Towards in silico Models of the Inflammatory Response in Bone Fracture Healing.

peer reviewedIn silico modeling is a powerful strategy to investigate the biological events occurring at tissue, cellular and subcellular level during bone fracture healing. However, most current models do not consider the impact of the inflammatory response on the later stages of bone repair. Indeed, as initiator of the healing process, this early phase can alter the regenerative outcome: if the inflammatory response is too strongly down- or upregulated, the fracture can result in a non-union. This review covers the fundamental information on fracture healing, in silico modeling and experimental validation. It starts with a description of the biology of fracture healing, paying particular attention to the inflammatory phase and its cellular and subcellular components. We then discuss the current state-of-the-art regarding in silico models of the immune response in different tissues as well as the bone regeneration process at the later stages of fracture healing. Combining the aforementioned biological and computational state-of-the-art, continuous, discrete and hybrid modeling technologies are discussed in light of their suitability to capture adequately the multiscale course of the inflammatory phase and its overall role in the healing outcome. Both in the establishment of models as in their validation step, experimental data is required. Hence, this review provides an overview of the different in vitro and in vivo set-ups that can be used to quantify cell- and tissue-scale properties and provide necessary input for model credibility assessment. In conclusion, this review aims to provide hands-on guidance for scientists interested in building in silico models as an additional tool to investigate the critical role of the inflammatory phase in bone regeneration

Computational Models of Material Interfaces for the Study of Extracorporeal Shock Wave Therapy

Extracorporeal Shock Wave Therapy (ESWT) is a noninvasive treatment for a variety of musculoskeletal ailments. A shock wave is generated in water and then focused using an acoustic lens or reflector so the energy of the wave is concentrated in a small treatment region where mechanical stimulation enhances healing. In this work we have computationally investigated shock wave propagation in ESWT by solving a Lagrangian form of the isentropic Euler equations in the fluid and linear elasticity in the bone using high-resolution finite volume methods. We solve a full three-dimensional system of equations and use adaptive mesh refinement to concentrate grid cells near the propagating shock. We can model complex bone geometries, the reflection and mode conversion at interfaces, and the the propagation of the resulting shear stresses generated within the bone. We discuss the validity of our simplified model and present results validating this approach

Towards a New Spatial Representation of Bone Remodeling

Irregular bone remodeling is associated with a number of bone diseases such as osteoporosis and multiple myeloma. Computational and mathematical modeling can aid in therapy and treatment as well as understanding fundamental biology. Different approaches to modeling give insight into different aspects of a phenomena so it is useful to have an arsenal of various computational and mathematical models. Here we develop a mathematical representation of bone remodeling that can effectively describe many aspects of the complicated geometries and spatial behavior observed. There is a sharp interface between bone and marrow regions. Also the surface of bone moves in and out, i.e. in the normal direction, due to remodeling. Based on these observations we employ the use of a level-set function to represent the spatial behavior of remodeling. We elaborate on a temporal model for osteoclast and osteoblast population dynamics to determine the change in bone mass which influences how the interface between bone and marrow changes. We exhibit simulations based on our computational model that show the motion of the interface between bone and marrow as a consequence of bone remodeling. The simulations show that it is possible to capture spatial behavior of bone remodeling in complicated geometries as they occur \emph{in vitro} and \emph{in vivo}. By employing the level set approach it is possible to develop computational and mathematical representations of the spatial behavior of bone remodeling. By including in this formalism further details, such as more complex cytokine interactions and accurate parameter values, it is possible to obtain simulations of phenomena related to bone remodeling with spatial behavior much as \emph{in vitro} and \emph{in vivo}. This makes it possible to perform \emph{in silica} experiments more closely resembling experimental observations.Comment: Math. Biosci. Eng., 9(2), 201

Treatment of a Femur Nonunion with Microsurgical Corticoperiosteal Pedicled Flap from the Medial Femoral Condyle

Introduction.Te vascularized corticoperiosteal fap is harvested from the medial femoral condyle and it is nourished by the articular branch of the descending genicular artery and the superomedial genicular artery. Tis fap is usually harvested as a free fap for the reconstruction of bone defects at forearm, distal radius, carpus, hand, and recently at lower limb too. Case Report. A 50-year-old Caucasian man referred to our department for hypertrophic nonunion of the distal femur, refractory to the conservative treatments. Te frst surgical choice was the revision of the nail and the bone reconstruction with a corticoperiosteal pedicled fap from the medial femoral condyle. We considered union to have occurred 3.5 months afer surgery when radiographs showed bridging of at least three of the four bony cortices and clinically the patient was able to walk with full weight bearing without any pain. At the last follow-up (25 months), the patient was completely satisfed with the procedure. Discussion. Te corticoperiosteal fap allows a faster healing of fractures with a minimal morbidity at the donor site. We suggest that the corticoperiosteal pedicled fap graf is a reliable and efective treatment for distal femur nonunion

Periprosthetic fracture fixation of the femur following total hip arthroplasty: a review of biomechanical testing – part II

BACKGROUND: Periprosthetic femoral fracture is a severe complication of total hip arthroplasty. A previous review published in 2011 summarised the biomechanical studies regarding periprosthetic femoral fracture and its fixation techniques. Since then, there have been several commercially available fracture plates designed specifically for the treatment of these fractures. However, several clinical studies still report failure of fixation treatments used for these fractures. METHODS: The current literature on biomechanical models of periprosthetic femoral fracture fixation since 2010 to present is reviewed. The methodologies involved in the experimental and computational studies of periprosthetic femoral fracture fixation are described and compared with particular focus on the recent developments. FINDINGS: Several issues raised in the previous review paper have been addressed by current studies; such as validating computational results with experimental data. Current experimental studies are more sophisticated in design. Computational studies have been useful in studying fixation methods or conditions (such as bone healing) that are difficult to study in vivo or in vitro. However, a few issues still remain and are highlighted. INTERPRETATION: The increased use of computational studies in investigating periprosthetic femoral fracture fixation techniques has proven valuable. Existing protocols for testing periprosthetic femoral fracture fixation need to be standardised in order to make more direct and conclusive comparisons between studies. A consensus on the ‘optimum’ treatment method for periprosthetic femoral fracture fixation needs to be achieved

Simulation-aided design of tubular polymeric capsules for self-healing concrete

Polymeric capsules can have an advantage over glass capsules used up to now as proof-of-concept carriers in self-healing concrete. They allow easier processing and afford the possibility to fine tune their mechanical properties. Out of the multiple requirements for capsules used in this context, the capability of rupturing when crossed by a crack in concrete of a typical size is one of the most relevant, as without it no healing agent is released into the crack. This study assessed the fitness of five types of polymeric capsules to fulfill this requirement by using a numerical model to screen the best performing ones and verifying their fitness with experimental methods. Capsules made of a specific type of poly(methyl methacrylate) (PMMA) were considered fit for the intended application, rupturing at average crack sizes of 69 and 128 μm, respectively for a wall thickness of ~0.3 and ~0.7 mm. Thicker walls were considered unfit, as they ruptured for crack sizes much higher than 100 μm. Other types of PMMA used and polylactic acid were equally unfit for the same reason. There was overall good fitting between model output and experimental results and an elongation at break of 1.5% is recommended regarding polymers for this application

Multiscale modeling of bone tissue Mechanobiology

Mechanical environment has a crucial role in our organism at the different levels, ranging from cells to tissues and our own organs. This regulatory role is especially relevant for bones, given their importance as load-transmitting elements that allow the movement of our body as well as the protection of vital organs from load impacts. Therefore bone, as living tissue, is continuously adapting its properties, shape and repairing itself, being the mechanical loads one of the main regulatory stimuli that modulate this adaptive behavior. Here we review some key results of bone mechanobiology from computational models, describing the effect that changes associated to the mechanical environment induce in bone response, implant design and scaffold-driven bone regeneration