professor mark saltzman:so, this week we're going to be talking about the subjectof tissue engineering. it's covered directly inchapter 14 but not in a lot of detail.i provided a couple of other readings which are listed hereon this slide, these are in the lecture notes.if you go that folder there's two papers, one from 1993 andone from 2002. i would read them in thatorder, read the one from 1993 and then the one from 2002.you'll see sort of how this
field, which i'm going todescribe today, has evolved over the last 15years or so. some of the challenges thatwere talked about in this article from 1993,you'll see, are still present today.it's turned out to be more difficult than biomedicalengineers thought to accomplish, some of these things.some of the things have gone faster, we've made more progressthan we thought we would in 1993.if you read those two papers,
read the bit from chapter 14about tissue engineering, and then chapter 16 i've alsogiven you. chapter 16 is aboutbiomaterials and artificial organs, but there might be somethings in there which are useful to you in understanding thissubject as well. section will meet this thursdayin the regular time and place. what's the motivation fortissue engineering? this slide has a lot of numberson it and the particular numbers are not important.i've posted it in the notes for
the course so you can look at itat your leisure, but the main point here is thatthere are many diseases that drugs cannot treat effectively.they're diseases that are prevalent, they don't occur insmall numbers. that's why all the numbers arehere so you can see how many incidences there are of thesedifferent--what is labeled on this slide organ and tissuedeficiencies. for example,you know that burns of the skin are quite common.some burns are not severe
enough that they need any othertreatment other than maybe some antibiotic lotion and a dressingwhile it heals. some burns are so severe,or so extensive, that they threaten the life ofthe patient who has them. if you lose enough of yourskin, you lose a lot of water through that open area of skin.you can become dehydrated to the point where you can die ofdehydration. your skin is an importantbarrier for keeping water inside your body.of course, your skin is a
barrier for keeping other thingsoutside the body, toxins, and in particular,microorganisms, viruses, and bacteria.so, your risk of infection is tremendous if you have largeburns over a significant part of your body.there's no way to--that we currently know to speed up thehealing of skin fast enough that patients that have severe skinburns can survive that injury. what's done is that you needskin transplants; you need preferably anautograft of skin,
taking skin from one place inyour body and putting it in another.if you have severe burns over much of your body,then there's no skin to graft. you might take an allograft,an autograft is a graft from you, from the individual to theindividual, taking some of your tissue andmoving them to another location; that's 'auto', self graft.allograft is from a similar individual but not you,somebody who might be matched but not perfectly matchedimmunologically to you and you
get a graft from them.when you get a blood transfusion from somebody that'snot you but there's some matching that's gone on to makesure that you're not going to be incompatible with the blood,that's an allograft. xenograft is a graft betweenspecies, so that would be a graft from another species tohuman, for example,or between species, so autograft,allograft, xenograft, good words to know for ourdiscussion on tissue
engineering.you can imagine there's a limited number of allografts,that is skin transplants that are available to treat burns.so, not all the patients that need them are able to get thesekinds of grafts and so life is threatened in that situation.not only burns but there are pressure sores,what are commonly known as bed sores for patients that have tospend significant time in bed because of an accident.let's say they've had a spinal cord injury and they have tospend a lot of time recovering
from that,or they can't move anymore on their own and they'll developsores which are very difficult to heal.diabetics because they--because diabetes can affect the sensorynerves in your extremities, often get sores in theirextremities, particularly in their feet or lower leg,which don't heal very well; partly because they can't feelthem as well anymore, and so they become injured andcontinue to get injured. partly because the process ofdiabetes slows down healing in
general, these--they get ulcersor lesions on their skin that don't heal.just this top category alone lots of patients,different indications, not enough tissue to treatthese tissue deficiencies of the skin;if you went down this list you would find many others as well.let me go down here, we're going to talk about insome detail the liver. when you get liver diseasethat's severe enough, the only medical option rightnow is a liver transplant.
we'll talk about why that's theonly option available for liver disease that becomes verysevere, that could result from somemetabolic disorder, from cirrhosis,or from liver cancer. in that case,a transplant is the only option.i'm sure you've all heard in the news about cases where thereis a patient, often a child,who has some--a disease, waiting for a transplant andcalls will go out to the
community. this is a familiar story in oursociety. the reason for that is becausethere are a significant number of patients that are in thiscategory. not as many as in the case ofskin, but a significant number. there is something liketens of thousands of patients that are eligible for livertransplants and waiting for them.why are they waiting? because there's not enoughdonor organs to satisfy the need
of people that have transplants.that's unlikely to change. for a liver transplant donor tobecome available, somebody has to die with ahealthy liver, they have to have consented tohave their organs used for another person,and they have to be matched immunologically with the patientwho's going to receive the donor.somehow, those two things have to come together.all of these things have to work right in order for a liverdonor and a recipient to match.
they have to match not onlybiologically, but it all has to match interms of timing as well, and that's a complicatedprocess. today, if you go and lookon this website, we, 'we' meaning 'we as asociety', have set up organizations andprocedures to try to help with this matching process.one of those is called the organ procurement andtransplantation network. they keep track of all of thepatients that are on lists
waiting for organ donations,they keep track of all the organs that are going to becomeavailable and a matching process occurs,and computers are involved, and all kinds of the resourcesyou would expect to be involved in this thing.if you look for any particular kidney transplants,there are currently as of yesterday 75,000 individuals inthe u.s. waiting for donor kidneys;in the liver there are 16,000. these are patients that todayneed an organ donation,
their physicians have decidedthat they're too sick to respond to any other treatment andthey're just waiting for an organ to appear.i talked--in the very first lecture you might remember,i showed you this picture to talk about--there's already veryhigh technology involved with this medical effort.part of the technology are things like this organprocurement network. this is run electronically onthe internet, using all the high tech toolsof communication that we have in
order to connect physicians whoare trying to treat patients with physicians who find thatthere's a donor available, and by other high techindustries like the airlines who can quickly move organs from oneplace to another. if the donor of the organ diedin california and the recipient is here in new haven,then you've got to get the organ as quickly as possiblefrom california to connecticut. that can be done now sometimes.another technology, which is embedded in this,is that some hours have to pass
between when the organ isharvested and the organ can be transplanted.you need to be able to preserve organs for that period,however long that period is. you'd like to be able topreserve them for a long period of time.what if we could preserve donor kidneys in the same way that wepreserve blood? blood--many of you have gonewhen the red cross has come here looking for blood donations.they take your blood, they store it in a special waysuch that it can be used up to
three weeks past the point whenyou donated. that creates many opportunitiesfor your blood to be useful. in the same way,if you donated organs and there were ways to preserve the organsthat would be--make them more useful as well.there's a whole technology behind this that i wanted to atleast describe to you in words and you could think about.biomedical engineers are currently working around theworld on better ways to preserve organs, but it's a difficultproblem.
it can be accomplished in bloodand certain kinds of blood cells, can be partiallyaccomplished with some tissues like skin,cannot really be done with livers or kidneys.not yet, but there's a great need for that.why--i wanted to say a little bit more about why youhave to take this extraordinary measure of transplant to treatdiseases like liver failure. when a liver becomes sodiseased that it cannot recover its function on its own,lots of things go wrong.
this chart is a table of someof the functions which are happening everyday in yourliver. the liver is an importantendocrine organ, we talked about the endocrinesystem, it makes hormones like igf1,it activates vitamin d which functions as a hormone,is important for structure of your bones, it produces thehormones that are used in your thyroid gland and many otherhormones. if your liver starts to die youstart to lose the ability to
produce those hormones and youcan imagine, then, that lots of things inyour endocrine system start to go wrong.the liver also produces many of the clotting factors;these are proteins that are needed for clotting blood if youhave an injury. if the liver starts to dieyou're not making as many of these, you can have a bleedingdisorder. it makes plasma proteins likealbumin, which have many functions in the body.it makes bile acids,
and bile acids are veryimportant as an excretory organ for getting rid of moleculesthat the kidney is not able to eliminate into urine.i could go on down the list. i put it here just to say thatwhen your kidney--when your liver fails thousands of thingsstart to go wrong. you could imagine treating anyone of these with drugs. if the problem is activation ofvitamin d you could take vitamin d, you could take pre-activatedvitamin d. if it was a thyroid hormone youcould take a thyroid hormone.
if it was any one of thesethings, there might be a medical solution for it.but when it's this whole list of things, because your wholeorgan is failing, you can't support that functionwith drugs alone. it's just too many things goingwrong at once. drug therapies are usuallyused for treating something where we understand what themolecule is involved is and where there's only one or twomolecules that are involved. it's some metabolic disorder,you're not making a particular
molecule that you need.so, you take it in the form of a pill, or you have an enzymethat's not working properly and so you take injections of thatenzyme. in the case of cancer,there's a single drug which can eliminate the unwanted cells incancer. these are areas where drugtherapy works. gene therapy,which we talked about a little bit, works in other kinds ofsituations. where you're missing an elementof a cellular process;
like in cystic fibrosis forexample, your lungs and other tissues are missing a membraneprotein that's important in transport of chloride acrossyour lung epithelium. now, you can't just take thatprotein because it won't get inserted into the cells in theright way. we talked about membranes andhow proteins are inserted in membranes.you can't just give the patient that membrane protein and haveit restored to the right location in the cell.because it's only one thing
that's going wrong,you can think about treating this with gene therapy,by giving those cells that are missing the protein a gene thatallows them to produce that protein on their own and tocorrectly insert into the membrane.gene therapy is possible to think about in diseases likecystic fibrosis and some diseases of the liver and otherorgans as well. in general, they're diseasesthat are caused by a single gene defect.when we're thinking about
liver failing lots of things aregoing wrong, many genes involved.gene therapy isn't really thinkable in that situationwhere the whole organ is starting to fail.whole organ transplantation is the only current solution,a surgical solution for problems like heart failure,kidney failure, liver failure,where the whole organ is starting to fail.the motivation, then, for tissue engineering isto try to think about another
way to treat these diseaseswhere you would somehow manufacture or create a tissuein the laboratory that could substitute for the transplantedtissue from another patient. the idea is to try to makesynthetic or semi-synthetic tissues that could take over thefunction of a failing liver, a failing kidney,a failing blood vessel, a failing heart.it is intended to treat these diseases that are too complex tothink about complex in the number of things that are goingwrong;
too complex to treat with anyof the other therapies we've talked about over the course ofthe--of our time here. this is a field that wasreally--has ancient roots, and those ancient roots arediscussed in your book. the idea of engineering tissueswas really only developed relatively recently,and first defined, really, in the 1980s.that first paper i gave you to read by langer &vacanti is really considered one of the first,most influential scientific
papers in this growing field.here's one definition of what tissue engineering is.i told you what the goals of it are kind of in broad terms,but it's the 'application of principles and methods ofengineering and life sciences toward fundamental understandingof structure function relationships in normal andpathologic mammalian tissues'. that's not the more interestingpart to me, the more interesting part to me is,'and the development of biological substitutes torestore, maintain,
or improve tissue function.'why is it only in the 1980s that people started thinkingabout this? there's really two reasons andone is an engineering reason, a broad reason,and the other is sort of life science and biology reason.we had come to the point in the 1980s where a lot of the biologythat we have talked about now was fairly well known.in particular, the biology of cells in cultureof taking cells out of organs and tissues,maintaining them in culture,
getting them to do the thingswe wanted to do in culture was fairly well known by the 1980s,it's a fairly mature technology. one could think about usingcell culture techniques to produce complicated structures.the other is an engineering advance and that is that we haddeveloped, by the 1980s, enough understanding ofartificial biomaterials that we could start to create materialsthat had unique properties which made them good candidates foruse in the kinds of applications i'll talk about.the innovations,
or the kind of foundations oftissue engineering, are our ability to culturecells, to do that reliably,reproducibly, to understand what cells aregoing to do when we maintain them outside the body,and our ability to build materials that are biocompatiblethat can be implanted into people and that can serve asscaffolds for new tissue. i'll say more about what thatmeans. just to try to put this inmore concrete terms,
here's two examples of how youmight artificially engineer a tissue,or two kinds of applications that people might think about ina heart that's failing. i use this as an examplebecause we know a lot about the cardiovascular system now and soyou'll understand both of these examples.we talked about the important function of the blood vessels ofthe heart, the coronary arteries.we also talked a little bit about how these vessels canbecome diseased in life,
particularly for patients inthe 6^(th) or 7^(th) decade of their life.this vessel might become diseased through a process ofarthrosclerosis; the lumen becomes narrowed suchthat blood no longer flows. the resistance gets too highfor blood to flow well, so you'd like to replace thisartery. the only thing that theartery has to do is carry blood from one place to the other,so really all you need is a tube.people have tried for years to
use different kinds of tubes toreplace this section; the operation is called acardiac-bypass. a surgeon will go in,he will remove this diseased section of tissue,or he'll just put a bypass around it,that is, a tube that goes from this location and connects tothis location. like a bypass on the highwayit's a clear route that allows you to get around a route that'sno longer passable. well, these vessels carry alot of blood.
they have to be very reliablevessels because they need to carry blood all the time becauseyour heart is constantly working,it needs a constant reliable source of blood.the best substitute for this is a natural one.so, one of the most successful operations here is to take ablood vessel from somewhere else in the patient's body and use itto create a bypass. you'd like it to be an artery.bypasses can be made, there's another artery that'snearby called the internal
mammary artery that surgeonscould take. you can take it from the tissuesort of near the heart, it doesn't really serve asimportant a function, and you can bypass it in here.now you have a new artery in place to continue to flow blood.that works, but what if you have more thanone site of blockage? what if you have a blockagehere, and a blockage here, and a blockage over here,and a blockage over here so you need multiple bypasses?you don't have enough arteries
in order to do that.then, the surgeon will go and take the saphenous vein fromyour leg. it's a large vein in your legthat returns blood that's flowed down to your leg back up to thevena cava. there are enough other veins inyour leg that you can lose that vein without any loss offunction in your leg. they can now take the vein andcut it up into segments, and use that to bypass allthese segments of artery that are clogged.that works as well,
but veins aren't the same asarteries, you remember that. if you take a vein which has adifferent anatomical structure and put it in the position of anartery that is exposed to the high pressures that you knowalready occur there, sometimes that works.sometimes the vessel changes and remodels and adapts so thatit functions, and sometimes it doesn't.sometimes those veins also become diseased and they nolonger serve as an effective bypass.then, what do you do?
if both of those options failyou can try to use synthetic materials.synthetic materials are used to replace blood vessels in manyparts of the body. if you have an aorta that hasan aneurism, a surgeon can put a synthetic piece of,basically dacron, a synthetic material.it will serve as a functional aorta and do a very nice job.it turns out that we know from experience, now,that that only works if the vessel is big enough,because for big vessels all of
these kinds of syntheticmaterials that we make. while they might have the rightmechanical properties to serve as an aorta, they're notbiological. so, blood will clot when ithits that unnatural surface. it's okay if blood clots onthe surface of a big artery because it's big enough that youcould have a lining of a clot here along the inside,and it would still be enough diameter to flow.if it's a small artery and it clots blood doesn't pass throughany longer.
we know now that the limit ofwhat one can do with synthetic materials is about half amillimeter to a millimeter, and that's the size of thesecoronary arteries. you can't use syntheticmaterials there. what we'd like to do is grow anartery outside the body. what if we could that by takingthe synthetic material and growing on it a lining ofnatural cells? the synthetic material wouldprovide the mechanical properties needed for it tofunction as an artery.
if we could grow naturalarterial and endothelial cells all over the surface of this,the blood wouldn't know that it's a synthetic material.it would only see the cells which are forming the naturalbarrier, the natural wall of a blood vessel,so that's tissue engineering--an example oftissue engineering to create an artificial artery to use inbypass. i'm going to talk more aboutthe details of where we are in that process and what theobstacles are next--on thursday.
let's say you didn't getthere in time and a particular patient--they didn't have abypass in time so they have a blockage.they have a mild cardial infarction or a heart attackbecause the blood becomes comprised to some area.this area of the heart doesn't get blood for some period oftime, and so this tissue in the wall of the heart dies.now, in general if that happens there's only a limited abilityof your heart tissue to heal after you have a heart attack.a scar is formed here and this
part of the heart doesn'tfunction in the same way that it did before.remember how it functions, is it has to transmitelectrical signals and it has to contract in response to thoseelectrical signals. it has to do that with aregular frequency, so it has to both conduct theelectrical signal and contract. this damaged cardiac muscledoesn't do that anymore. well, sometimes that's okay.you might not need all of your cardiac muscle to be functioningin order to have a reasonable
efficient heartbeat,but sometime the area of this is so large that it compromisesthe ability of your heart to deliver the cardiac output youneed to stay alive. what if you could make anartificial cardiac muscle? what if you could take somekind of a material and grow cardiac muscle cells on it?grow them in such a way that they filled up this material andthey started to function like heart,that is, they functioned in the right electrical way and theyfunctioned in the right
mechanical way.then, maybe a physician could come in and just sew this patchthat you've created outside the body into place on the tissue.maybe that patch would start to function like that part of theheart wall that didn't function. now, where would the cells comefrom that you did that with if we think about this particularapplication, we're going to create a patchfor repairing myocardial defects.where would the cells come from? what would be your first choiceof cells that you use for this?
justin?student: fromthe heart.professor mark saltzman: from the heart.from what heart? student: from thepatient's heart.professor mark saltzman: from thepatient's own heart. what if you could take a smallbiopsy of tissue from somewhere else in the heart?you could take a small sample of those cells,and you could take them outside the body and grow them inculture. well, this is where our abilityto culture cells comes in very
handy because we could take asmall sample, isolate the cells we want,propagate them in culture until we had millions of those cells,put them into the patch, put the patch back into thepatient. now, the patient has anautograft of cells, but placed in the rightconfiguration so that they function as a tissue.what are the problems with that? what's the problem with that? student: the entireorgan is
diseased.professor marksaltzman: if the disease was too big you couldn't do that.why couldn't you do that? because you couldn't growenough cells, you think,or--student: because [inaudible]doesn't use tissue [inaudible].professormark saltzman: yeah. you might--there might be somepractical limits to it but you're getting close to what thereal problem with that would be. think about the timing of it.how long would it take you to
take this biopsy and grow thecells and make a new artificial--probably would takeweeks to do. could the patient survive thoseweeks while you're making the tissue engineered solution?maybe, maybe not, it would depend on howextensive the failure of the heart was, as justin described.what would be another solution to that?well, let's not take cells from the patient but let's create abank of heart cells. that might be possible,but you have to be able to
preserve heart cells.you have to have a bank of cells with all the rightimmunological markers labeled, you have to have them in enoughquantity that they would be available rapidly.there's problems with that but maybe you could do it that way.maybe you could use stem cells. we talked about stem cellsbefore and some of their capabilities,but one of the real advantages of what people think of as usingstem cells to treat diseases in adults is just exactly whatwe're talking about here.
being able to create anenvironment or an engineering solution in which stem cellscould be used to create functional tissue.in this case you'd want stem cells that could very quicklybecome cardiac muscle cells that could be differentiated in thecardiac muscle cells. ideally, you'd want stem cellsfrom the same person, you'd like to isolate them fromthe same person somehow, or from a donor that wasmatched. you're starting to see both theopportunity, i hope,
and the problems that have tobe solved in creating these new solutions.i list on this slide a few of the characteristics of tissueengineering that we're going to talk about,not in quite this organized a way, but i hope that by the endof the week you'll be able to look back at this list and say,'oh, i understand what that characteristic means in terms ofwhat we're trying to accomplish in tissue engineering.'the first is what i've been talking about up to this point.the tissue engineering really
represents kind of a modern orcontemporary logical extension of conventional medical andsurgical practices. if we're going to make anengineered tissue, in many cases,we're going to give them to a surgeon and they're going to dowhat they know how to do, which is replace an organ or atissue. you're just giving anotherresource to surgeons to do what they know how to do already.we're using it to extend medical practices to diseasesthat can't be treated by drugs
or gene therapy or other kindsof medicine. what i want to talk aboutfor most of the rest of the time today is this second bullethere, that tissue engineeringinvolves control or regulation of normal healing processes.that if we want to understand and use tissue engineering weneed to know something about how the body heals itself and takeadvantage of those natural mechanisms of tissueregeneration. we'll talk over the course ofthe next two lectures about
tissue engineering as an attemptto replace the cellular component of diseased tissues.whereas in drug therapy we're thinking about the molecularcomponent, now we're replacing cells,that it uses cellular processes sometimes to control drugdelivery. we'll talk about how you coulduse tissue engineering as a drug delivery system,and that tissue engineering produces new models for thestudy of human physiology. i won't say anything moreabout that this week,
so let me just say that now,that what if you could produce heart tissue like this fortransplantation? another use for it would be ifi can make this tissue outside the body that behaves like thehuman heart, i can use it to study how thehuman heart works outside the body in a much more reliableway, or a much more sophisticatedway than i could with ordinary cell cultures.because now you not only have the cells of the heart but youhave the cells of the heart
arranged in the right kind ofconfiguration, so i could understand--i coulduse it to understand how the heart develops.i could expose it to different drugs and ask,'what are the toxicities of these drugs to the normalheart?' without doing it in patients,and with doing it in a system where i have a lot of controland a lot of ability to look inside and see what's happening.let me go back to this point now, tissue engineeringinvolves control or regulation
of the normal healing process.we're all familiar with at least some aspects of healingbecause you've all had a cut in the skin that has maybe causedyou some distress in the short term.maybe it was a cut that was deep enough, and this shows youthe structure of the skin. here's the outer layer of theskin here that forms this sort of thick barrier layer,the epidermis that things can't penetrate;water can't penetrate easily. you put water on top of yourskin, it beads up there,
it doesn't get absorbed.likewise, water inside doesn't come out and that's why youdon't get dehydrated. microorganisms can't go throughbecause of this barrier. underneath is a moreconnective tissue layer called the dermis and inside thisdermis there's cells that are producing an extracellularmatrix of collagen, largely.we talked about extracellular matrixes several weeks ago.within that collagenous matrix there are blood vessels,arteries red here,
veins blue.those blood vessels bring blood to the skin to provide oxygen,and to get rid of carbon dioxide in these cells in yourliving skin. you get a cut in this tissueand what happens if it's a deep enough cut you bleed.you got to do something to stop the bleeding.you've had this and so you put some pressure on and you waitfor clotting to occur, but you've disrupted thesevessels. they have clotted so that aclot has formed inside these
vessels so that the bleedingstops. usually a clot forms at thesurface. if you look at this afteryou've got the bleeding stopped you have a red looking area.it looks different from your skin, that's the beginning ofthe healing process, is that your body hascoagulated blood at that site to replace the tissue that's beenlost. you'll have a red spot therethat turns into a reddish looking scab.that's your body responding to
stop the immediate insult,the bleeding, and to fill up the space ofthis tissue that's been damaged. cut's too big,this can't happen, you can't just put pressure onit and stop it, and so what do you do?you go to the emergency room, you get some stitches.they bring the sides of that wound back together withstitches, they hold it closed. the same thing happens but inthe smaller space now, because they've just broughtthe tissue together so that your
body could produce thisprovisional tissue. the provisional tissue at thebeginning is just a blood clot. after that point manythings start happening within the skin, and a complex processof cells sending out signals and cells responding to signals in acoordinated and regulated way occurs.what this diagram shows is some little fingers of tissueentering into this coagulated provisional matrix that wasformed by the blood clot. these cells are initially cellsthat are called fibroblasts
which live in the dermis.normally, they're just sitting there sort of in a quiescentstate, not reproducing very rapidly,making collagen, providing matrix to keep upsort of the normal structure of your skin.when there's an injury, they get turned on and theymigrate into the wound. they migrate into thisprovisional matrix and they start changing it.they start digesting the clot and they start making newextracellular matrix of
collagen.they do that so that there can be a pathway for these bloodvessels to regrow. the blood vessels need toregrow, renourish the skin so that you can start to get thenormal composition back, the normal cellular components,and you'll see these blood vessels starting to form sproutsthat enter into this provisional matrix.now, you've watched the process of a scar healing onyour own body and you've seen the stages that it goes through.it will go from the red
appearance to a duller red,and eventually become a white, or it doesn't look red at all.after some period of time you won't even see where the cut wasat all. the end process of thesefibroblasts coming in, replacing, remodeling thematrix of blood vessels regrowing back in,establishing new cells from the epidermis start to grow in overthis matrix in the end. first they'll grow over the topand so you might see a little bump here.eventually the whole tissue
through this elegantself-regulated process heals itself so you can't see wherethe cut was, we've all had that experience.probably we've also had the experience when we got a worsecut and it didn't end up looking right.you might still have a scar from some cut that you got onyour hand or your arm where it was too severe.now, what happened there? the same process of remodelinghappened but it happened in a more aggressive or more vigorousway because the signals that
control this were large.it was a large wound, big problem,lots of cells got activated, they made a lot of collagen,they remodeled this provisional matrix very aggressively.why? so, that you could heal,and so that you wouldn't have a wound here that was open toinfections or loss of blood or loss of water.your body knows how to respond to very severe injuries,more severe than we usually encounter in our lives.the result is you'll get a scar
form that because the responsewas too aggressive. our ancestors,who lived much more dangerous lives than we did,who might get attacked by a lion or a bear,needed to have a very aggressive healing response sothey didn't die if they got attacked under somecircumstances. we don't get attacked by lionsor bears so often anymore and so we don't necessarily need thataggressive healing response. we might like a gentler healingresponse that leads to a better
functional--that doesn't have ascar, for example. how can you control healingin that case? well, one of the ideas oftissue engineering is to provide materials that would guide,or regulate, or change that natural responseof healing. you have a wound and the woundis going to heal on its own in some way.you would like it to heal in way that you control so that theoutcome is more to your liking. now, maybe the outcome is thatit heals much faster,
maybe the outcome is that itheals without a scar; maybe the outcome is that itheals and new kinds of cells are woven into the tissue in placeof the ones that were there formerly.maybe this wound was created by a surgeon who removed a cancerhere, and you're trying to replace the cancer cells withnormal cells. what are the options interms of doing this? well, one is that you could puta material in here and the material goes into the wound.that material has some
function, and maybe that itserves as a better provisional matrix then the clot would have.'better' means what? maybe it regulates how cellsgrow in or how cells attach, or how cells synthesizecollagen after they enter. maybe you could design amaterial that changes the healing response locally.that's one way that you might engineer a tissue.now, here i haven't put any cell cultures in,i've just put in a fancy material that i designed.we'll talk about what those
might be a little bit later.maybe you don't need material at all,but maybe you could replace this with cells.maybe i could just take cells, maybe recovered or harvestedfrom some other place in the patient.maybe these are skin cells that i got from a normal location andi put them back into a wound in order to speed up the process ofhealing at that site. maybe they're stem cells thatcame from somewhere, or maybe they're just cells.often times the best
combination seems to be to putcells in together with some material.here, the material might function in a couple ofdifferent ways. it might function in this waywe talked about here, by giving signals to the normaltissue to regulate the healing response that's going to occuranyhow. that material might containcells that you have derived somehow, that you want to holdin that site; that you want to hold locallyand provide an environment where
they can grow and take over thefunction of the tissue. these are some sortschematic ways to think about how one might use tissueengineering to control the normal healing process.i've shown this, i've given you examples of thisthat--where i motivated it with thinking about the skin,but this doesn't have to be the skin.this could be your liver. maybe i put a material intoyour liver that allows it to regenerate.maybe i put liver cells derived
from some other source back intothe liver, and they take over the function of the liver.maybe i put materials on cells and create a new liver tissue.so, you could extend this idea to almost any tissue or organ.here's an example of that, where just the material is usedto guide the healing process. i think this is conceptually avery simple idea and one that works to some extent.this is a nerve. 'proximal' means closer to thebrain, so maybe this is a nerve in your leg and it's got severedby some kind of injury or it got
crushed and somehow the nerve isdamaged in this region here. this nerve is sending sensorysignals from the distal part, back up the nerve into thebrain; it's sending motor signals downfrom the brain to the more distal regions.if this tissue--if this nerve gets damaged by trauma somehow,then you're not going to get sensory signals sent through it,you're not going to get motor signals.so, you can't feel, you can't move and all of thetissue that's distal or
downstream of that site.how do--how would you repair that?well, it turns out that surgeons know that if it's asmall region and they go back in and they take the damaged endsof the nerves and they put them back together,you will recover much of the function of that nerve.maybe not 100%, but if they do it quickly andthey do it well that these cells will regrow the connections thatare lost in this section of trauma.you will, over a period time,
begin to feel in that tissueagain and you'll be able to move.if the damage is too big, you can't physically bring themback together. your leg is a fixed link and ifthe area of damage is too big you can't bring these tissuesback together. they found that you can use anautograft, that is take a nerve from somewhere else.if i cut the nerve out of another spot and then put it inthis region in between the two ends, the nerves will regrowagain.
problem with that is you don'thave a lot of nerves that you're not using.so, in order to repair this nerve you had to sacrifice anerve somewhere else. maybe you could do thatsame thing with a material, so what would the material looklike? the material might look likethis, and this is just a cylindrical cuff and it's acomplete cylinder. it's shown as a cutout herejust so that you can see inside, but it's a complete cylinderthat's hollow and you put one
end of the nerve into one end,and one end of the nerve into the other.now, you've placed these nerves, not in physical contact,but you've created a compartment through which theycan communicate. you don't have this end of thenerve dangling out in space and this end of the nerve danglingout in space. remember it's not going to be anice picture like this where the nerve is existing on its own,but there's muscles and blood vessels and other kinds ofthings around in this area.
by putting a channel with anerve in both ends you've isolated the area of the nerveyou want to regenerate from all the rest of the tissue.does that make sense? you hope that you get someregrowth through here. what scientists have foundis that if you do this you will get some regrowth.you don't get complete regrowth of a thick nerve,but you get a thin nerve with less fibers,less nerve tissue, less function but you get somerecovery.
so it works,and we've known for about 20 years or so that it works but itdoesn't work well enough, so how could i make it better.well, one way you could make it better is by changing thematerial. maybe the properties of thematerial weren't right, maybe the cuff on the outsideis too impermeable and you'd like to have moleculesexchanging in some way. maybe it's not permeable enoughand so you need to regulate it that way.maybe you don't want a nerve
cuff that's filled with just airor just water, but maybe you'd like a nerveconduit that's filled with a material that promotes thegrowth and reconnection of these fibers.maybe you'd like some kind of a gel in there that nerves couldregenerate through. so, the obvious place to gofor that is to use the kinds of materials that the body uses forrepairing tissues. fill up this channel not justwith water or saline, or some kind of a solution,but fill it up with an
extracellular matrix,like the kind of extracellular matrix we talked about weeksago, that all of your tissues have.a supporting gel like structure, formed from proteinsand carbohydrates that are secreted by cells,and through which cells normally grow and live.taking natural proteins like collagen, forming gels out ofthem and putting these gels inside the material increasesthe number of fibers that grow across a gap like that.this is just an example
of--a simple example,no cells involved here of a material that's designed inorder to enhance the healing of a wound and how one mightengineer properties of that material to make it better atsupporting the healing function. that's what i wanted to sayabout tissue engineering involves control or regulationof the normal healing process. i want you to keep that in mindas we go through the examples that we'll talk about inthursday's lecture. i'm going to stop there.questions?
see you on thursday.
0 comments:
Post a Comment