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Module 1: Introduction to Tissue Engineering

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Video 1: Motivation and Current Treatments
So, we will start with the basic Introduction for Tissue Engineering today.So, we briefly looked at the course contents, so I also kind of said what tissue engineeringwas.Today we will go into depths, so we will have a few classes where we discuss introductionto tissue engineering.So, what is the motivation for tissue engineering?what do we really want to do?Tissues are actually lost and damaged every day, right?So, it could be due to injury, disease or congenital malformations and so on.So, due to different reasons tissue is usually damaged, so but you want to restore thesedamaged tissues, right?So, you want the dream is to restore it, so that life can go on forever.Especially for loved ones and we want to make sure that tragedy never strikes us, right?So, that we do not have to go through the pains of whatever the process is.So, this idea would have is not new, it is obviously, it is it should have come to ahuman being when the first death occurred, or when the first lost limb was seen.So, why have we not been able to achieve it?Because we have always had dreams, we have; as humans we have wanted to fly we have beenable to invent an airplane and so on; so most of our dreams we have kind of achieved it,at least.So, whereas here which is one of the most fundamental dreams, right?So, we want to basically create another life; so why have not been able to do it?The simple reason is the challenges life; Life itself is very complicated and beautiful.See we do not think about it.So, most of us here have a biology or a biotechnology background.So, we do know some of the things about how life starts, but we actually do not sit backand think about it.So, just think about this.So, what you have is, what I have shown here is basically what I call the power of onecell.All organisms whether it is a mosquito or a human being start from one cell, right?So, this is very unique if the cell, the single cell basically divides and starts differentiatingto form different tissues.So, it starts migrating and it has to differentiate to form various types of tissues, it couldbe a skin tissue or a bone tissue or a cartilage or a heart tissue and so on.So, all these migrations and differentiation have to happen over a period of time.And finally, this eventually it develops into the right organism; So, a human being or anelephant or a mosquito, all of these develop from this one cell within a very short periodof time.So, if you were to take humans, it takes only 282 days for a cell to become a fully-grownbaby; And that is a very short period of time.Considering our life spans and the life span of the earth itself, it is actually a veryvery small period.And within that time there is such regulated control, which is phenomenal; Almost alwayswe get proper development, right?And that requires so much control over how the cells migrate, how the cells actuallydivide, how the cells differentiate and so on.For us to first understand what is happening itself has been a challenge; we still do notfully understand what is happening and why it is actually happening the way it is happening.So, for us to first understand and then to actually recreate it is the challenge of tissueengineering.So, to create an entire human is completely out of question in this point.But to create tissues, can we understand enough to know that what is required for creatingthis tissue.And that itself is a big challenge.So, that is where the field is, and we are working on it.So, we need to understand some of the fundamentals.Because, see tissue engineering when it started, actually had a lot of promises which weremade.Because it was primarily just a engineers who are starting it and with some doctors.So, probably we did not have enough of an understanding of the complexities associatedwith a basic biology.So, there was actually one paper which promised to deliver a heart in a Petri dish by theturn of the century, and this paper was published in 93 or something 1993.So, within 7 years people were thinking, they can create a heart in a tissue.Because, what they thought was you take the material, you put the cells, you will havethe heart.It just turned out it was not that simple, and people are still struggling to get evena beating tissue.So, recently maybe about a year and half back, there was this huge rage, which was the videoswere being forwarded where a small piece of tissue which was beating was actually created.So, it has taken us more than 25 years to create that small tissue, and valves are awhole another ball game.So, there are so many challenges which were not foreseen.And as we started doing more and more, people have started realising there is a lot of challengesassociated with this field, and people are trying to address them, and that is wherewe as researchers should contribute.Currently, people do treat damaged tissues, right?So, there are different techniques you can use.So, graft implantation is basically the approach.So, there are different types of grafts you can have; you can have an autograft whichis basically from yourself.So, here the advantage is, it will not get rejected because it is part of your body;it is not going to get rejected.But the problem is there is very limited availability, it is not easily accessible because you willhave only limited tissue in your body; I cannot completely harvest a particular tissue.And if that, if it is an organ like for example, if you have diabetes and you want to replaceyour pancreas; then you do not have another pancreas you cannot take it from your ownbody.So, you need to get it from an allograft which is another person from the same species.So, here there is a risk of disease transmission; there is a higher availability, but thereis always a risk of disease transmission and rejection.Even with transplants which have been very well established.So, what is a most common transplant that you can think of?organ transplant?Students: Livers.Liver.Heart valves, kidneys.Heart valves, kidneys; kidney is probably the most common one.Liver is also done but liver is much more complicated procedure than kidney.So, kidney is probably something which is very commonly done, but heart valves usuallya cadaver heart valves are also used, but people use from other animals as well.So, that would be a xenograft; So, where you take from pig or from cows and you take themfor your xenograft.Yeah, that is; that is also a transplantation part.So, if you are talking about an organ transplant like kidney which has been well established,it has been done for almost half a century now.Even for that, people still have to take immunosuppressive drugs for their life; that puts them at arisk of getting infected at any point.So, it is a serious problem to even have one of the most well-established surgeries.So, that is a problem with allograft; And xenograft obviously, it is going to, risksare going to be much higher compared to allograft; because you are now talking about a differentanimal altogether.So, your chances of disease transmission and immunological rejection are significantlyhigher.So, the last option is using synthetic materials; People use polymers, metals and so many othertypes of biomaterials, so that it can actually be used for implantation.So, this also has inflammatory responses and there can be a vascular barrier.So, cells may not infiltrate for example, if you are using a hip and joint replacementwhich is made of metals; Cells are not going to infiltrate.It is not actually a biologically active tissue you have placed; what you have is just a mechanicallysupportive device, which is been placed.So, that causes some discomfort, there can always be complications because of that.In some cases, like where you have plates and screws for broken bones; you might haveto go back and remove them because there might be some immunological issues.So, these kinds of problems exist with the graft implantation, but that is not the onlyreason you want to do tissue engineering.Because tissue engineered products can also have similar problems, right?Because you are also use going to use synthetic materials or materials which are not commonin your body.And you are probably going to use cells which are not your own.So, tissue engineered products could also have the same kind of problems; then why dotissue engineering.The answers?Maybe it is the best chance for us to mimic the living cell condition in the body.Ok So, probably you can get a closer tissue which is closest, but would not an allograftbe the closest?Like; obviously, an autograft would be the best, but autografts you might not be available.So, if I can get it from another human being; that is God’s creation, right?limited source.Ok, limited source; yes.So, the major problem is this; this is the statistics from US, you can see how the trendshave been when it comes to the number of transplants, number of donors and the number of peoplein the waiting list.The grey curve you see is the number of people on the waiting list and the orange one isthe transplants and blue is the donors.So; obviously, the transplants are higher than the donors because a donor can actuallydonate more than one organ right.So, this is the trend and the gap seem widening, right?From 91 to 2017; the gap is much wider.And the problem is; this is for a developed nation like US, where you actually have 54percent of the people registered for organ donation.

Video 2: Historical Development of Tissue Engineering
So, we will start with history; so, this is something which you would see in any tissueengineering book; not exactly these images, what you would see is an image of Chimera.So, this is to say that people have been dreaming of enhancing organs and enhancing tissuesand so on ok.So, this is basically what people start within a tissue engineering book.So, I always felt we should why start with the Greek mythology; why not our own mythologies;so right; so this is where we all, this is something we have all seen.And you would; I would also go to the other mythologies and show how similar our imaginationshave been.But the cool thing is people have actually dreamt of this; people have actually thoughtof xenografts, right?Lord Ganesha is a xenograft, technically right?So, why I said that disclaimer was again I am not saying a xenograft was actually performed.It is something which people want, people have been thinking about, right?This is basically what people were trying to do, so the images I have are a Lord Ganeshaand Lord Narasimha.So, Narasimha was just an avathar, who came down with a head of a lion and so on.Ganesha was proper xenograft where the head was chopped off, and you placed an elephantshead; so the other two things which you see the Kamadhenu and Yali are more of mythologicalcreatures which are basically designed based on what we think is cool what features youwould like to have, right?.So, why I said there is similarity is, look at the other cultures; the one you see herewhich is Al-Buraq; so this is a mythological creature by Islam.And you see that it is a white animal half mule, half donkey with wings on its sidesand a women’s head and tail of a peacock; it looks eerily similar to what you see asKamadhenu right.So, Kamadhenu instead of mule, they imagined it to be a cow; cow being the sacred animalfor Hindu mythology and a women’s head with on the feathers and peacocks tail and so on.So, you see that people were thinking along the same lines and Chimera is actually verysimilar to what you would see as Yali; Yali is a Tamil mythological creature.So, if you go to any of the temples, the older temples in Tamilnadu; you would actually beable to see Yali; so these are there on all the statues ok.So, Chimera has something similar; Chimera is actually a Greek mythological creaturewhich is a lion with the head of a goat from its back and a tail with the snake’s head.And actually, Yali is also that; Yali has the lion head and the tail is actually a snake,but you also have teeth; which is from elephant.So, it is like wanted to look at all the cool features, put it them together.So, Taresque is a Christian mythological creature and it is a dragon with a lion’s head anda bear’s legs; ox like body covered in turtle shell and so on.So, why I show this is; this is what people imagine, people thought of doing this, becausepeople were looking to enhance tissues, people were looking to add additional features towhat would be a regular animal.So, leaving beside mythological history; if you were to go into the real history thereare folklores of nose transplants which happened in 1000 BC.So, 3000 years back people had lost noses because of bat, because they were in battlesand they got syphilis.And during; say if you, if syphilis proceeds to extreme cases, you actually lose your extremitiesand or some nose and ears and things like that.So, losing a nose was really a problem because you looked ugly when you do did that right.So, people wanted to replace that and they tried to put transplants and the officialrecorded plastic surgery was done here in India and this was done 800 BC by Sushruta;who is considered as the father of surgery.So, here he tried to use skin grafts to create reconstructive surgery; which is what is beingdone even now, when you actually try to do skin grafts so that is what an auto autograftwould be.An autograft when somebody goes through a burn injury, you actually take your own skinand try to apply.Can you think of another autograft other than skin?Sometimes we use saphenous vein.Ok. during bypass surgery.Bypass surgeries.So, bypass surgeries usually use your own vein and that is would be an autograft too.And there is actually a long gap between 800 BC and 16th century, there is not much ofa record of what has happened between that time.But in the 16th century people tried to build nose replacements using the forearm flapsand transplantation of teeth, cornea, skin were all performed in the 1700s and 1800s.And in 1933; this is what people were looking at immune rejection and they were trying tounderstand how you can protect some implant from an immune system; so, what they did wasthey took tumour cells and wrapped it using a polymer.And implanted it in a pig to show that this polymer can actually prevent immune rejectionand kidney transplant was first done unsuccessfully in 1936 and liver and bone marrow transplantswere done in 1960s and so on.Lung transplant was done in 1963, heart transplant in 1967 ok.So, a modern era of tissue engineering itself started sometime in the 1980s and this isa very recent development.So, this is a modern-day Chimera; it was actually done by Charles Vacanti and what he did washe took a polymer scaffold and seeded it with cow knee chondrocytes.Chondrocytes are basically cells which are there in cartilage and put that in a SCIDmice; this is a immune deficient mice and showed that you can actually create a ear.So; obviously, this is not a functional ear; this should only be for plastic surgery justto for the aesthetic reasons.It cannot really help you in listening or anything, but it was a start and this wasdone in 1997; there have been many other recent studies.So, these you might have seen; so, I do not know if anybody has seen this image whereyou see the forehead having a nose.So, this was on the first page of Hindu; maybe a couple of years back.So, this was done in China; so, this guy met; met with an accident and lost his nose.So, the Chinese doctors decided to put a polymer scaffold on his forehead and let the cellseed themselves and create a new nose.And this was eventually transplanted to his nose and he is I am hoping he is healthy.But the other one you see is a ear on a forearm.So, this has been done multiple times now; so, recently it was done for a US army officer;some do not know I do not remember her name, so but anyways; so, she had lost her ear incombat and they grew a ear on her forearm and replaced it.Again, its only for aesthetic reasons I do not think it provides the functionality the,but it has been reasonably successful.And there was actually an article which basically said forearm is the best place to grow a earor something like that.So, people have been quite successful in doing that.So, these are the more recent studies probably happened within the last 5 years or so.

Video 3: Tissue Engineering
So, what is tissue engineering?So, this is the definition of tissue engineering.So, the term itself was defined by the paper; in a paper published in Science, 1993.So, this was written by Robert Langer and Joseph Vacanti; Joseph Vacanti is differentfrom the Charles Vacanti; they were not related.So, Joseph Vacanti is a medical doctor and Robert Langer is a chemical engineer.So, these two people came together to write a paper; so, this was a review article whichwas published in 1993.So, they defined tissue engineering as an interdisciplinary field that applies the principlesof engineering and life sciences; towards the development of biological tissues thatrestore, maintain or improve tissue function or a whole organ, ok; so, this is what thedefinition itself is.So, what you see here is basically an image from Wikipedia.So, there is a damaged tissue you take some cells out of the person with the damaged tissue;you then culture the cells, you get enough of the cells, you put them along with a scaffoldand give them the signals.So, with this you now should have a fully functional tissue; which should replace thedamaged tissue and the person is ok after that.So, that is what this image represents; this is exactly what you try to do.The challenges with identifying what type of cells, how to isolate the cells, how toculture the cells, how to design scaffolds, how to make sure the cells attached to thescaffolds, how to make sure the scaffolds do not get rejected, what kind of signalsshould be provided, and what time it should be provided, at what rate it should be provided;whether it should be provided in sequences or not, and what are the biophysical cuesare required, and then with all that hopefully it will have the function to the end ok.So, that is the idea; so those are the challenges in the steps which have been shown here.So, the first term in this definition was interdisciplinary field right.So, it is also one of the hot tags to have, but it this true this is truly an interdisciplinaryfield and it was defined as an interdisciplinary field 25 years back; it is not because youwant to get funding; so we call it interdisciplinary right.So, why do I say it is interdisciplinary?What disciplines do you want, what expertise do you want?Life sciences, materials science.Ok, life sciences, material sciences.Doctor; get medicine expert.Medicine; Ok, what else?Mechanical engineer Ok, mechanical engineers, you also have tojustify why you are saying all these, but we will get to that.Chemist.Chemistry, ok.It is developmental biology.Ok, So developmental biology.Also, maybe synthetic biology.Synthetic biology; Ok, anything else that you can think of?Aesthetic biology.What?Aesthetic.Aesthetic biology?Like aesthetic experts.Ok, so aesthetics.So, are you from engineering design?Someone who knows it like from the art side for ethics.Ethics, from; from what side?The arts; humanities.Oh, humanities ok; humanities is different from arts.Chemical engineer.Ok, thanks; otherwise I will be wasting my time.Instrumentation.Ok, so let us first justify why we have all this.So, life sciences; it is quite obvious we are working with living system; so, we shouldhave life sciences.So, why specifically development biology?Because we can take; so, if you want to regrow some kind of cells, you can make the cellsinto tissues by using stem cells.So, I have to read upon that actually.Ok.So, development biology is the domain which actually says how tissues are actually developing.So, if you have an understanding of that hopefully you can recreate it ok.So, good what about material sciences; why do you want material sciences?Biocompatible main thing, the materials whatever we are taking it should be biocompatible.So, why do we even need materials?Of course, we are dealing with polymers because many of the things; we should not do the.Why, why should we use polymers?So, why should we even use materials; why not just use cells?As a medium for cells, scaffold Mammalian cells are adherence cells; theyneed a substrate to which they can adhere to, they cannot just grow and suspension likebacterial cells; so that is why we need materials.So, now continue what do you want, so why do you need a material scientist?So, there are some of the materials which can be biocompatible in nature.Ok.So, material sciences people can know what are the materials can be actually biocompatiblein nature.So they can design the materials which would be compatible and also functional.So, it can; it is not just compatibility; compatibility can just mean that it is nottoxic; that it should also it could also require some functionality with that, ok; why do weneed medical experts?To execute it.To execute it.So, that is the.To perform clinical trials and stuff.So you are reducing them to technicians; they are more useful than that.So, End goal is put it in the human body.Sorry.Our end goal is to put it in a human body.Ok.And they have understanding of it.Ok getting information about the anatomy and physiology sure.And they will require building and anything surgery will be required to.Ok, so finally, for implanting it you need them a surgeon ok; what else?They are the ones who can actually identify the problem; so, it starts from them.So, see many a times what happens is we as engineers do not really know the need.So, some of the needs are like we just take it for granted; we do not think it is a bigneed, but turns out they are actually big needs.So, see recently I was talking to a doctor who was saying.So, he is a dentist actually so, but he is a; he was saying there is a serious problemin dental issues, where people undergo cancer; bone cancer.And you need to have some small diameter vascular graft which have to be placed.And engineering those have been a big challenge and he was looking to understand what wouldbe the issues there.So, I would not have thought of vascular grafts as an application for dental procedures andespecially in cancer patients.I would have thought of it for an application in cardiovascular procedures.So, those kinds of things we might not know because those were the guys who are actuallydoing it every day right.So, it is important to have a conversation with them.So, there was another doctor who gave an; gave a talk here sometime back.So, he actually was saying the heart valve, so I do not know if you have you anybody;has anybody seen a heart valve not, not of real one like the mechanical heart valveshave you seen a photograph or anything ok.So, the mechanical heart valve basically looks something like; it looks like a regular heartvalve with the flap and there is a cylindrical metal which is covered by a cloth.So, this cloth is usually present, so that it can be sutured to the patient and it willkey hold it in the in place.So, the metal which comes in contact with the blood, all that the flaps which come contactwith the blood all that are quite biocompatible and people try to coat it with different materialsto ensure that it is compatible.But this cloth was something which was causing a problem, but without a cloth; they couldnot implant it otherwise it will get displaced.But all they had to do was finally, these guys were sitting together and with an engineer,with a group of engineers and they figured just remove the cloth and put holes in thecylinder.And that holds it in place and it removes a major limitation which has been causingclogs and clots in the implant.So, it is a very simple solution which was covered, which was proposed by an engineer,but nobody would have guessed that there was a problem there; unless a doctor came to themand said that hey this is a problem ok.So, doctors are very useful in identifying the problem ok; so why mechanical engineers?For if you are designing a blood vessels and the flow dynamics of the blood when and howit could impact the like.Ok.Every designer has modelled for it so that we can probably test it before we implantit.Or if you are modelling anything for bones, so will the material which we were using beable to take on the stress which would be applied on it ones implanted or any body motionthat can it; can implant actually be will be able to perform all the different.Yeah.Case in which we can move.So, the mechanical property is and the mechanical stresses which our tissues go through haveto be understood.And you need some expertise in that and there is also mechanical signals which can actuallyregulate how the cells migrate and cells differentiate; so, that also needs to be looked at.So, there are different aspects where a mechanical engineer could contribute.See we are all standing upright right; it is actually the worst thing to do.It is not good for your knees; it is not good for your joints; you are putting all yourbody weight on your ankles which are probably crying for you to sit down.You are much better off when you walk in force because your stress is now, your body weighthas distributed much better.So, you are; obviously, going through something which is the stresses which you are goingthrough are severe and this needs to be understood and this need this might have to be emulated;for making it into a viable tissue ok.So, mechanical engineers can help you there.So, chemistry; why chemistry?I do not know whether is clarity or not, but that there are prosthetic; prosthetics, aprosthetic arms and all which can detect whatever if the person thinks in a particular way thatis reflects the fingers; the fingers actually reflects.So, can chemist chemical signals be used in that way?I do not know exactly what is being used to get that I know; I have also seen those videosand like seen lectures where that is possible.But I do not think it is chemistry, it is more with electrical engineering because itis not that it is being implanted in their body for them to actually have a chemicalconnection.It is mostly just put on top of an amputated; arm or something.So, I would think it is more about the electrical signals rather than the chemistry.Nervous system.Yeah.So, I do not have enough understanding of the electrical engineering aspect to actuallycomment on that.But that brings to an aspect where electrical engineers can also be useful because you havea nerves and heart which have electrical signals right and muscles.So, all these things have electrical signals which are being processed.So, chemists can actually be very useful because chemists are the ones who can actually tellyou how to design materials ok.So, that is one major step where they can help you and they can help in how to actuallyfunctionalize materials.So, may I if you are going know; what you need to know what chemistry is required foractually functionalizing a material and so on.And aesthetics yeah that is quite obvious and humanities as you said; for ethics, itcould be useful to have a humanities person and, but probably I would like to bring themand to the; at the end of the project so that they do not kill the project on day one.So, chemical engineers; so chemical engineers are basically working in this domain for along time because they have the expertise with respect to polymer engineering and alsowith respect to transport, fluid mechanics.So, the chemical engineers know a little bit of everything.So, like when I joined chemical engineering; one of my professors used to say this chemicalengineers can speak chemistry to engineers and engineering to chemist, so that you canbasically show off as if you know something; even when you do not.So, you can actually fool people that way.So, you are actually know a little bit of everything; so people can actually contribute.So, at least I hope I can.

Video 4: Interdisciplinary Nature of Tissue Engineering
So, we will go into the; so some of this some of what I have, we have already mentioned.So, we will see what else I have basic biology.So, in that you had mentioned developmental biology.You also would like to have cell biology and molecular biology because you are ultimatelygoing to know; how want to know how the cells are to be cultured and if they have to beengineered in some way and immunology because ultimately you want to know what the rejectionprocess would be and how you can prevent that.Engineering, I have just clubbed all engineering’s together and put it as transport properties,mechanics 3d; 2d, 3d tissue growth, reactors and even storage and shipping; so, whereinindustrial engineer would be useful right.So, chemistry and materials people have clubbed together because they kind of works hand inhand because you want to design biomaterials; look at compositions and structures; so, howthe scaffolds can be biocompatibility, surface functionalization and characterization.See any time you prepare a material you have to characterize it thoroughly to fully characterizeit; you need to have enough expertise in chemistry without that you would not be able to understandwhat you see for a FTIR or an XPS and so on.So, then I would have to spend a little more time on the characterization aspects.So, it is crucial to understand how you can characterize biomaterials.So, physics people are also useful because they also have understandings of the fluidmechanics, mechanical and electrical effects on cell differentiation, electrical propertiesof tissues and so on.so there arejust too many technologies which have come up in the last 10 years which have which arenow giving a lot more promise towards the field of tissue engineering; evolving intosomething which is fully successful.Thank you.