Januari 05, 2017
so today i will talk a little bit about someof the work we're doing beyond joint replacement, the totaljoint replacement you hear about. i was hoping to benefit from dr. laurencin'sintroduction to tissue engineering. but, i’ll talk a little moreabout some of the work we’ve been working on.so, this tissue engineering has captured the public imagination because it's actually areally simple concept, kike many great ideas.what you do is take the patients’ own cells, provide, in some cases, a scaffold system,scaffold designed to mimic the extracellular matrix, and voila,you have tissue.
of course, the devil is in the details -- howdo you engineer that tissue that's functional and that'sphysiologically relevant? something we're working on.so tissue engineering is a relatively new field. for the past three decades, we havebeen working on optimizing this methodology i talked about,taking the patient cells or taking cells putting on a scaffoldsystem and engineering functional tissues. so as a field advances, what happens, we'rebeginning to think about assembly of different types oftissues. this means that connecting different typesof tissues together to form complex tissue
systems, multi-tissue and more organized or more physiologically relevant.and to do so, understanding that interface between different types of tissues is a criticaljuncture, almost a threshold before we can move to engineeringcomplex tissue systems. this is recognized by the field.so now this importance of connecting different tissues together is much more relevant inthe musculoskeletal system.some major challenges of bone regeneration is really the regeneration of soft tissues,such as cartilage lining the surface of joints, ligaments whichconnect bone to bone and muscles, which, –sorry,
tendonswhich connect muscle to bone. current grafting systems are biologicallybased off tissue graft system. what was difficult with the systems is thelong term outcomes are sometimes mixed because of lack ofintegration between the existing grafting system.the research question we're interested in in our laboratory, how do you achieve biologicalfixation of soft tissue grafts, whether it's biologicallyderived the graft or tissue engineering graft systems?i think the analogy that i want to make is how do you connect a rope to the wall withoutusing fixation
pins or screws or any sort of mechanical device.what surgeons do nowadays, they take soft tissuegrafts, use pins, fixation devices, metallic screws or degradable polymer screws, somethingto connect that to the wall, which is bone, in this case.some examples of systems: this is a shoulder, which is muscle. this is the bone, tendon,and the super spineaous tendon. here is the anterior cruciateligament which connects the femur to the tibia, and alsoosteo counter interface, which connects cartilage to bone.this is a very small transition in humans, looking at about 100 microns, actually extremelycomplex, you
can see in the schematics and also in histologythat you see here, ligaments connectible to a differenttype of tissue. this small piece of tissue, small transitionis further divided into two regions; one is non-calcified, one iscalcified. why such complexity? in nature, complexity is not accidental.this complexity is important for a variety of reasons, because it involves a gradientof cellular, chemical and biological properties, and especiallymechanical properties that allow you to first transit from softtissue to hard tissue. soft tissue that primarily sustains tension to something that primarilysustains
compression, such as bone, and also to minimizesformation of stress concentrations. so you can go from soft to semi-hard, thento hard tissue. the deformation is not sudden. so failureis limited. so this interface is extremely critical, whenyou're trying to connect different tissues together toassemble a total joint. given these motivations, work that we havebeen working on in the field by many researchers follows acouple of areas. first, we look at the interface itself. how does nature connect a rope tothe wall, in this case a ligament or a tendon to bone and alsounderstand the fact that you’re connecting
different typesof tissues together so different cell populations have to work together in order to engineeror repair that transition that is lost? these new formationsfit into biomimetic scaffolding design, the scaffold systemthat ultimately will allow you to integrate soft tissue with bone.and like all tissue in the systems, this is evaluated in vitro and also in vivo and optimizedbased on these results.so in the interest of time, i'll talk about some of the work we have done in terms ofanterior cruciate ligament system in the acl, which is alsothe most commonly injured ligament of the
knee.fixation of the acl grafth is a significant problem.one of the first studies we looked at is looking at the postnatal remodeling of the insertionsite. so how does the insertion change?specifically relevant for acl patients, demographics between 15- to 35-year-olds, so you have peoplewho are skeletally immature, still growing, and those patients who are skeletally mature.so you see the interface is different with the function of age as tissue engineer whenyou try to design an interface, you have to think about thepatient. what is the patient demographic that you'reworking with? so this is illuminating what
about type ofinterface, organization, which engineer scaffold system.we also looked at what are the mechanicalproperties. if i’m trying to design something, i needto know how strong something is or how strong should i selectthe material to be. we looked at the mechanical property acrossa 100-micron range and looking at non-calcified versuscalcified regions. this is important information which allows us to design our scaffolds tomake them biomimetic.in addition to looking at what are the biomimetic design properties, looking at the interfaceitself, we
had to think about working with biologiststo elucidate the mechanism of repair. so how does theinterface repair? currently that is not known. so there's a lot of work going into this area.one of the hypotheses is when you put a piece of ligament or soft tissue next to hard tissue,we found clinical observation that sometime over time,a wall builds between them. so how does that wall get built?then the hypotheis that was formulated is that the interactions between the cells fromthe soft tissue and cells from the bone tissue, that communicationis critical in initiating the repair response. more importantly, their communication is importantin inducing the differentiation of stem cells,
actually ultimately the ones who are repairingthe interface itself. so through a series of co-culture and tri-culturemodel systems, we elucidate the mechanism underlyinginterface regeneration in terms of how do the cells have to interact with each otherso that you can actually re generate interface between softtissue and hard tissue. so cell to cell communication through pericleanas cell to cell physical contact have been found to beextremely critical in connecting soft tissue to bone.so taking all this information together, how do you assemble that and actually design afunctional
grafting system that can actually indeed connectdifferent types of tissues together? so to bring this home, this is the characterizationthat shows the ligament, the interface and the bone.and this is our scaffold system in which you have a ligament phase, interface phase andbone phase. three different types of cell populationsare seatedon the phase a, b and c. they’re working together to regenerate acontiguous graft. this is in vivo tracking of the three cellpopulations over 28 days in vivo. the cell -- three different type of cellsare implanted, over time. indeed, cells are true tissue engineers.they engineer three different types of tissues.
this grafting system is a continuous scaffoldthat is soft tissue is seamlessly integrated with bone.so this is our end goal, in terms of engineering complex tissue to be able to connect softtissue with hard tissue in a biomimetic manner.now in terms of application of this system: we are using the system to -- using for totalacl cell repair, for total acl graft that is actually pre-engineered at interface so you have the bone phase, interface phase and you have the ligamentphase, so this is a total ligament prosthesis thatyou have pre-engineered integration. when it comes to in vivo,you only have to worry about osteo integration
or bone to bone integration.another way that you can potentially utilize this scaffold system is to use them to induceinterface formation on current acl reconstruction grafts.this can be done in a variety of ways which i won't go into detail here.but the idea is to be able to design systems, grafting systems that enable biological fixationin terms of connecting a rope to the wall without mechanicalfixers and to multi-tissue formation. i have given an overview of the work we havedone the past 7 or 8 years, how to regenerate differenttissues simultaneously. what is next?from a patient perspective what can you expect
down the road?what we're doing next, if you think about it, our work has illustrated work on morethan one cell type is necessary to engineer more than one type oftissue. but from a clinical perspective, translationalperspective, that's extremely cumbersome. you cannot ask a patient to come in and donatethree different types of cell and come back for thesurgery one more time. so we're designing what we’re calling smartscaffold systems that allow you to seat a single cellpopulation, whether it is mesenchymal stem cell, adult stem cells or ips cells, and thenthe cells are
smart enough to know in phase a they becomeligament like tissue. phase b, they form the interface that allowsus to connect to, phase c, they form the bone like tissue.this is what we're working towards, sort of, actually, making this translational to thebed side. in addition, i think the work has to in thecontext of in the not so distant future. you heard questions about total joint replacement.there's advancements made in joint replacement and niams has played a significant role bringingthat to fruition.however, total joint replacements, along with an increase in the number of implantationswith the joint
systems, there is also an increased numberof revision surgeries. that is because we are an aging and physicallyactive population. the demands placed on our body in an agingpopulation is extremely significant. there's cause for concern for some of thetotal joint replacement systems. so these systems work very well within theconfines of their design. however, they're not optimal.by engineering complex tissues or thinking about how different types of tissues can beconnected together, our goal is, if necessary, engineeringtotal joint systems. a lot of times, when you can connect softtissue to bone, you can actually negate, potentially,
the needfor total knee replacement. total knee replacements are performed because of cartilage damage,so if you can attach cartilage to bone in a functionalmanner; you don’t have to get a total knee replacement.total hip is a different story. but some things you can, by understandinghow different types of tissues together you can moderatethe type of clinical treatment, make them less aggressive, and, when necessary, youcan make total joint regeneration that would allow you to be ableto engineer a joint that’s interconnected. as far as the patient is concerned, at endof the day, they should not have any synthetic
material insidethem. that's the goal ordream of tissue engineeringthat you have your own tissue that’s grown by your owncells, but with a little help from tissue engineer scaffold systems.that is a dream for the future. so i want to acknowledge the contributionsfrom the students who have actually performed all this workthat i have talked about here and also the collaborators. i have had many collaboratorswho i have had in bringing this work about, especially scottrodeo at hospital for special surgery, who is our long-termcollaborator on the acl project.
and also adele boskey, also at hospital forspecial surgery, and steve doty, who helped us tounderstand the interface and characterizing the functional properties.as well as faye chen, who was at columbia, and later at niams intramural, who workedwith us closely on the co-culture and tri-culture models toelucidate some of the mechanism governing cell to cellinteractions and its relevance for multi-tissue regeneration.and also i want to acknowledge my mentors who -- we stand on the shoulders of giants.in terms of interface tissue engineering and complex tissues, we really are building uponall of the
knowledge base that has been gathered in thepast three decades in tissue engineering. and i want to acknowledge my mentors, solpollack and paul ducheyne at university of pennsylvaniawhere i did all my undergraduate and graduate training and they taught me how to becomeacademicians, and my post-doctoral mentors, dr. cato laurencin and dr. david kaplan attufts university, working with dr. laurencin, whoactually really stimulated my interest in tissue engineering. iwas not a tissue engineer before i started my post-doc. and, i also think working withhim, one thing that was very valuable i learned was to workwith clinicians.
how do you work in an interdisciplinary team?by working with clinicians in tissue engineering, you can actually understand how you can bettertranslate your technology, a scaffold design to something that can go into a patient.i also want to acknowledge the support from nih and niams for funding our work, and also,when i first started as an assistant professor at columbia,my first year i applied for 10 proposals. i wrote 10 proposals.the last one got funded. and most of my proposals that i applied forwere nih proposals. and the one that was funded was not an nihproposal, it was a whitaker proposal. so it was verydepressing.
sbut i think what was really helpful to me,is that i had the guts to call nih and find out what should i do.and not like the dmv so that i had a view that this experience, my grants proposalswent to a black box, were chewed up and spit back out.so that's how i felt at the end of the first year, but i would like to thank the niamsstaff and the nih csr who helped me understand the process and alsowriting a better proposal. i also want to acknowledge the women's forumwhich really, i think, helped mentor a lot of femalescientists and it’s also where i met dr. joan mcgowan.these served as a role model for us, for young
investigators, so that we don't have -- becausewhen someone asks me do you have any horror storiesto tell, as a woman scientist, no, i don't. i'm very fortunate and i think this is thanksto all the mentoring i have received, been fortunate enoughto receive in my career. finally, i want to thank the funding resourcesfor supporting this work, also say happy birthday, niamsand a special hello from columbia bme department. we have only 18 full time faculty members,but eight of us are funded by niams, so we want toespecially thank you for supporting us and also to congratulate you on this auspiciousoccasion.
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