Showing papers by "Georg N. Duda published in 2015"
TL;DR: In this paper, a void-forming hydrogel was used to control mesenchymal stem cell osteogenesis and cell deployment in vitro and in vivo, respectively, by modifying the hydrogels' elastic modulus or its chemistry.
Abstract: The effectiveness of stem cell therapies has been hampered by cell death and limited control over fate. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells and provide molecular cues to direct cell phenotype. Stem cell behaviour can also be controlled in vitro by manipulating the elasticity of both porous and non-porous materials, yet translation to therapeutic processes in vivo remains elusive. Here, by developing injectable, void-forming hydrogels that decouple pore formation from elasticity, we show that mesenchymal stem cell (MSC) osteogenesis in vitro, and cell deployment in vitro and in vivo, can be controlled by modifying, respectively, the hydrogel's elastic modulus or its chemistry. When the hydrogels were used to transplant MSCs, the hydrogel's elasticity regulated bone regeneration, with optimal bone formation at 60 kPa. Our findings show that biophysical cues can be harnessed to direct therapeutic stem cell behaviours in situ.
366 citations
TL;DR: A detailed summary of studies where the use of biomaterials favorably influenced muscle repair is presented, and promising future trends in the field of muscle regeneration are outlined involving a deeper understanding of the endogenous healing cascades.
330 citations
01 Sep 2015
TL;DR: By developing injectable, void-forming hydrogels that decouple pore formation from elasticity, this work shows that mesenchymal stem cell osteogenesis in vitro, and cell deployment in vitro and in vivo, can be controlled by modifying the hydrogel's elastic modulus or its chemistry.
243 citations
TL;DR: The interdependency of the time cascades of inflammation, angiogenesis, and tissue regeneration is highlighted to early identify patients at risk as well as to overcome critical clinical conditions that limit healing.
Abstract: Delayed healing or nonhealing of bone is an important clinical concern. Although bone, one of the two tissues with scar-free healing capacity, heals in most cases, healing is delayed in more than 10% of clinical cases. Treatment of such delayed healing condition is often painful, risky, time consuming, and expensive. Tissue healing is a multistage regenerative process involving complex and well-orchestrated steps, which are initiated in response to injury. At best, these steps lead to scar-free tissue formation. At the onset of healing, during the inflammatory phase, stationary and attracted macrophages and other immune cells at the fracture site release cytokines in response to injury. This initial reaction to injury is followed by the recruitment, proliferation, and differentiation of mesenchymal stromal cells, synthesis of extracellular matrix proteins, angiogenesis, and finally tissue remodeling. Failure to heal is often associated with poor revascularization. Since blood vessels mediate the transport...
122 citations
TL;DR: The data suggest that pharmaceutical strategies augmenting physical exercise should consider this dysfunction in the mechanical regulation of bone (re)modeling to more effectively combat age‐related bone loss.
Abstract: Physical activity is essential to maintain skeletal mass and structure, but its effect seems to diminish with age. To test the hypothesis that bone becomes less sensitive to mechanical strain with age, we used a combined in vivo/in silico approach. We investigated how maturation and aging influence the mechanical regulation of bone formation and resorption to 2 weeks of noninvasive in vivo controlled loading in mice. Using 3D in vivo morphometrical assessment of longitudinal microcomputed tomography images, we quantified sites in the mouse tibia where bone was deposited or resorbed in response to controlled in vivo loading. We compared the (re)modeling events (formation/resorption/quiescent) to the mechanical strains induced at these sites (predicted using finite element analysis). Mice of all age groups (young, adult, and elderly) responded to loading with increased formation and decreased resorption, preferentially at high strains. Low strains were associated with no anabolic response in adult and elderly mice, whereas young animals showed a strong response. Adult animals showed a clear separation between strain ranges where formation and resorption occurred but without an intermediate quiescent "lazy zone". This strain threshold disappeared in elderly mice, as mechanically induced (re)modeling became dysregulated, apparent in an inability to inhibit resorption or initiate formation. Contrary to what is generally believed until now, aging does not shift the mechanical threshold required to initiate formation or resorption, but rather blurs its specificity. These data suggest that pharmaceutical strategies augmenting physical exercise should consider this dysfunction in the mechanical regulation of bone (re)modeling to more effectively combat age-related bone loss.
107 citations
TL;DR: In vivo experiments demonstrate the efficacy ofStructured hydrogels showing form stability and elastic properties individually tailorable on different length scales in biomaterial-induced bone regeneration, not requiring addition of cells or growth factors.
Abstract: Structured hydrogels showing form stability and elastic properties individually tailorable on different length scales are accessible in a one-step process. They support cell adhesion and differentiation and display growing pore size during degradation. In vivo experiments demonstrate their efficacy in biomaterial-induced bone regeneration, not requiring addition of cells or growth factors.
94 citations
TL;DR: Research approaches and findings on bone healing and regeneration that were presented at a workshop at the 60th annual meeting of the Orthopedic Research Society in New Orleans in 2014 are summarized.
Abstract: We summarize research approaches and findings on bone healing and regeneration that were presented at a workshop at the 60th annual meeting of the Orthopedic Research Society (ORS) in New Orleans in 2014. The workshop was designed to discuss the role of inflammation in bone regeneration in the context of fundamental biology, and to develop therapeutic strategies that involve immune modulation. Delayed or non-healing of bone is a major clinical problem, with around 10% of fracture patients suffering from unsatisfying healing outcomes. Inflammation is traditionally seen as a defense mechanism, but was recently found essential in supporting and modulating regenerative cascades. In bone healing, macrophages and T- and B-cells interact with progenitor cells, bone forming osteoblasts and remodeling osteoclasts. Among the cells of the innate immunity, macrophages are promising candidates for targets in immune-modulatory interventions that would overcome complications in bone healing and bone-related diseases. Among the cells of the adaptive immune system, CD8+ T cells have been shown to have a negative impact on bone fracture healing outcome, whereas regulatory T cells could be promising candidates that have a positive, modulating effect on bone fracture healing. This workshop addressed recent advances and key challenges in this exciting interdisciplinary research field.
89 citations
TL;DR: Results suggest that the diminished adaptive response to mechanical loading in adulthood is in part due to a reduction in the strains induced within the bone.
82 citations
TL;DR: The current finite element analysis demonstrates that plate working length significantly influences interfragmentary movements, thereby affecting the biomechanical consequences of fracture healing.
75 citations
TL;DR: A novel method that combines in vivo microCT with a computational approach is a powerful tool to monitor bone turnover in animal models now and is waiting to be applied to human patients in the near future.
60 citations
TL;DR: Investigation of the combined effects of scaffold architecture and BMP stimulation on bone regeneration found similar structural properties on a microscopic and sub-micron level seem to emerge in both BMP-treated and scaffold only groups.
TL;DR: A simple theoretical model is used to investigate cellular and matrix organization as a result of mechanical feedback signals between cells and the surrounding ECM and shows that a group of contractile cells will self-polarize at a large scale, even in homogeneous environments.
Abstract: Physical cues play a fundamental role in a wide range of biological processes, such as embryogenesis, wound healing, tumour invasion and connective tissue morphogenesis. Although it is well known that during these processes, cells continuously interact with the local extracellular matrix (ECM) through cell traction forces, the role of these mechanical interactions on large scale cellular and matrix organization remains largely unknown. In this study, we use a simple theoretical model to investigate cellular and matrix organization as a result of mechanical feedback signals between cells and the surrounding ECM. The model includes bi-directional coupling through cellular traction forces to deform the ECM and through matrix deformation to trigger cellular migration. In addition, we incorporate the mechanical contribution of matrix fibres and their reorganization by the cells. We show that a group of contractile cells will self-polarize at a large scale, even in homogeneous environments. In addition, our simulations mimic the experimentally observed alignment of cells in the direction of maximum stiffness and the building up of tension as a consequence of cell and fibre reorganization. Moreover, we demonstrate that cellular organization is tightly linked to the mechanical feedback loop between cells and matrix. Cells with a preference for stiff environments have a tendency to form chains, while cells with a tendency for soft environments tend to form clusters. The model presented here illustrates the potential of simple physical cues and their impact on cellular self-organization. It can be used in applications where cell-matrix interactions play a key role, such as in the design of tissue engineering scaffolds and to gain a basic understanding of pattern formation in organogenesis or tissue regeneration.
TL;DR: It is shown that the link between the mineral nanoparticles and known damage propagation trajectories in dentin are linked, suggesting a previously overlooked compression-mediated toughening mechanism.
Abstract: The tough bulk of dentin in teeth supports enamel, creating cutting and grinding biostructures with superior failure resistance that is not fully understood. Synchrotron-based diffraction methods, utilizing micro- and nanofocused X-ray beams, reveal that the nm-sized mineral particles aligned with collagen are precompressed and that the residual strains vanish upon mild annealing. We show the link between the mineral nanoparticles and known damage propagation trajectories in dentin, suggesting a previously overlooked compression-mediated toughening mechanism.
TL;DR: The results suggest that after surgical ATR repair, higher AT stiffness, but not a longer AT, may contribute to deficits in plantarflexion moment generation, and further support the claim that post‐ATR tendon regeneration results in the production of a tissue that is functionally different than noninjured tendon.
Abstract: Achilles tendon rupture (ATR) alters tissue composition, which may affect long-term tendon mechanics and ankle function during movement. However, a relationship between Achilles tendon (AT) properties and ankle joint function during gait remains unclear. The primary hypotheses were that (a) post-ATR tendon stiffness and length differ from the noninjured contralateral side and that (b) intra-patient asymmetries in AT properties correlate to ankle function asymmetries during gait, determined by ankle angles and moments. Ultrasonography and dynamometry were used to assess AT tendon stiffness, strain, elongation, and rest length in both limbs of 20 ATR patients 2-6 years after repair. Three-dimensional ankle angles and moments were determined using gait analysis. Injured tendons exhibited increased stiffness, rest length, and altered kinematics, with higher dorsiflexion and eversion, and lower plantarflexion and inversion. Intra-patient tendon stiffness and tendon length ratios were negatively correlated to intra-patient ratios of the maximum plantarflexion moment and maximum dorsiflexion angle, respectively. These results suggest that after surgical ATR repair, higher AT stiffness, but not a longer AT, may contribute to deficits in plantarflexion moment generation. These data further support the claim that post-ATR tendon regeneration results in the production of a tissue that is functionally different than noninjured tendon.
TL;DR: The presentation of the collagen I-derived DGEA ligand is a feasible approach for selectively inducing an osteogenic phenotype in encapsulated MSCs, and the osteogenic differentiation of M SCs encapsulated within alginate hydrogels presenting the DGEa ligand was enhanced.
Abstract: Interactions between cells and the extracellular matrix (ECM) are known to play critical roles in regulating cell phenotype. The identity of ECM ligands presented to mesenchymal stem cells (MSCs) has previously been shown to direct the cell fate commitment of these cells. To enhance osteogenic differentiation of MSCs, alginate hydrogels were prepared that present the DGEA ligand derived from collagen I. When presented from hydrogel surfaces in 2D, the DGEA ligand did not facilitate cell adhesion, while hydrogels presenting the RGD ligand derived from fibronectin did encourage cell adhesion and spreading. However, the osteogenic differentiation of MSCs encapsulated within alginate hydrogels presenting the DGEA ligand was enhanced when compared with unmodified alginate hydrogels and hydrogels presenting the RGD ligand. MSCs cultured in DGEA-presenting gels exhibited increased levels of osteocalcin production and mineral deposition. These data suggest that the presentation of the collagen I-derived DGEA ligand is a feasible approach for selectively inducing an osteogenic phenotype in encapsulated MSCs.
TL;DR: The results suggest that the muscle shape of the quadriceps vastii is independent of muscle dimensions or sex and that the prediction method could be sensitive enough to detect changes in muscle volume related to degeneration, atrophy, or hypertrophy.
Abstract: The present study investigated the applicability of a muscle volume prediction method using only the muscle length (L(M)), the maximum anatomical cross-sectional area (ACSA(max)), and a muscle-specific shape factor (p) on the quadriceps vastii. L(M), ACSA(max), muscle volume, and p were obtained from magnetic resonance images of the vastus intermedius (VI), lateralis (VL), and medialis (VM) of female (n = 20) and male (n = 17) volleyball athletes. The average p was used to predict muscle volumes (V(p)) using the equation V(p) = p × ACSA(max) × L(M). Although there were significant differences in the muscle dimensions between male and female athletes, p was similar and on average 0.582, 0.658, 0.543 for the VI, VL, and VM, respectively. The position of ACSA(max) showed low variability and was at 57%, 60%, and 81% of the thigh length for VI, VL, and VM. Further, there were no significant differences between measured and predicted muscle volumes with root mean square differences of 5-8%. These results suggest that the muscle shape of the quadriceps vastii is independent of muscle dimensions or sex and that the prediction method could be sensitive enough to detect changes in muscle volume related to degeneration, atrophy, or hypertrophy.
TL;DR: Mechanical frame conditions can be significantly influenced by type and placement of the screws in locking plate osteosynthesis of the distal femur by varying plate working length stiffness and IFM are modulated.
Abstract: Background Extent and orientation of interfragmentary movement (IFM) are crucially affecting course and quality of fracture healing. The effect of different configurations for implant fixation on successful fracture healing remain unclear. We hypothesize that screw type and configuration of locking plate fixation profoundly influences stiffness and IFM for a given load in a distal femur fracture model. Methods Simple analytical models are presented to elucidate the influence of fixation configuration on construct stiffness. Models were refined with a consistent single-patient-data-set to create finite-element femur models. Locking plate fixation of a distal femoral 10mm-osteotomy (comminution model) was fitted with rigid locking screws (rLS) or semi-rigid locking screws (sLS). Systematic variations of screw placements in the proximal fragment were tested. IFM was quantitatively assessed and compared for different screw placements and screw types. Results Different screw allocations significantly affect IFM in a locking plate construct. LS placement of the first screw proximal to the fracture (plate working length, PWL) has a significant effect on axial IFM (p Conclusion Mechanical frame conditions can be significantly influenced by type and placement of the screws in locking plate osteosynthesis of the distal femur. By varying plate working length stiffness and IFM are modulated. Moderate axial and concomitantly low shear IFM could not be achieved through changes in screw placement alone. In the present transverse osteotomy model, ratio of shear/axial IFM with simultaneous moderate axial IFM is optimized by the use of appropriate plate working length of about 42–62mm. Fixation with sLS demonstrated significantly more axial IFM underneath the plate and may further contribute to compensation of asymmetric straining.
Journal Article•
TL;DR: TBI results in an increased formation of callus and mineral density compared to normal bone healing in mice, and this fact combined with a tendency towards accelerated gap bridging leads to increased torsional strength.
Abstract: INTRODUCTION: The combination of traumatic brain injury (TBI) and long-bone fractures has previously been reported to lead to exuberant callus formation. The aim of this experimental study was to radiographically and biomechanically study the effect of TBI on bone healing in a mouse model. MATERIALS AND METHODS: 138 female C57/Black6N mice were assigned to four groups (fracture (Fx) / TBI / combined trauma (Fx/TBI) / controls). Femoral osteotomy and TBI served as variables: osteotomies were stabilized with external fixators, TBI was induced with controlled cortical impact injury. During an observation period of four weeks, in vivo micro-CT scans of femora were performed on a weekly basis. Biomechanical testing of femora was performed ex vivo. RESULTS: The combined-trauma group showed increased bone volume, higher mineral density, and a higher rate of gap bridging compared to the fracture group. The combined-trauma group showed increased torsional strength at four weeks. DISCUSSION: TBI results in an increased formation of callus and mineral density compared to normal bone healing in mice. This fact combined with a tendency towards accelerated gap bridging leads to increased torsional strength. The present study underscores the empirical clinical evidence that TBI stimulates bone healing. Identification of underlying pathways could lead to new strategies for bone-stimulating approaches in fracture care. Language: en
TL;DR: The results of the present study suggest that aiming for an optimal initial mechanical stimulus may be misleading because the initial mechanical environment is not preserved throughout the bone modeling process.
TL;DR: The findings that the new tissue formed in response to controlled loading and physiological loading had similar bone composition and that controlled loading enhanced bone composition in elderly mice further supports the use of physical activity as a noninvasive treatment to enhance bone quality as well as maintain bone mass in individuals suffering from age-related bone loss.
TL;DR: Data show that plate constructs with interfragmentary lag screw reveal similar axial and torsional stiffness values compared to intact bone as opposed to bridging plate constructs that showed significantly lower stiffness for both loading conditions.
TL;DR: Using a standard uncemented femoral component, high pre- and post-operative variability of femoral anteversion and neck-shaft angles was found with a significant decrease of the post-operatively anteversions and slight increase of the neck-Shaft angles, but without any impact on clinical outcome.
Abstract: The accurate reconstruction of hip anatomy and biomechanics is thought to be important in achieveing good clinical outcomes following total hip arthroplasty (THA). To this end some newer hip designs have introduced further modularity into the design of the femoral component such that neck-shaft angle and anteversion, which can be adjusted intra-operatively. The clinical effect of this increased modularity is unknown. We have investigated the changes in these anatomical parameters following conventional THA with a prosthesis of predetermined neck-shaft angle and assessed the effect of changes in the hip anatomy on clinical outcomes. In total, 44 patients (mean age 65.3 years (standard deviation (SD) 7); 17 male/27 female; mean body mass index 26.9 (kg/m²) (SD 3.1)) underwent a pre- and post-operative three-dimensional CT scanning of the hip. The pre- and post-operative neck-shaft angle, offset, hip centre of rotation, femoral anteversion, and stem alignment were measured. Additionally, a functional assessment and pain score were evaluated before surgery and at one year post-operatively and related to the post-operative anatomical changes. The mean pre-operative neck-shaft angle was significantly increased by 2.8° from 128° (SD 6.2; 119° to 147°) to 131° (SD 2.1; 127° to 136°) (p = 0.009). The mean pre-operative anteversion was 24.9° (SD 8; 7.9 to 39.1) and reduced to 7.4° (SD 7.3; -11.6° to 25.9°) post-operatively (p < 0.001). The post-operative changes had no influence on function and pain. Using a standard uncemented femoral component, high pre- and post-operative variability of femoral anteversion and neck-shaft angles was found with a significant decrease of the post-operative anteversion and slight increase of the neck-shaft angles, but without any impact on clinical outcome.
TL;DR: This paper presents a meta-modelling system that automates the very labor-intensive and therefore time-heavy and expensive and expensive process of designing and implementing translation systems for basic science and technology projects.
Abstract: Translation in an academic environment requires a support system—people, goals, models, partnerships, and infrastructures—that will push promising basic science and technology projects forward into the clinic.
TL;DR: Light is shed on the steps involved in structural formation of the mineralized tissue in midshafts of C57BL/6 femurs, shortly after birth, by combining 3D micrometer-resolution X-ray microtomography with 2D histology to study the transformation of the tissue from a partially-mineralized scaffold into a compact bone structure.
TL;DR: Computer simulations are used to test the consequences of different hypotheses of the mechanoregulation at the cellular level on the patterns of tissues formed during healing and found that the course of healing was virtually unaltered in case of scenario (3) where tissue maturation proceeded independent of mechanical stimulation.
Abstract: The formation of different tissues in the callus during secondary bone healing is at least partly influenced by mechanical stimuli. We use computer simulations to test the consequences of different hypotheses of the mechanoregulation at the cellular level on the patterns of tissues formed during healing. The computational study is based on an experiment on sheep, where after a tibial osteotomy, histological sections were harvested at different time points. In the simulations, we used a recently proposed basic phenomenological model, which allows ossification to occur either via endochondral or intramembranous ossification, but tries otherwise to employ a minimal number of simulation parameters. The model was extended to consider also the possibility of bone resorption and consequently allowing a description of the full healing progression till the restoration of the cortex. Specifically, we investigated how three changes in the mechanoregulation influence the resulting tissue patterns: (1) a time delay between stimulation of the cell and the formation of the tissue, (2) a variable mechanosensitivity of the cells, and (3) an independence of long time intervals of the soft tissue maturation from the mechanical stimulus. For all three scenarios, our simulations do not show qualitative differences in the time development of the tissue patterns. Largest differences were observed in the intermediate phases of healing in the amount and location of the cartilage. Interestingly, the course of healing was virtually unaltered in case of scenario (3) where tissue maturation proceeded independent of mechanical stimulation.
TL;DR: A new murine long‐term survival multiple trauma model mimicking clinical relevant injury patterns and previously published human posttraumatic immune response is proposed, revealing hemorrhagic shock as a causative factor that triggers sIL‐6R formation underscoring the fundamental pathophysiologic role of the transsignaling mechanism in multiple trauma.
TL;DR: The concept that disease-deduced growth factor variants are promising lead structures for novel therapeutics with improved clinical activities is supported, as microCT and histological analyses indicate that GDF5(N445T)-treated defects show faster and more efficient healing compared to GDF 5 wild type (GDF5 (wt))-treated defects.
TL;DR: The data suggest that, during growth and skeletal maturation, the response of bone to mechanical loading is a deposition of new bone matrix, where the tissue amount but not its mineral or elastic properties are influenced by animal age.
09 Dec 2015
TL;DR: It is suggested that in mice, bone does not require as much stability as is required in rat to reach timely healing, emphasizing the need to further investigate the species-specific mechano-biological regulation of bone regeneration.
Abstract: Mechanical signals are known to influence bone healing progression. Previous studies have postulated inter-species differences in the mechanical regulation of the bone healing process. The aim of this study is to investigate whether mechanical “rules” explaining tissue formation patterns during bone healing in rat can be translated to a mouse model of bone regeneration. We have used an established mechano-biological computer model that uses finite element techniques to determine the mechanical conditions within the healing region and an agent-based approach to simulate cellular activity. The computer model is set up to simulate the course of bone healing in a femoral osteotomy model stabilized with an external fixator. Computer model predictions are compared to corresponding histological data. Generic mechano-regulation “rules” able to explain bone healing progression in the rat are not able to describe tissue formation over the course of healing in the mouse. According to the differentiation theory proposed by Prendergast, mechanical stimuli within the healing region immediately post-surgery are determined to be favorable for cartilage and fibrous tissue formation. In contrast, in vivo histological data showed initial intramembraneous bone formation at the periosteal side. These results suggest that in mice, bone does not require as much stability as is required in rat to reach timely healing. This finding emphasizes the need to further investigate the species-specific mechano-biological regulation of bone regeneration.
TL;DR: Backscattered electron images are perfectly suited for registration into µCT reference frames, since both show structures based on the same physical principles, and this routine was able to exactly locate structural information in the 3D bone volume.
Abstract: Purpose/Aims of the study: Bone’s hierarchical structure can be visualized using a variety of methods. Many techniques, such as light and electron microscopy generate two-dimensional (2D) images, while micro-computed tomography (µCT) allows a direct representation of the three-dimensional (3D) structure. In addition, different methods provide complementary structural information, such as the arrangement of organic or inorganic compounds. The overall aim of the present study is to answer bone research questions by linking information of different 2D and 3D imaging techniques. A great challenge in combining different methods arises from the fact that they usually reflect different characteristics of the real structure.Materials and methods: We investigated bone during healing by means of µCT and a couple of 2D methods. Backscattered electron images were used to qualitatively evaluate the tissue’s calcium content and served as a position map for other experimental data. Nanoindentation and X-ray scat...