Prof. Ralph Müller

Machine Learning with little data: PCE on agent-based model of osteoporosis and its treatments

Combine two exploding fields in computer science: machine learning and agent-based modelling. Based on preclinical and in vitro studies of cell behaviour and cytokine reaction-diffusion and mechanical tests we have generated an in-house biofidelic agent-based model of the human skeleton and its response to diseases and their treatments. This model reproduces the effects of several widely used osteoporosis treatments on key parameters used to quantify fracture risk. This rule-based approach involves studying bone mechanobiology at the cell scale and extrapolating this to millions of cells at the tissue scale to understand the pharmacokinetics of treatments and identify possible new therapies and approaches to patient-specific treatment. An alternative approach to in silico prediction of response to treatment is a supervised learning approach where we simply input baseline and follow-up bone scans to a CNN with twelve layers constructed using keras. We then attempt to dive into the black box and quantify what characteristics of the input govern the response of our model. The issue is the clinical data is not big enough to do this well so we use the agent-based model as input to the ML approach to construct a proxy model! This also helps us understand, validate and quantify the uncertainty in the agent-based model. To decide which runs of the agent-based model to use as input to the ML approach to construct the proxy model we use polynomial chaos expansion.

Keywords

machine learning, artificial intelligence, uncertainty quantification, polynomial chaos expansion, agent-based modelling, bone mechanobiology, osteoporosis, patient-specific treatment, personalized medicine, innovation, therapy, medical research, fragility, fractures

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Semester Project , Bachelor Thesis , Master Thesis

Description

Osteoporosis is a skeletal condition characterized by decreased density (mass/volume) of normally mineralized bone. It is a major cause of morbidity in older people. _In silico_ simulations aim to provide fast, inexpensive, and ethical alternatives to prolonged and expensive animal and/or human trials for studying the deregulation of bone remodelling during osteoporosis and the effect of therapeutics [1]. Given the multiscale nature of biological systems, the integration of phenomena at different spatial and temporal scales has emerged to be essential in capturing mechanobiological mechanisms underlying bone remodelling processes [2]. In this context, the micro-multiphysics agent based (micro-MPA) models explicitly incorporate the complex cellular and molecular mechanisms causing metabolic bone diseases and the pathways involved in their treatments. At the ETH Laboratory for Bone Biomechanics, we are developing a Python and C++ based micro-MPA model [3,4] to predict the evolution of bone as a result of different pathological conditions and their prescribed therapies. The micro-MPA model considers eight different types of cells namely osteocytes, osteoclasts, osteoblasts, pre-osteocytes, pre-osteoclasts, pre-osteoblasts, lining cells, and hematopoietic stem cells (HSCs). It also includes signalling molecules RANK-L, OPG, TGF-ß, sclerostin, and estrogen. The micro-MPA model is characterized by approximately 150 input parameters. More than two thirds of these parameters have no basis in literature as they have never been measured clinically while the remaining one third have values in clinical literature that span sometimes several orders of magnitude. Moreover, the parameter settings used vary across research groups, prohibiting the comparison of results. Therefore, there is a strong need to perform the Uncertainty Quantification (UQ) analysis of the proposed model. While simulations provide estimates of real-world values, UQ measures the uncertainty (or error) associated with these estimates [2]. The significance of computational model verification, validation, and uncertainty quantification (VVUQ) has been demonstrated in various biomedical fields such as systems biology [5], in-stent restenosis [6-8], cardiovascular haemodynamics [9], etc. The objective of this project is to analyse the sensitivity and uncertainty of the micro-MPA model outputs with respect to changes in inputs. To do so, the uncertainties in the selected model parameters will be considered. UQ Labs, the framework for UQ [10] at ETH Zurich, will be used to generate the set of input parameter combinations according to the assumed probability distribution and perform sensitivity analysis for the selected model parameters. The Sobol indices will then be obtained from post-processing as a measure of the sensitivity of the modelling outcome corresponding to the individual input parameters. As a result of the UQ study performed in this project, the model will predict the evolution of bone under different pathological conditions/therapies while appropriately considering the importance of all the model parameters and in turn increase the confidence in the predicted simulation results. Sparse PCE on a database of iliac crest micro-CT scans and the corresponding virtual biopsies at different time points and in different disease and treatment scenarios generated using an agent-based model. The postdoc who started this project left to take a software engineering job at Max Planck. You will pick up where he left off. You will be supervised by Prof. Dr. Ralph Müller, h-index > 100, the most influential researcher in the bone biomechanics field worlwide, the developer of micro-computed tomography to analyse bone morphometrics and by his doctoral student Charles Ledoux, the president of the scientific staff association at ETH. You will also have an interim meeting and a final meeting with Prof. Marelli, one of the world's top experts on uncertainty quantification. Enhance your programming skills by applying some of the most searched for skills on the job market to a very concrete problem with a visual output representing changes in bone structure over time. Look at how your C++ and python code impacts the changes in the behaviour of the osteoclasts and osteoblasts remodelling the bone surface. Learn standard parallel processing techniques in MPI and openMP and how these impact the weak and strong scaling efficiency of your runs on Piz Daint at the Swiss National Supercomputer, the 6th fastest computer in the world! Most importantly there is a very motivating aspect to doing medical research. Of all people 50 and above, one third of women and one fifth of men will suffer a fragility fracture in their remaining lifetime. The Physiome Project and the Virtual Physiological Human project and other large-scale efforts to model the human body are recognized as a paradigm shift in personalized medicine that could put a significant dent in the tens of millions of fragility fracture that occur every year and the associated horrific and unacceptable reduction in quality of life. [1] Ledoux, C., Boaretti, D., Sachan, A., Müller, R. and Collins, C.J., (2022). Clinical Data for Parametrization of In Silico Bone Models Incorporating Cell-Cytokine Dynamics: A Systematic Review of Literature. Frontiers in bioengineering and biotechnology, 10. [2] Hambli, R., Katerchi, H., Benhamou, C.L., (2011) Multiscale methodology for bone remodelling simulation using coupled fnite element and neural network computation. Biomech Model Mechan 10:133–145. doi: https://doi.org/10.1007/s10237-010-0222-xhttps://doi.org/10.1016/j.bone.2019.07.024 [3] Tourolle, D. (2019). A Micro-scale Multiphysics Framework for Fracture Healing and Bone Remodelling ETH Library. ETH Zurich Res. Collect. doi:10.3929/ethzb-000364637 [4] Tourolle, D., Dempster, D. W., Ledoux, C., Boaretti, D., Aguilera, M., Saleem, N., et al. (2021). Ten-Year Simulation of the Effects of Denosumab on Bone Remodeling in Human Biopsies. JBMR plus 5, 5. doi:10.1002/JBM4.10494 [5] Marino, S., Hogue, I. B., Ray, C. J., and Kirschner, D. E. (2008). A Methodology for Performing Global Uncertainty and Sensitivity Analysis in Systems Biology. J. Theor. Biol. 254, 178–196. doi:10.1016/j.jtbi.2008.04.011 [6] Nikishova, A., Veen, L., Zun, P., and Hoekstra, A. G. (2018). Uncertainty Quantification of a Multiscale Model for In-Stent Restenosis. Cardiovasc. Eng. Tech. 9, 761–774. doi:10.1007/s13239-018-00372-4 [7] Nikishova, A., Veen, L., Zun, P., and Hoekstra, A. G. (2019). Semi-intrusive Multiscale Metamodelling Uncertainty Quantification with Application to a Model of In-Stent Restenosis. Phil. Trans. R. Soc. A. 377, 20180154. doi:10.1098/rsta.2018.0154 [8] Ye, D., Nikishova, A., Veen, L., Zun, P., and Hoekstra, A. G. (2021a). Non-intrusive and Semi-intrusive Uncertainty Quantification of aMultiscale In-Stent Restenosis Model. Reliability Eng. Syst. Saf. 214, 107734. doi:10.1016/j.ress.2021.107734 [9] Fleeter, C. M., Geraci, G., Schiavazzi, D. E., Kahn, A.M., and Marsden, A. L. (2020). Multilevel and Multifidelity Uncertainty Quantification for Cardiovascular Hemodynamics. Computer Methods Appl. Mech. Eng. 365, 113030. doi:10.1016/j.cma.2020.113030 [10] Marelli S. and Sudret, B., (2014) UQLab: A Framework for Uncertainty Quantification in MATLAB, In The 2nd International Conference on Vulnerability and Risk Analysis and Management (ICVRAM 2014), University of Liverpool, United Kingdom, July 13-16, pp. 2554–2563.

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Published since: 2024-03-19 , Earliest start: 2024-04-01 , Latest end: 2025-01-01

Applications limited to ETH Zurich , EPFL - Ecole Polytechnique Fédérale de Lausanne , Empa , Eawag , Paul Scherrer Institute , University of Zurich , Wyss Translational Center Zurich , Zurich University of Applied Sciences , Swiss Institute of Bioinformatics , Swiss National Science Foundation , Balgrist Campus , Berner Fachhochschule , CERN , Corporates Switzerland , CSEM - Centre Suisse d'Electronique et Microtechnique , Department of Quantitative Biomedicine , Hochschulmedizin Zürich , IBM Research Zurich Lab , Institute for Research in Biomedicine , Sirm Institute for Regenerative Medicine , Università della Svizzera italiana , Université de Neuchâtel , University of Basel , University of Berne , University of Fribourg , University of Geneva , University of Lausanne , University of Lucerne , University of St. Gallen , RWTH Aachen University , Ludwig Maximilians Universiy Munich , University of Cambridge , University of Oxford , UCL - University College London , Imperial College London , Delft University of Technology , Maastricht Science Programme , IDEA League

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Ledoux Charles

Topics Information, Computing and Communication Sciences , Biology

A Personalized Bone Organoid Diagnostic Framework for Predicting Drug Response in Children with Rare Bone Diseases

Rare genetic disorders are defined by a prevalence of fewer than 1/2000 people, are chronic and affect patients throughout their lifespan. Osteogenesis imperfecta (OI) is a heterogeneous group of rare genetic bone disorders. OI is a debilitating condition that involves impaired mobility, high fracture incidence and subsequent limb deformities. No treatment exists today that targets the underlying abnormal collagen structure and organization. The mainstay in pediatric care of OI remains antiresorptive therapy with bisphosphonates, despite concerns of long-term effects on depressed bone turnover. While antiresorptive monoclonal antibody treatments are currently undergoing clinical trials in children and young adults, anabolic treatments that directly increase bone formation are currently approved for adults only and decrease in efficacy over a relatively short time span. The experience with these drugs in OI therapy is limited, as clinical studies are still ongoing.

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bone organoid, diagnostics, bone diseases, 3D bioprinting, personalized medicine

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Semester Project , Internship , Bachelor Thesis , Master Thesis , ETH Zurich (ETHZ)

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Published since: 2024-03-15 , Earliest start: 2023-11-01 , Latest end: 2024-07-31

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Schädli Gian Nutal

Topics Engineering and Technology

Unraveling Calcium Dynamics and Immune Interactions in Bone Graft Substitute Environments through Advanced Ratiometric Imaging

This project endeavors to explore the dynamic interplay among calcium ions, bone graft substitutes, and resident immune cells in both orthotopic and ectopic environments, employing advanced ratiometric imaging techniques.

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Bone Graft Substitute, Calcium, Ratiometric Imaging, Immune Cells, in vitro, in vivo, Intravital Microscopy

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Semester Project , Internship , Bachelor Thesis , Master Thesis

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The indispensable role of the skeletal system in enabling motion and providing structural support to vital organs underscores the imperative for efficacious interventions in the context of substantial bone defects. Notably, Bone Graft Substitutes (BGS) have emerged as a viable therapeutic avenue, exhibiting success in promoting bone formation through their inherent osteoinductive potential. Despite the considerable promise associated with BGSs, the intricate mechanisms governing material-induced osteoinduction remain elusive. Bohner et al. have recently proposed a novel mechanism termed Sustained Local Ionic Homeostatic Imbalance (SLIHI) as a potential instigator of material-induced osteoinduction. The hypothesis posits that localized depletion of calcium and phosphate during the calcification process may lead to SLIHI, thereby modulating inflammation and instigating an osteoinductive response. Calcium signaling assumes a pivotal role in diverse biological and cellular processes, with a particular impact on skeleton mineralization. The continuous remodeling of the skeleton, involving bone resorption and new bone deposition, results in fluctuating extracellular calcium levels corresponding to different phases of remodeling. To comprehensively explore SLIHI, it becomes imperative to scrutinize the spatial distribution and concentration of calcium. This investigation can be effectively conducted through quantitative imaging techniques utilizing calcium-sensitive ratiometric probes. Ratiometric imaging is a scientific approach that utilizes specialized probes to quantitatively assess variations in calcium concentrations outside cells. This technique relies on the simultaneous acquisition of signals at two distinct wavelengths, allowing for the calculation of a ratio that is sensitive to changes in extracellular calcium levels. Here, we aim to assess the impact of ion-regulating BGS on extracellular calcium concentrations and the concurrent influence on adjacent immune cells.

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Published since: 2024-03-12 , Earliest start: 2024-04-01 , Latest end: 2024-12-31

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Wissmann Stefanie

Topics Engineering and Technology , Biology

Development of a Heterocellular Human Bone Organoid for Precision Medicine and Treatment

Our goal is to establish a heterocellular 3D printed bone organoid model comprising all major bone cell types (osteoblasts, osteocytes, osteoclasts) to recapitulate bone remodeling units in an in vitro system. The organoids will be produced with the human cells, as they could represent human pathophysiology better than animal models, and eventually could replace them. These in vitro models could be used in the advancement of next-generation personalised treatment strategies. Our tools are different kinds of 3D bioprinting platforms, bio-ink formulations, hydrogels, mol-bioassays, and time-lapsed image processing of micro-CT scans.

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3D printing, bone organoids, co-culture, bioreactor, hydrogels, drug testing

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Semester Project , Internship , Bachelor Thesis , Master Thesis , ETH Zurich (ETHZ)

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Published since: 2024-03-08 , Earliest start: 2022-08-01 , Latest end: 2024-08-31

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Steffi Chris

Topics Engineering and Technology , Biology

Unravelling the spatial and biomechanical dynamic of fracture healing in mice

Fracture healing is a complex process that involves inflammation, angiogenesis, and bone remodeling. The remodelling process helps maintain bone density, repair micro-damage that occurs due to everyday activities, and adapt bones to the specific needs of an individual's body. Mechanical loading is a crucial factor in the regulation of fracture healing. The forces and strains experienced by the bone during everyday activities influence the cellular responses, callus formation, bone deposition, remodelling, and, ultimately, the successful recovery of the fractured bone. The mechanisms underlying spatial cell reorganization during loading, which contributes to fracture healing, remain unclear. The project aims to investigate and explore the fracture healing process of mice using spatial transcriptome changes in response to mechanical loading. By shedding light on this aspect, the project aims to contribute to the broader understanding of fracture healing and potentially pave the way for more effective treatment strategies in the future.

Keywords

Spatial transcriptomics, Dimensionality reduction, Spatial expression pattern, Spatial interaction, Cell Segmentation and Visualization, Fracture healing, Bone

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IDEA League Student Grant (IDL) , Semester Project , Course Project , Internship , Bachelor Thesis , Master Thesis , ETH for Development (ETH4D) (ETHZ) , ETH Zurich (ETHZ)

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**Who We are:** Laboratory for Bone Biomechanics (Müller Group) works on musculoskeletal systems. The group develops a quantitative model of bone at the cellular, molecular, tissue, and organ levels. We seek a highly motivated Bachelor's or master’s student dedicated to creating a multimodal transcriptome analysis framework to deepen bone fracture healing. This project offers an opportunity to gain valuable work experience within a highly interdisciplinary and international team. **Project Description** Fracture healing is a complex process that involves a series of biological events, including inflammation, angiogenesis, and bone remodelling. This remodelling process helps maintain bone density, repair micro-damage that occurs due to everyday activities, and adapt bones to the specific needs of an individual's body. In essence, bone remodelling during fracture repair is a sophisticated and dynamic orchestration of cellular activities that reabsorb excess bone and revitalize the bone tissue to its former strength and functionality, ultimately facilitating a seamless and enduring restoration of the injured bone. The healing process is physiologically complex, involving both biological and mechanical aspects. Mechanical loading is a crucial factor in the regulation of fracture healing. The forces and strains experienced by the bone during everyday activities influence the cellular responses, callus formation, bone deposition, remodelling, and, ultimately, the successful recovery of the fractured bone. Effective control of mechanical loading is pivotal in treating and recovering fractures, ensuring the best possible healing and functional results. However, the mechanisms underlying spatial cell reorganization during loading, which contributes to fracture healing, remain unclear. Therefore, the project aims to investigate and explore the fracture healing process of mice using spatial transcriptome changes in response to mechanical loading. By shedding light on this aspect, we aim to contribute to the broader understanding of fracture healing and potentially pave the way for more effective treatment strategies in the future.

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Published since: 2024-03-07 , Earliest start: 2024-03-07 , Latest end: 2024-08-01

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Singh Amit

Topics Medical and Health Sciences , Mathematical Sciences , Information, Computing and Communication Sciences , Engineering and Technology , Biology , Physics

Exploring the 3D Mineralization Behavior in Material-Induced Osteoinduction Through a Multiscale Micro-CT Imaging Approach

The project aims at investigating material-induced osteoinduction using the available mouse model of orthotopic or ectopic bone graft substitute application. Through the 3D-3D registration of ex vivo and in vivo multiscale micro-CT images, crucial 3D mineralization of the BGS can be investigated.

Keywords

Femur, Bone Graft Substitute, Critical Size Defect, Osteoinduction, in vivo, micro-CT, 3D-3D Image Registration, Image Analysis, Image Processing, Python, Computational

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Semester Project , Bachelor Thesis

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Bone defects that do not heal spontaneously despite surgical stabilization and require further surgical intervention are termed critical sized defects (CSD). They pose dramatic consequences to a person’s well-being and life expectancy due to their impact on the skeletal system’s integrity. Bone graft substitutes (BGS) present a treatment approach by enhancing and facilitating the natural healing capacity of the bone tissue using their osteoconductive and osteoinductive potential and filling up the physical space of lost bone for mechanical support. The key property of a BGS in treatment of a large bone defect is osteoinduction. Physiological processes in bone usually happen on different spatial scales, spanning from the whole organ, to tissue, to cellular and even to the molecular level. Therefore, an ideal imaging setup to unravel the underlying mechanisms of material-induced osteoinduction would require a multiscale approach to connect orang and tissue level processes with the cellular and subcellular scale. Micro-CT can be considered the gold standard in hierarchical 3D imaging of bone structure and function and allows a non-destructive _ex vivo_ and _in vivo_ image acquisition. Time-lapsed _in vivo_ micro-CT images can reveal distinct information on the longitudinal development of implant calcification or resorption. However, its resolution is relatively low and certain details can not be detected. _Ex vivo_ micro-CT on the other hand allows scans of higher resolution and therefore complements the _in vivo_ micro-CT well. The 3D-3D registration of high-resolution _ex vivo_ and low-resolution _in vivo_ micro-CT images generates a multiscale micro-CT imaging approach. Advanced image analysis methods can help identify newly formed bone and generally distinguish bone and the BGS. By combined analysis of multiscale micro-CT measurements of murine femur samples with implanted ectopic or orthotopic BGS, critical 3D mineralization behavior in material-induced osteoinduction can be investigated.

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Published since: 2024-03-06 , Earliest start: 2024-04-01 , Latest end: 2024-12-31

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Lindenmann Sara

Topics Medical and Health Sciences , Engineering and Technology

Investigating compromised bone fracture healing in mouse models using time-lapsed in vivo CT imaging and histological analysis.

Delayed bone healing or failed non-unions account for 5 – 10% of all bone fractures and present a challenging problem in regenerative medicine. The impact of delayed unions or non-unions can be devastating with prolonged rehabilitation, decreased quality of life and significant health care costs. Our lab has conducted fracture healing studies in young and prematurely-aged mouse models with different defect sizes. The aim of this project is to analyse data from mice which exhibit delayed unions and non-unions.

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Bone, Fracture Healing, Image Processing, Histology

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Semester Project , Internship , Bachelor Thesis , Master Thesis

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Published since: 2024-02-23 , Earliest start: 2024-02-01 , Latest end: 2025-02-01

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Mathavan Neashan

Topics Engineering and Technology

Agent-based modelling of bone regeneration in ageing populations

Are you a motivated Bachelor's or Master's student willing to learn and develop a micro-Mulitphysics Agent-Based (micro-MPA) model to predict adaptation and regeneration of aged bone? This project offers an opportunity to gain valuable work experience in computational modelling within a highly interdisciplinary Lab.

Keywords

agent-based, machine learning, artificial intelligence, modelling, bone mechanobiology, ageing, personalized medicine, medical research, biomechanics

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Semester Project , Internship , Bachelor Thesis , Master Thesis , ETH Zurich (ETHZ)

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Published since: 2024-02-21 , Earliest start: 2024-02-19 , Latest end: 2024-09-30

Applications limited to ETH Zurich

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Kendall Jack

Topics Medical and Health Sciences , Engineering and Technology , Biology

Establishing Volumetrically Bioprinted Human In Vitro Bone Organoid Models

Laboratory-grown miniature bones (organoids) can facilitate the investigation of the biology in healthy and diseased human bone, thereby replacing animal experiments and providing a mechanistic understanding of bone remodeling. The goal of this research is to establish an in vitro technique for volumetric 3D bioprinting of structurally complex human bone organoids. This bone organoid has the potential to enable studying human bone remodeling in the laboratory without the need for animal models.

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volumetric bioprinting, hydrogels, bone tissue engineering, bone remodeling

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Semester Project , Internship , Master Thesis

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Published since: 2024-02-12 , Earliest start: 2024-01-03 , Latest end: 2024-12-23

Organization Müller Group / Laboratory for Bone Biomechanics

Hosts de Bregje

Topics Engineering and Technology , Biology

Screening Microenvironmental Cues for In Vitro Human Bone Models

3D in vitro models provide a valuable way to study human biology without using animals. However, these models are primarily based on poorly defined animal-derived hydrogels, such as Matrigel or collagen. This limits our detailed understanding of cell-material interactions in bone development, maintenance, and repair. Importantly, these mechanisms are often disrupted in various bone diseases, highlighting the needs for more advanced in vitro models.

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biomaterials, hydrogels, in vitro models, tissue engineering

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Published since: 2024-02-12 , Earliest start: 2023-10-01 , Latest end: 2024-02-29

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Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Qin Xiao-Hua, Prof. Dr. , Horrer Marion

Topics Medical and Health Sciences , Engineering and Technology , Chemistry , Biology

Human Organoid-on-Chip to Study Rare Bone Disease

To date, there is still very limited progress in developing organoid models for human musculoskeletal tissues such as bone. A major challenge is reconstructing the native bone microenvironment which is structurally and functionally complex. In this project, we leverage interdisciplinary advances in tissue engineering and microtechnologies to generate a microengineered bone-organoid-on-chip platform for both fundamental and translational research in medicine.

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microfluidics, 3D cell culture, bone, disease modeling, hydrogels

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Semester Project , Internship , Master Thesis

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Published since: 2024-01-17 , Earliest start: 2024-02-01 , Latest end: 2025-03-31

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Organization Müller Group / Laboratory for Bone Biomechanics

Hosts Zauchner Doris , Qin Xiao-Hua, Prof. Dr.

Topics Engineering and Technology , Chemistry , Biology