living matter lab
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==mission statement==
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<div class="publicationheader">check out our latest COVID-19 outbreak predictions... </div>
one of the most challenging applications of the mechanics of solid materials
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today is certainly
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the field of computational biomechanics, a well-recognized, fast-growing but not yet
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clearly defined subject that is unquestionably an interdisciplinary science par
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excellence. it provides a vast number of
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new and fascinating areas of application such as
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the internal and external remodeling of bones,
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the healing of fracture,
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the growth of tumors,
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wound healing of the epidermis,
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the regeneration of microdamaged muscles,
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functional adaptation and
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general repair processes of the cardiovascular system to name but a few.
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besides a basic knowledge in medicine, biology and chemistry,
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research in the field of computational biomechanics requires a profound
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theoretical background in thermodynamics, continuum mechanics
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and structural mechanics paired with the ability to develop efficient
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robust and stable computational simulation tools.
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<b>our ultimate goal is to establish an interactive computer-based biomechanical lab
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college campuses are COVID-19 superspreaders [https://www.forbes.com/sites/mishagajewski/2021/01/13/college-campuses-are-covid-19-superspreaders-study-says/?sh=2578217052fd forbes], [https://www.usnews.com/news/health-news/articles/2021-01-13/college-campuses-are-covid-superspreaders-study-finds US news & world report]<br>
that supports the solution of medically and technologically challenging
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are colleges superspreaders [https://www.insidehighered.com/news/2021/01/13/college-openings-led-increase-community-cases-research-says inside higher ed]<br>
biomechanical problems.</b>
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college campuses can be superspreaders? [https://academictimes.com/college-campuses-can-be-superspreaders-but-safe-reopening-possible-study/ academic times]<br>
 +
are college campuses COVID-19 superspreaders? [https://newsroom.taylorandfrancisgroup.com/new-study-suggests-that-college-campuses-are-covid-19-superspreaders/ t&f press release], [https://www.upi.com/Health_News/2021/01/13/College-campuses-may-be-COVID-19-super-spreaders-study-finds/5661610548574/ united press international]<br>
 +
new study suggests that campuses are COVID-19 superspreaders [https://www.eurekalert.org/pub_releases/2021-01/tfg-nss011121.php eurekalert!], [https://consumer.healthday.com/b-1-13-study-confirms-college-campuses-as-super-spreader-centers-2649875013.html healthday]<br>
 +
les campus universitaires sont des super-epandeurs [https://www.crumpi.com/2021/01/13/les-campus-universitaires-sont-des-super-epandeurs-de-covid-19-les-epidemies-sur-les-campus-locaux-se-propagent-rapidement-dans-tout-le-comte/ crumpi]<br>
 +
reopening college campuses could initiate superspreading [https://www.news-medical.net/news/20201224/Reopening-college-campuses-could-initiate-COVID-19-superspreading.aspx med life sciences]<br>
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a new class explores how to safely reopen a campus during covid-19 [https://engineering.stanford.edu/magazine/article/new-class-explores-how-safely-reopen-campus-during-covid-19 stanford report] [http://biomechanics.stanford.edu/paper/CMECH20b.pdf reopening paper]<br>
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data-driven modeling of covid-19-lessons learned
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[http://biomechanics.stanford.edu/paper/EML081220.jpg webinar announcement] 
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[https://www.youtube.com/watch?v=lBMPfltcDqs&feature=youtu.be webinar]
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[http://biomechanics.stanford.edu/paper/EML20.pdf paper] <br>
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how COVID-19 spread has been contained by travel bans [https://www.sciencedaily.com/releases/2020/05/200504191018.htm science daily] [https://infosurhoy.com/news-summary/how-covid-19-spread-has-been-contained-by-travel-bans/ infosurhoy] [http://biomechanics.stanford.edu/paper/CMBBE20.pdf cmbbe paper] <br>
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covid-19 travel restrictions have saved millions of people [https://www.health24.com/Medical/Infectious-diseases/Coronavirus/covid-19-travel-restrictions-have-saved-millions-of-people-from-being-infected-mathematical-modelling-shows-20200507-2 health24 ]  [https://medrxiv.org/cgi/content/short/2020.05.01.20088047v1 medRxiv Rvalues]<br>
 +
how COVID-19 spread has been contained by travel bans [https://newsroom.taylorandfrancisgroup.com/how-covid-19-spread-has-been-contained-by-travel-bans/# press release] [http://biomechanics.stanford.edu/paper/CMBBE20.pdf cmbbe paper] [http://biomechanics.stanford.edu/paper/CMECH20a.pdf mobility paper]<br>
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was haben die grenzschliessungen tatsachlich gebracht? [https://www.srf.ch/news/schweiz/kampf-gegen-das-coronavirus-was-haben-die-grenzschliessungen-tatsaechlich-gebracht swiss public radio] <br>
 +
wie sinnvoll sind reisebeschrankungen wirklich? [https://www.welt.de/vermischtes/article207810451/Corona-Krise-und-Grenzen-Wie-sinnvoll-sind-Reisebeschraenkungen-wirklich.html welt] [http://biomechanics.stanford.edu/paper/CMBBE20.pdf cmbbe paper] <br>
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so bremsen reisebeschrankungen das coronavirus aus [https://www.mdr.de/wissen/corona-reise-verbot-eindaemmung-covid-modell-100.html mdr wissen] [https://medrxiv.org/cgi/content/short/2020.05.01.20088047v1 medRxiv Rvalues]<br>
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using math to understand COVID-19 outbreak dynamics [https://med.stanford.edu/cvi/mission/news_center/articles_announcements/using-math-to-understand-covid-19-outbreak-dynamics.html stanford medicine] [http://biomechanics.stanford.edu/paper/BMMB20.pdf bmmb paper]
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[https://www.medrxiv.org/content/10.1101/2020.05.23.20111419v1 asymptomatic]<br>
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predict covid's spread and recovery [https://engineering.stanford.edu/magazine/article/brain-inspired-model-can-help-predict-covid-s-spread-and-recovery?sf120699572=1 stanford engineering] [https://www.medrxiv.org/content/10.1101/2020.04.06.20055863v2 medRxiv in the us] [https://medrxiv.org/cgi/content/short/2020.04.18.20071035v1 medRxiv in europe]<br>
  
==selected research accomplishments==
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[[Image:research_us.jpg|720px]]
in contrast to traditional engineering materials, <b>living</b> organisms show the
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remarkable ability to adapt not only their geometry, but also their internal
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architecture and their material properties to environmental changes.
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although this functional adaptation of biological tissues has been known
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since julius wolff published his fundamental law of bone remodeling in 1892,
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research in biomechanics mainly focuses on the passive behavior of tissues
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rather than taking into account their <b>active response</b>
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to changes in mechanical loading. instead of following mainstream research and
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applying standard
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classical constitutive equations to biological materials,
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my personal research was driven by the desire to formulate appropriate continuum
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equations that properly account for the <b>functional adaptation</b> of
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living tissues. this adaptation is known to occur in three different forms which
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have dominated my previous research:
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<div>
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<div class="publicationheader">... and the other cool stuff we do</div>
[[<img src="../peoplepics/EK.jpg">|200px|left]]
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{| class="projecttable"
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! density growth
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! colspan="2"| ellen kuhl
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|-
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| class=firstcolumn | title: || assistant professor
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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growth is a distinguishing feature of all living things. throughout the past century, the growth of living systems has fascinated physiologists, biologists, and clinical scientists alike. yet, most of their efforts remain exploratory and mainly qualitative.
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<b>in the living matter lab, we use the fundamental laws of physics and create interactive simulation tools to predict the physiology and pathology of living systems.</b> we strive to understand the mechanisms by which living systems grow, develop, evolve, and adapt. this is not always straightforward: living systems can undergo extreme deformations, change their mass, generate active contraction, and develop prestrain and residual stress.  these phenomena are non-intuitive to traditional engineers and often difficult to grasp. they require us to advance the classical field theories of mechanics towards living matter physics, design our own mathematical models, and create our own simulation tools. here are some examples of projects that we are currently addressing:
  
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<div class="publicationheader">the living heart project</div>
  
<div>
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our heart is not only our most vital, but also our most complex organ: precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. while numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. with support of the nsf career award, our lab has designed the first fully coupled electro-mechanical model for excitation-contraction coupling within a single, unified finite element framework. [http://biomechanics.stanford.edu/paper/LivingHeartEK.mp4 our heart model] has become a true success story: since may 2013, we have worked with the largest commercial finite element company, abaqus/dassault systemes, towards implementing our core algorithms into the abaqus infrastructure. together with the living heart team at dassault systemes, we have established the first four-chamber heart simulator for human heart function. the [http://www.3ds.com/heart living heart project] was officially launched in may 2014. since then, our work has received broad media attention and was featured in several
[[Image:Project1.jpg|200px|left]]
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[http://www.sciencedirect.com/science/article/pii/S0997753814000564 scientific publications]. to date, the living heart ecosystem has grown to 32 contributing member organizations, with more than 150 cardiovascular specialists from research, industry, and medicine, who have free access to our heart simulator to test and accelerate the development of the living heart via crowdsourcing.  
{| class="projecttable"
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! density growth
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|-
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|when characterizing engineering structures with the help of classical continuum field theories, we typically think of closed thermodynamic systems for which the amount of matter within a fixed material domain is constant throughout the entire thermodynamical process. the appropriate characterization of living biological structures, however, goes far beyond this traditional point of view. it falls within the framework of <b>open system thermodynamics</b>. in order to account for biological growth, the traditional balance of mass is enriched by additional mass source and flux terms that account for cell growth, cell shrinkage, cell division or cell migration on a phenomenological level. it is obvious, that the exchange of matter with the environment not only effects the balance of mass itself since the newly generated or inflowing mass typically carries a specific amount of momentum, energy and entropy. we have developed  a general theoretical framework for open system thermodynamics which has been implemented in a finite element based simulation tool for density growth in biological tissues. for example, a medically relevant application of this model that has led to a pronounced industrial interest in our work is the optimization of <b>modern implant design</b> in hip replacement surgery.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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[[Image:research01.jpg|720px]]
  
<div>
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<b>figure 1.</b> the living heart project. in collaboration with abaqus/dassault systemes, we have created the first fully finite-element based whole heart model for realistic human heart simulations of excitation-contraction coupling.
[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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! volume growth
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|-
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|while growth phenomena in hard biological tissue can essentially be attributed to local changes in density, growth in soft biological tissues typically takes place in the form of huge volumetric changes. motivated by the classical ideas in large strain plasticity, we have adopted the <b>concept of a fictitious configuration</b> to characterize the kinematics of growth. we have developed an efficient simulation tool for volumetric growth which has been applied to the simulation of <b>atherosclerosic plaque growth</b>. the model was implemented in a commercial finite element package and applied it to the simulation of <b>in-stent restenosis</b>. the results of the simulation are based on <b>patient-specific geometries</b> generated from computer tomography.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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figure 1 illustrates our first prototype of the living heart model, which allows us to explore and understand the key features, physics, and technologies required to create an integrative, predictive model of the living human heart. ultimately, the living heart project will unite leading cardiovascular researchers, medical device manufacturers, regulatory agencies, and practicing cardiologists on the shared mission to develop and validate personalized digital human heart models and establish a unified foundation for in silico cardiovascular medicine. our computational models, which form the core of these efforts are documented in more than 20 peer-reviewed journal publications and in several [http://biomechanics.stanford.edu/paper/MEheart.pdf featured articles] and
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[https://www.youtube.com/watch?v=6hsx_da1vVs animations].
  
<div>
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<div class="publicationheader">cardiac optogenetics</div>
[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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! microstructural remodeling
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|-
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|by virtue of their collagenous microstructure, soft biological tissues show a pronounced anisotropic response. In the early stages of tissue development, the underlying collagenous scaffold is found to reorient itself with respect to the principal loading directions. in a corresponding continuum model, characteristic microstructural orientations can be represented by fiber vectors. guided by minimization principles, we have developed a concept of <b>fiber reorientation</b> in which a single characteristic microstructural orientation is allowed to gradually align with the maximum principal strain direction. a typical application of this model can be found within the field of <b>tissue engineering</b> where tissue replacements are grown outside the human body. due to the absence of mechanical loading, these in vitro engineered functional tissue constructs typically lack a pronounced microstructural orientation. however, the formation of this orientation can be stimulated by subjecting the growing tissue to different mechanical loading scenarios. In close collaboration with experts intissue engineering from the university of michigan, we have been able to qualitatively validate our fiber reorientation model. the long term goal of this project is the <b>optimal stimulation of microstructural growth</b>. conceptually speaking, we strive for finding the optimal amount, frequency and direction of loading with the aim of reproducing the in vivo conditions as realistic as possible.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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heart disease is the primary cause of death in industrialized  nations, claiming more than 16 million lives worldwide every year. in the united states alone, almost half a million people die each year as a result of heart rhythm disorders. despite its invasive nature, electrical stimulation remains the gold standard treatment to control rhythm disturbances through direct contact stimulation. together with our clinical collaborators, we have pioneered a novel technology to control heart rhythm disorders at a distance by means of light using a new concept known as [http://biomechanics.stanford.edu/paper/BIOPJ11.pdf optogenetics]. we have created mathematical models and computational tools to decipher the mechanisms by which optogenetics can regulate cardiac function with the ultimate goal to create a biological pacemaker of genetically engineered cardiac cells.
  
==short term goals - immediate research interests==
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[[File:research02.jpg|720px]]
based on our expertise in computational biomechanics, we would like to pursue the following immediate research areas:
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<div>
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[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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! on the tissue level - optimal implant design
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|-
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|based on our expertise in simulating the functional adaptation in bones, we have started an industrial collaboration aiming at improving implant design in artificial <b>hip replacement surgery</b>. since our computational tools have proven extremely powerful in predicting bone remodeling and implant loosening, I would like to continue this research guided by the following fundamental questions: how can we gain qualitative three-dimensional patient-specific information about the response to hip replacement surgery? how can the prosthesis' material and its geometry be improved to increase long-term biocompatibility? how can aseptic loosening of the prosthesis be avoided?
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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<b>figure 2.</b> cardiac optogenetics. optical stimulation opens a cation channel to initiate a photocurrent, which increases the sodium concentration. this triggers an increase in the electric potential and initiates mechanical contraction.
  
<div>
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we prototyped a [http://biomechanics.stanford.edu/paper/JMPS12.pdf multiscale computational model] for the optogenetic control of human hearts, which we have calibrated across four biological scales as illustrated in figure 2. we used this model to make patient-specific predictions of ion channel dynamics, virtually probe landscapes of process parameters, and identify optimal photostimulation sequences in silico before testing them in vivo. this work is documented in five journal articles and has initiated a broad interest in the general media including several
[[Image:Project1.jpg|200px|left]]
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[http://www.nsf.gov/discoveries/disc_summ.jsp?cntn_id=129057 featured stories],
{| class="projecttable"
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[http://www.scienceupdate.com/?powerpress_pinw=8660-podcast podcasts], and
! on the tissue level - simulation of atherosclerosis
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[http://biomechanics.stanford.edu/paper/Deutschlandfunk.mp3 radio interviews].
|-
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|to diagnose and localize atherosclerosis it is important to know the medical history of each individual patient. we are collaborating with radiologists who provide patient-specific geometries in the form of <b>computer tomography</b> images. these images typically consist of two-dimensional data sets at cutting distances of several millimeters. as such, they can be used to generate individual three-dimensional finite element models for patient-specific simulations. hoping to improve the understanding of <b>atherosclerotic plaque growth</b>, we would like to address a number of open questions: how can realistic in vivo boundary conditions for the artery be simulated? how can the vivo loading conditions be modeled appropriately? how can the concept of pre-stress be incorporated in the formulation?
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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<div class="publicationheader">characterizing living skin</div>
  
<div>
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skin is our interface with the outside world. in its natural environment, it displays unique mechanical characteristics including prestrain and growth. while there is a general agreement on the physiological importance of these features, they remain poorly characterized mainly because they are difficult to access with standard laboratory techniques. our lab has established a novel, inexpensive technique to [http://biomechanics.stanford.edu/paper/ABM14.pdf characterize living skin] using multi-view stereo and isogeometric analysis. based on easy-to-create hand-held camera images, we quantify prestretch, deformation, and growth in a controlled porcine model of chronic skin expansion. over a period of five weeks, we gradually inflate subcutaneouly implanted balloons, take weekly photographs of the experimental scene, reconstruct the geometry from a tattooed surface grid, and create parametric representations of the skin surface.
[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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! on the cellular level - improved understanding of migration phenomena
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|-  
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|the theoretical tools and computational models that have been proven successful in previous research have to face the criticism of lacking a profound micromechanical basis. to gain a better understanding of the phenomenological parameters of growth, we would like to dedicate part of our immediate research to an improved understanding of the transport phenomena taking place on the cellular level. based on previous research on <b>nonlinear diffusion phenomena</b> coupled with <b>surface tension</b> of cahn-hilliard type, we particularly aim at elaborating the following issues: how are transport phenomena driven? how does cell migration occur? how can cell migration be related to a phenomenologically introduced mass flux on the continuum level?
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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[[Image:research04.jpg|720px]]
  
==long term goals - visions==
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<b>figure 3.</b> skin expansion in pediatric forehead reconstruction.
in the long run, we would like to dedicate our scientific activities in particular to the following aspects:
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<div>
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[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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! from natural form to engineering design
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|-
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|by applying principles of growth and remodeling, nature seems to generate optimal structures by continuously depositing and withdrawing matter and by rearranging microstructural orientations. can we actually learn from nature by adopting fundamental design concepts? indeed, the developed biomechanical algorithms for growth and remodeling can be applied for various engineering purposes. in structural mechanics, similar concepts are known from <b>topology optimization</b>. in material sciences, they are referred to as <b>microstructural optimization</b>. both obviously generate structures of maximum stiffness at minimum weight. at the beginning of the 20th century, even architectural design has been guided by a similar paradigm: <b>form follows function</b>. in a collaboration with scientists from different fields, we would like to gain a broader understanding of natural design concepts and develop tools for the <b>optimal design of modern lightweight materials</b>.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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we analyzed these representations and quantified the average area prestretch to 1.44 and the average area growth to 2.25. we used these data to calibrate our skin growth model to simulate clinical cases of skin expansion in [http://biomechanics.stanford.edu/paper/JTBIO12.pdf pediatric forehead reconstruction]. our simulations accurately predict the clinically observed mechanical and structural response of living skin both acutely and chronically. our living skin model can easily be generalized to arbitrary biological membranes and serve as a valuable tool to virtually manipulate living systems, simply by means of changes in their mechanical environment. our skin research was initially motivated by a [http://biomechanics.stanford.edu/paper/JMPS11a.pdf class project] in fall 2010 and has, to date, inspired twelve conference papers and eleven [http://biomechanics.stanford.edu/paper/JTBIO12.pdf  peer-reviewed journal articles].
  
<div>
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<div class="publicationheader">physical biology of brain development</div>
[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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! from engineering materials to tissue engineering
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|-
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|the huge field of <b>tissue engineering</b> which aims at creating living artificial tissue substitutes with human cells can certainly be identified as one of the most promising applications in computational biomechanics. functionally engineered tissue constructs typically show an enhanced long-term biocompatibility as opposed to traditional engineering materials such as, e.g.,ceramics or titanium. in close collaboration with experts from cellular biology, we hope to <b>optimize mechanical stimuli</b> that induce tissue growth and remodeling under in-vivo-like environmental conditions.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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the developing human brain remains one of the few unsolved mysteries of science. advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. however, the precise role of mechanics throughout this process remains under appreciated and poorly understood. we have recently shown that mechanical stretch plays a crucial role in [http://biomechanics.stanford.edu/paper/SREP14.pdf brain development].
  
<div>
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[[Image:research03.jpg|720px]]
[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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! from in vivo and in vitro to in silico
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|-
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|in contrast to experiments with traditional engineering materials, experiment with living biological tissues are not only extremely costly but also ethically questionable. sometimes it is even absolutely impossible to access the desired information via appropriate in vivo experiments. research in biomechanics is thus constantly facing the questions: how can the number of in vivo experiments be reduced to an absolute minimum? how can the scientific budget spent on expensive in vitro experiments be minimized? we strongly believe that computational biomechanics provides tools that will help to gradually replace in vivo and in vitro experiments by in silico experiments. one of our long-term scientific interests is thus the creation of an <b>interactive computer-based biomechanical lab</b> which contains not only the databases of different hard and soft  tissues but also a collection of computational tools to effectively simulated various different biomechanical phenomena of interest.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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<b>figure 4.</b> variety of mammalian brains. caitlin, adrian, ellen, james, moritz, mona, rijk, maria.
  
<div>
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using the nonlinear field theories of mechanics, supplemented by the theory of finite growth, we have modeled the human brain as a living system with a morphogenetically growing gray matter surface and a growing white matter core. this approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. to characterize the stiffness of gray and white matter tissue, we have designed new protocols for [http://biomechanics.stanford.edu/paper/JMBBM15.pdf indentation testing] and demonstrated that white matter, with an average modulus of 1.9kpa, is stiffer than gray matter, with an average modulus of 1.4kpa. our simulations suggest that anisotropic white matter growth, as an emergent property from [http://biomechanics.stanford.edu/paper/ABME15a.pdf chronic axon elongation], intrinsically induces symmetry breaking, and predicts surface morphologies in agreement with magnetic resonance images from very preterm neonates. our model predicts that deviations in cortical thickness, elasticity, and growth induce morphological abnormalities. using the gyrification index, the ratio between the total and exposed surface area, we have shown that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. understanding the mechanisms of human brain development has direct implications on the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism. In the past year, we have published six peer reviewed
[[Image:Project1.jpg|200px|left]]
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[http://biomechanics.stanford.edu/paper/JMPS14b.pdf journal articles] and edited a
{| class="projecttable"
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[http://link.springer.com/article/10.1007/s10237-015-0662-4 multi-author review] on brain mechanics.
! from the cell level to the tissue level
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|-
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|in computational biomechanics, most scientists work on the microscopic cellular level. fewer but still many work on the mesoscopic substructural level. traditionally, there are actually only very few scientists in biomechanics who work on the macroscopic continuum level. nevertheless, we believe real biomechanical applications such as modern implant design  can only be approached efficiently on the macroscopic level. we would like to contribute to <b>bridging the gap from the cell level to the tissue level</b> by making use of appropriate tools from <b>statistics</b> and <b>homogenization</b> to carry relevant information from the microscopic to the macroscopic scale. the ultimate goal is the successive replacement of all macroscopic phenomenological material parameters by microscopically motivated quantities such as geometric dimensions or fundamental properties of the cell.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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[[previous research accomplishments 02]]<br>
 
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[[previous research accomplishments 01]]<br>
<div>
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[[Image:Project1.jpg|200px|left]]
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{| class="projecttable"
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!from empirical medicine to patient-specific medical treatment
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|-
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|in modern biomechanics research, a strong trend from diagnostic empirical evidence based medicine towards predictive medicine guided by <b>reliable computational simulations</b> can be observed. taking into account the tremendous developments of modern computer technologies in combination with diagnostic imaging, we strongly believe that we will soon be able to simulate each patient's problems individually and provide patient-specific medical treatment. individual real-time computer simulations will certainly be a major achievement in health science.
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|}
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</div>
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<div class="spacer">&nbsp;</div>
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<b>our lab hopes to significantly contribute to shape pathways to tomorrow's scientific breakthroughs in patient-specific medical care by providing efficient and robust state-of-the-art computational simulation tools based on micromechanically motivated multi-scale models.</b>
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Latest revision as of 13:38, 13 January 2021

check out our latest COVID-19 outbreak predictions...

college campuses are COVID-19 superspreaders forbes, US news & world report
are colleges superspreaders inside higher ed
college campuses can be superspreaders? academic times
are college campuses COVID-19 superspreaders? t&f press release, united press international
new study suggests that campuses are COVID-19 superspreaders eurekalert!, healthday
les campus universitaires sont des super-epandeurs crumpi
reopening college campuses could initiate superspreading med life sciences
a new class explores how to safely reopen a campus during covid-19 stanford report reopening paper
data-driven modeling of covid-19-lessons learned webinar announcement webinar paper
how COVID-19 spread has been contained by travel bans science daily infosurhoy cmbbe paper
covid-19 travel restrictions have saved millions of people health24 medRxiv Rvalues
how COVID-19 spread has been contained by travel bans press release cmbbe paper mobility paper
was haben die grenzschliessungen tatsachlich gebracht? swiss public radio
wie sinnvoll sind reisebeschrankungen wirklich? welt cmbbe paper
so bremsen reisebeschrankungen das coronavirus aus mdr wissen medRxiv Rvalues
using math to understand COVID-19 outbreak dynamics stanford medicine bmmb paper asymptomatic
predict covid's spread and recovery stanford engineering medRxiv in the us medRxiv in europe

Research us.jpg

... and the other cool stuff we do

growth is a distinguishing feature of all living things. throughout the past century, the growth of living systems has fascinated physiologists, biologists, and clinical scientists alike. yet, most of their efforts remain exploratory and mainly qualitative. in the living matter lab, we use the fundamental laws of physics and create interactive simulation tools to predict the physiology and pathology of living systems. we strive to understand the mechanisms by which living systems grow, develop, evolve, and adapt. this is not always straightforward: living systems can undergo extreme deformations, change their mass, generate active contraction, and develop prestrain and residual stress. these phenomena are non-intuitive to traditional engineers and often difficult to grasp. they require us to advance the classical field theories of mechanics towards living matter physics, design our own mathematical models, and create our own simulation tools. here are some examples of projects that we are currently addressing:

the living heart project

our heart is not only our most vital, but also our most complex organ: precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. while numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. with support of the nsf career award, our lab has designed the first fully coupled electro-mechanical model for excitation-contraction coupling within a single, unified finite element framework. our heart model has become a true success story: since may 2013, we have worked with the largest commercial finite element company, abaqus/dassault systemes, towards implementing our core algorithms into the abaqus infrastructure. together with the living heart team at dassault systemes, we have established the first four-chamber heart simulator for human heart function. the living heart project was officially launched in may 2014. since then, our work has received broad media attention and was featured in several scientific publications. to date, the living heart ecosystem has grown to 32 contributing member organizations, with more than 150 cardiovascular specialists from research, industry, and medicine, who have free access to our heart simulator to test and accelerate the development of the living heart via crowdsourcing.

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figure 1. the living heart project. in collaboration with abaqus/dassault systemes, we have created the first fully finite-element based whole heart model for realistic human heart simulations of excitation-contraction coupling.

figure 1 illustrates our first prototype of the living heart model, which allows us to explore and understand the key features, physics, and technologies required to create an integrative, predictive model of the living human heart. ultimately, the living heart project will unite leading cardiovascular researchers, medical device manufacturers, regulatory agencies, and practicing cardiologists on the shared mission to develop and validate personalized digital human heart models and establish a unified foundation for in silico cardiovascular medicine. our computational models, which form the core of these efforts are documented in more than 20 peer-reviewed journal publications and in several featured articles and animations.

cardiac optogenetics

heart disease is the primary cause of death in industrialized nations, claiming more than 16 million lives worldwide every year. in the united states alone, almost half a million people die each year as a result of heart rhythm disorders. despite its invasive nature, electrical stimulation remains the gold standard treatment to control rhythm disturbances through direct contact stimulation. together with our clinical collaborators, we have pioneered a novel technology to control heart rhythm disorders at a distance by means of light using a new concept known as optogenetics. we have created mathematical models and computational tools to decipher the mechanisms by which optogenetics can regulate cardiac function with the ultimate goal to create a biological pacemaker of genetically engineered cardiac cells.

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figure 2. cardiac optogenetics. optical stimulation opens a cation channel to initiate a photocurrent, which increases the sodium concentration. this triggers an increase in the electric potential and initiates mechanical contraction.

we prototyped a multiscale computational model for the optogenetic control of human hearts, which we have calibrated across four biological scales as illustrated in figure 2. we used this model to make patient-specific predictions of ion channel dynamics, virtually probe landscapes of process parameters, and identify optimal photostimulation sequences in silico before testing them in vivo. this work is documented in five journal articles and has initiated a broad interest in the general media including several featured stories, podcasts, and radio interviews.

characterizing living skin

skin is our interface with the outside world. in its natural environment, it displays unique mechanical characteristics including prestrain and growth. while there is a general agreement on the physiological importance of these features, they remain poorly characterized mainly because they are difficult to access with standard laboratory techniques. our lab has established a novel, inexpensive technique to characterize living skin using multi-view stereo and isogeometric analysis. based on easy-to-create hand-held camera images, we quantify prestretch, deformation, and growth in a controlled porcine model of chronic skin expansion. over a period of five weeks, we gradually inflate subcutaneouly implanted balloons, take weekly photographs of the experimental scene, reconstruct the geometry from a tattooed surface grid, and create parametric representations of the skin surface.

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figure 3. skin expansion in pediatric forehead reconstruction.

we analyzed these representations and quantified the average area prestretch to 1.44 and the average area growth to 2.25. we used these data to calibrate our skin growth model to simulate clinical cases of skin expansion in pediatric forehead reconstruction. our simulations accurately predict the clinically observed mechanical and structural response of living skin both acutely and chronically. our living skin model can easily be generalized to arbitrary biological membranes and serve as a valuable tool to virtually manipulate living systems, simply by means of changes in their mechanical environment. our skin research was initially motivated by a class project in fall 2010 and has, to date, inspired twelve conference papers and eleven peer-reviewed journal articles.

physical biology of brain development

the developing human brain remains one of the few unsolved mysteries of science. advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. however, the precise role of mechanics throughout this process remains under appreciated and poorly understood. we have recently shown that mechanical stretch plays a crucial role in brain development.

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figure 4. variety of mammalian brains. caitlin, adrian, ellen, james, moritz, mona, rijk, maria.

using the nonlinear field theories of mechanics, supplemented by the theory of finite growth, we have modeled the human brain as a living system with a morphogenetically growing gray matter surface and a growing white matter core. this approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. to characterize the stiffness of gray and white matter tissue, we have designed new protocols for indentation testing and demonstrated that white matter, with an average modulus of 1.9kpa, is stiffer than gray matter, with an average modulus of 1.4kpa. our simulations suggest that anisotropic white matter growth, as an emergent property from chronic axon elongation, intrinsically induces symmetry breaking, and predicts surface morphologies in agreement with magnetic resonance images from very preterm neonates. our model predicts that deviations in cortical thickness, elasticity, and growth induce morphological abnormalities. using the gyrification index, the ratio between the total and exposed surface area, we have shown that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. understanding the mechanisms of human brain development has direct implications on the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism. In the past year, we have published six peer reviewed journal articles and edited a multi-author review on brain mechanics.

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