resulting hip reaction forces and their symmetry and orientation were analyzed. MIS THR seemed less influential on the symmetry index of hip reaction forces between the operated and nonoperated leg when compared to the standard lateral approach. Hip reaction forces at peak loads of the standard transgluteal approach were 24% higher on the contralateral side when compared to MIS approaches. Our results suggest that MIS THR contributes to a greater symmetry of hip reaction forces in absolute value as well as force‐orientation following THR.

How Good is Good Enough? Lessons in Musculoskeletal Model Validation With the Anybody Modeling System

In the last two decades a steady evolution has taken place in the realm of musculoskeletal simulation, which is now taking an increasingly central role in guiding ergonomics evaluations, influencing medical device design, and informing clinical decisions. Musculoskeletal simulation holds tremendous promise to help bring safer, more innovative products to market more quickly and to drive optimized, patient-specific care. But, to effectively deliver on these challenging goals, both the software and the models created from it must meet high expectations for verification and validation so that critical choices influenced by simulation can be made with confidence. Verification is the job of the software developer, but due to the breadth of modeling applications, the task of validation falls to the user. Rigorous model validation is time consuming and often technically difficult. And so, the question arises, in the context of both verification and validation, “How good is good enough?” The goal of this paper is to offer a response to that question. The discussion will be complemented by relevant validation examples from the open literature pertaining to one commercial musculoskeletal simulation software, the AnyBody Modeling System (AMS).Copyright

Metatarsal Loading During Gait-A Musculoskeletal Analysis.

Detailed knowledge of the loading conditions within the human body is essential for the development and optimization of treatments for disorders and injuries of the musculoskeletal system. While loads in the major joints of the lower limb have been the subject of extensive study, relatively little is known about the forces applied to the individual bones of the foot. The objective of this study was to use a detailed musculoskeletal model to compute the loads applied to the metatarsal bones during gait across several healthy subjects. Motion-captured gait trials and computed tomography (CT) foot scans from four healthy subjects were used as the inputs to inverse dynamic simulations that allowed the computation of loads at the metatarsal joints. Low loads in the metatarsophalangeal (MTP) joint were predicted before terminal stance, however, increased to an average peak of 1.9 times body weight (BW) before toe-off in the first metatarsal. At the first tarsometatarsal (TMT) joint, loads of up to 1.0 times BW were seen during the early part of stance, reflecting tension in the ligaments and muscles. These loads subsequently increased to an average peak of 3.0 times BW. Loads in the first ray were higher compared to rays 2-5. The joints were primarily loaded in the longitudinal direction of the bone.

The Glasgow-Maastricht foot model, evaluation of a 26 segment kinematic model of the foot

BackgroundAccurately measuring of intrinsic foot kinematics using skin mounted markers is difficult, limited in part by the physical dimensions of the foot. Existing kinematic foot models solve this problem by combining multiple bones into idealized rigid segments. This study presents a novel foot model that allows the motion of the 26 bones to be individually estimated via a combination of partial joint constraints and coupling the motion of separate joints using kinematic rhythms.MethodsSegmented CT data from one healthy subject was used to create a template Glasgow-Maastricht foot model (GM-model). Following this, the template was scaled to produce subject-specific models for five additional healthy participants using a surface scan of the foot and ankle. Forty-three skin mounted markers, mainly positioned around the foot and ankle, were used to capture the stance phase of the right foot of the six healthy participants during walking. The GM-model was then applied to calculate the intrinsic foot kinematics.ResultsDistinct motion patterns where found for all joints. The variability in outcome depended on the location of the joint, with reasonable results for sagittal plane motions and poor results for transverse plane motions.ConclusionsThe results of the GM-model were comparable with existing literature, including bone pin studies, with respect to the range of motion, motion pattern and timing of the motion in the studied joints. This novel model is the most complete kinematic model to date. Further evaluation of the model is warranted.