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Video 1: Basics of Hydrogels
Today I will talk about Hydrogels.I hope you are familiar with what hydrogels are, but we will discuss them with a contextof tissue engineering.We will first look at the fundamentals associated with hydrogels and we will discuss as to howwe can prepare these hydrogels and what materials are used for these and so on ok.So, what are hydrogels first?. Substance that retain water, moisture.Yes, as long as it can absorb and retain water it is a hydrogel.So, that is the basic requirement for something to be a hydrogel.It is properly defined as interconnected networks of macroscopic dimensions, which consistsof hydrophilic or amphiphilic building blocks that are rendered insoluble due to the presenceof crosslinks.So, the initial monomers or the building blocks which are used are actually soluble in water.But you create crosslinks and as the degree of crosslinking increases, at some point thismacroscopic material becomes insoluble in water and that is called as a hydrogel.So, this kind of network can actually absorb and retain a lot of water, ok.So, these can be formed from soluble monomers or multifunctional polymers.You can also use insoluble microscopic entities such as nanofibrils or nano and micro particles.So, which would have initially been formed using hydrophilic molecules and you have thesenano structures or micro structures which can then be fused together or interacted togetherto form hydrogels.. With what does it form crosslinks with?We will discuss that.So, crosslinking is one of the major aspects when it comes to creating hydrogels.So, it depends on the polymer you are using and there are different types of crosslinking.We will talk about that in this lecture.So, crosslinks are physical or chemical; these are technically the junction points wheretwo polymeric chains or microscopic objects crossover.So, this is general, the hydrogels are generally used at a temperature higher than the glasstransition temperature.So, what is glass transition temperature?Polymer chemistry you would have studied glass transition temperature or even basic materialscience material technology courses.Ok use the, use English to define what it could be glass transition temperature.Ok above this temperature, the material will behave like a rubber whereas, below it, itwill be a solid; it will be like a glass, ok.So, from glassy stature, it will move to a rubbery stature.So, that transition happens at a temperature called as a glass transition temperature.So, hydrogels will be used at temperatures higher than the glass transition temperature.So, that it will have a rubbery texture.If it is used, if it is below the glass transition temperature, it would be glassy and it cannotbe used in a biomedical application, ok.So, they can absorb a lot of water because there are many hydrophilic functional groupson the polymer backbone which is used for preparing these hydrogels.And the resistance to dissolution itself happens because of the crosslink density between thenetwork chains.So, you have many crosslinks as I was saying.As the crosslinking increases you create an insoluble hydrogel which has the ability towithstand the environment.So, why hydrogels?Why should we use hydrogels?We have talked about a few scaffold fabrication techniques are like, we had, I specificallyam discussing hydrogels.Why do you think hydrogels are important?This is one of the most well studied systems when it comes to tissue engineering scaffolds.Why has this attracted so much attention?Ok yeah, It can be used for drug delivery.I am asking about in tissue engineering, why do you think hydrogels are important?Ok in wound healing, the moist environment provides.Ok, so the application of wound healing, it will provide a moist environment which canhelp in the healing process ok.But that is not the only application where hydrogels are used, it is used in other tissueengineering applications as well.Can you think of reasons why?Ok.So, the idea is the anytime we use a material, the goal is to emulate what is there in natureright.The hydrogel has a structural and compositional similarity to ECM.So, that is why hydrogels are preferred like.So, they have, the ECM actually behaves like a hydrogel it looks and has the propertiessimilar to that of a hydrogel.It also has extensive framework for cell proliferation and survival.So, any time you use a scaffold, it should be able to support cell adhesion and cellproliferation right.So, hydrogels usually have good ability to do that.They are also well studied, there is good understanding and there is potential for engineeringthis.So that we can actually improve cell attachment, molecular response, structural integrity,biodegradability, biocompatibility and solute transport.So, these are actually crucial factors because for example; for example, with respect tosolute transport; if you have a scaffold which is a 3D structure, I even without vascularization;there has to be some amount of solute transport, only then the cells can survive at the initialphase.Assuming that vascularization eventually forms, you still need to have good efficient solutetransport initially right.So, for that reason hydrogel would be a good material where you would have very rapid solutetransport.So, that helps the cells which are seeded.So, as I said hydrogels are created through crosslinking procedure.So, what happens is the subunits form a network of macroscopic dimensions.Initially the subunits start growing and branch out, but remain soluble and there is, theyare dispersed in the solution.But as the number of crosslinks increase, you are going to have clusters which are formingand these clusters are going to grow in size.Eventually this, these clusters become infinite in size in the sense that they start interactingenough that they will form something like a gel.So, at this point gelation happens.So, this is called the gelling point.So, this gelation could happen due to different reasons; it could be because of the polymerconcentration itself or the crosslinker concentration, temperature.There are many factors or pH; there are many factors which can actually trigger gelationok.So, and the factor which triggers gelation probably depends based on the type of polymeryou are using and the type of crosslinking you are going to be performing.So, all subunits are linked to each other at multiple points.So, that there is strong interaction between these subunits which have been used for preparingthese hydrogels.So, the crosslinks ensure that they maintain the structural and mechanical integrity andprevents dissolution in an aqueous environment.The hydrogel is inherently heterogeneous.It actually has, when you put it in a water medium; it is going to have solid-rich regionswhich are distributed within a liquid environment.Because when you have a hydrogel what happens is, it will actually swell significantly whenyou put it in water.So, there are going to be regions where the polymer is present which should be the solid-richregions and the gaps are going to be filled by the water or buffer or media, which youare using.So, that is going to be the liquid environment in which this solid is present.So, water can actually freely diffuse or be loosely bound or tightly associated to thenetwork depending on where it is present ok.So, if it is present close to the points where it can form hydrogen bonds, then it will bevery closely, very strongly bound or it could just be loosely bound like what is being adheredto the surface which can just be blotted off with the paper or it could be freely, freelydiffusing through the pores which are present in the hydrogel.So, the solid-like material would; so, this actually behaves like a solid because it hasinfinite viscosity.It would actually not flow right; so, hydrogel will not flow.So, it would have an infinite viscosity and it also has defined shape and modulus.So, this makes it a solid, but it also has liquid like properties because solute candiffuse freely and this helps in the solute transport.The only condition is the solute size has to be smaller than the average mesh size.So, mesh size would be the size of the, between these crosslinks, not exactly the pore size,but like size between the crosslinks, ok.So, you might have a nonporous hydrogel as well.It is possible to prepare non-porous hydrogels.Hydrogels can have different porosity.So, mesh size is not purely dependent on porosity, it is dependent on the crosslinks.Given that it is heterogeneous both the mesh, mesh size vary from place to place.Yes, it will.That is why I said average mesh size.So, it will be different, but you would have, you can prepare it with reasonable distributions.So, if you are going to have chemical crosslinking.For example, depending on the functional groups density; you are going to have similar crosslinkingright.So, you can alter crosslinking concentration, sorry crosslinker concentration to get uniformcrosslinking and so on.So, the physical structure itself depends on the starting monomer or the macromer whichyou are using right.And it also will be defined by the synthesis procedure in the fabrication methods thatyou are going to be using.The solvent conditions in which these hydrogels are prepared are, will also influence thestructure of this hydrogel.So, after your hydrogel is prepared while you are using, there is going to be some amountof degradation and there is going to be mechanical loading depending on where you are being,where you are using it.So, even cartilage people use hydrogels right.So, people use different kinds of hydrogels for cartilage repair.So, there you are going to have significant mechanical loading.So, this is going to cause damage to the tissue so and the hydrogels.So, that could actually change the physical structure of the hydrogel.So, the crosslink structure is characterized by the junctions which could be either chemicallinkages or permanent or temporary physical entanglements or micro crystallite formationsor weak interactions like hydrogen bonding ok.These are all the different things which can actually be present as the crosslinking structure.So, when you are talking about the network, the hydrogel network; there are differentparameters which are usually described.So, the three parameters which are very commonly described are - the polymer volume fractionin a swollen state.So, when you take a hydrogel and immerse it in PBS or water, it is going to swell tillit reaches equilibrium right.At the point of equilibrium, you are going to have some fraction which is polymer andthe rest is going to be water.So, depending on the water fraction the polymer fraction, you know what is the swelling ofthe material.So, this is one parameter which is used.Average molecular weight between the crosslinks is another parameter which is used to definethe density of crosslinking and the other aspect is the measure of distance betweenthe crosslinks which is the mesh size.So, this will help us in understanding what solutes can pass through the hydrogel andwhat cannot ok.So, these are the parameters which are used.So, while I was describing this, I said that swelling reaches in equilibrium right.Why do you think it reaches an equilibrium?Why not just keep swelling?When a hydrogel is placed in water; let us say, there is excess amount of water.So, you say I, let us say, I take 10 grams of a hydrogel and place it in 500 kilogramsof water.So, there is a lot of water it can absorb.Why does not it keep absorbing it?What is actually preventing it?It has limits.Yeah.Into wide water saturated.So, it has limits to for the points where it can actually adhere to water.And also, there are forces which act against swelling, right.So, the number of crosslinks are going to prevent the hydrogel from swelling, right.So, you are going to have water which is coming in, which is forcing the hydrogel to swelland the crosslinks which are trying to hold the hydrogel together.These two are counteracting forces and at some point, these forces are going to reachequilibrium right.So, that is also going to play a role in how much the hydrogel can swell.Solute transport is one of the most critical parameters which is used for designing a hydrogel.So, the here, this actually defines the mass transfer parameters for nutrients, gases,waste products, bioactive agents and other molecules which should be involved in the,during cell culture and cell growth.So, in a solute transport convection usually does not play a role because when you keepthis in a physiological environment, you are actually not going to have flow in this directionright.So, convection will not play a major role unless if your pore size is very large.So, if your pore sizes are very large, then there can actually be convective forces withinthese pores, even when you are in a static environment.

Video 2: Methods of Hydrogels
So, diffusion is the driving transport phenomenon.And there are different factors which can actually influence diffusion being mesh size,pH and temperature right.So, all these can actually affect the mesh size of, affect the diffusion parameters forin which helps the solute transport ok.So, this basically talks about the types of hydrogels and we will look at some of thepolymers which are used for preparing natural and synthetic hydrogels.So, there are, this is not a comprehensive list.So, you can actually prepare hydrogels using many many types of polymers as long it ishydrophilic and it can absorb and retain water.You can try to prepare a hydrogel using that; only a, only thing would be to optimize thecrosslinking procedure.So, that it actually forms the stable hydrogel, ok.So, what I have listed here is just a brief introduction for what are all the materialsthat are used.So, basically you can classify them as two things; one is the natural polymers whichare used and the synthetic polymers that are used.So, natural polymers such as hyaluronic acid, alginate, pectin, carrageenan, chitosan, polylysine,collagen carboxymethyl chitin, carboxymethyl cellulose, dextran, agarose, pullulan; allthese have actually been studied for preparing hydrogels.For different applications people have tested these.And so, people are people have also use these along with the synthetic hydrogels, syntheticpolymers to get desirable mechanical properties and degradation properties ok.So, amongst these there, they have classified it as anionic, cationic, amphipathic and neutralpolymers depending on the charge of it.So, the polymers which are used that are anionic would be hyaluronic acid and alginic acidor alginate and so on.And you can have cationic polymers like chitosan which also can be used for preparing hydrogels.So, these charges actually play a role when it comes to cell attachment and cellular interactionsok.So, you can design hydrogels using these.And you also have neutral polymers like dextran, agarose and pullulan which have also beenused for preparing hydrogels.So, when it comes to synthetic polymers again the list is endless.So, whatever is shown here is a very small fraction of what you would find in literature,you can use many many things.So, polyethylene glycol is one of the more well studied hydrogel systems; so, is polyHEMA.So, these are materials which have been studied extensively for different applications andpeople have shown the properties of hydrogels using these materials ok.So, combinations of natural and synthetic have also been studied and here are just afew which have been studied and which you can find in literature.So, in natural polymers the other way to look at the categorization would be to talk aboutwhat type of a molecule it is.One you have protein-based molecules and polysaccharide-based molecules which can be used.So, whatever they have listed here some are polymers, but collagen is a protein, polylysineis a polypeptide and so on.And you could have, you could actually prepare hydrogels using protein-based materials orpolysaccharide-based materials ok.And all these have very good water retention properties.So, based on the method of preparation, hydrogels can be classified as homopolymers, copolymers,multipolymer or interpenetrating polymer network hydrogels.Homopolymers are the ones where you have a single type of hydrophilic monomer which isused and it is crosslinked to prepare the hydrogel.Copolymer is two or more monomeric units are used to prepare the hydrogels and multipolymerat least uses three or more co-monomers reacting with each other to form the hydrogels.Interpenetrating network, interpenetrating polymer networks are slightly different frommultipolymers.So, here also there are more than one polymers which are used; however, what is done is thefirst polymer network is formed initially and the second network is formed after followingthe initial network.So, thereby there is an interpenetrating network.The first network and the second network are not covalently attached to each other.They just are interacting with each other.So, this is why it is called as an interpenetrating polymer network.There are also things like double network hydrogels and a many other types of hydrogels.So, people have tried to do these to alter the mechanical properties and degradationproperties of the hydrogels.So, based on the nature of crosslinking you can classify them as physical hydrogels andchemical hydrogels.Physical hydrogels basically involves physical interactions like molecular entanglement,ionic interactions or hydrogen bonding, whereas chemical hydrogels actually have crosslinkerswhich form covalent bonds.And examples for physical hydrogel would be gelatin or agar and chemical hydrogels wouldbe PMMA, poly HEMA and so on.Based on the charge of the building block, hydrogels can be classified as neutral, anionic,cationic or ampholytic.So, all these have their own advantages depending on the application, people try to use differentthings.So, when we talk about hydrogels, swelling is the most important parameter we are lookingfor right.So, because it can actually absorb a lot of water and that is one of the most desirableproperties of a hydrogel.So, what does this mean?So, when one or more highly electronegative atoms are present, what happens is there ischarge asymmetry which promotes hydrogen bonding with water.So, thereby you have a lot of water which is retained by this hydrogel.So, this hydrophilic material can absorb a lot of water when it is completely dry.A dry hydrogel is called as a xerogel and when you place it in water, it will startswelling and absorbing a lot of water.So, by definition the water must constitute at least 10 percent of the total weight ofa material to, for it to be called a hydrogel.So, that is actually a very small number most hydrogels actually absorb a lot more than10 percent.So, in some cases the water content can actually exceed more than 95 percent of the total weightor volume and these hydrogels are considered to be superabsorbent.So, the hydrogels that we prepare in our lab can actually absorb anywhere between 2 to10 times its weight.So, depending on the application, we can actually prepare different kinds of hydrogels.So, to understand and quantify swelling; hydrogel swelling, a term called degree of swellingor swelling ratio is used.So, this is calculated as wet weight minus dry weight divided by dry weight times 100ok.So, you just take the hydrogel.So, there are different ways you can do it; you can look at swelling kinetics which isbasically taking the dry hydrogel, putting it in buffer or water and measuring its weightafter certain time intervals to see how actually the swelling progresses or you can look atonly the equilibrium swelling.So, you take it and place it in water leave it for like 2 hours and then take it out andsee what is the final state in which it is present.So, in some, most cases, people want hydrogels that can swell very rapidly right.So, there can also be specific needs where hydrogels do not swell at certain conditions,but the hydrogels which are generally prepared swell very quickly and within an hour theyreach equilibrium.So, why is this factor, degree of swelling important?Why do we need to measure this as a part of characterization?So, how much weight it can retain.Ok so, it will tell us how much water it can retain, but more than that from an applicationstand point, it helps us understand the solute diffusion through the hydrogel.And also, the properties; surface and properties and the surface mobility on the material andalso the mechanical property.Because you are going to be using this material in its swollen state right.So, you need to understand what the, how the mechanical properties can be altered whilethe swelling happens.So, those factors can be identified when with this value.So, there are many hydrogels which are very highly swollen.Some of the hydrogels are listed here; cellulose, polyvinyl alcohol, polyethylene glycol.So, what are, what is common between these molecules?They are all polymers like, huge polymers.No, they are all polymers fine, but why does that mean they have to be highly swollen hydrogels?So, I am trying to say try to, I am asking you what property of all these three makesthem to form highly swollen hydrogels.Hydrogen bonding with water.Hydrogen bonding with water is possible, but what is their structural feature which causesthe hydrogen bonding with water.OH groups, Hydroxyl groups.Hydroxyl groups.So, they have a lot of OH groups ok.So, that is why you have, makes them highly hydrophilic and they can actually swell alot and absorb a lot of water ok.So, there are also moderately swollen hydrogels like poly HEMA and copolymerization can bedone to optimize the swelling ratios to get desired swelling ratios using two differentmaterials.So, while you are preparing hydrogels; the mesh size, shape, swelling, permeability charactersall will depend on the method of preparation itself.So, the method of preparations can be based on chemical or physical crosslinking.You can also have graft polymerization and radiation crosslinking.So, which can cause either chemical crosslinking or physical crosslinking depending on howthe polymer which is being used.So, the advantage of using physical crosslinking is no crosslinker is needed.Any time you add additional chemicals, it can cause problems right.So it, the crosslinker could be toxic, although your material might not be toxic your crosslinkercould be toxic or there could be excess crosslinker which could have other adverse effects evenif it is not toxic, it could have other biological effects which are unintended.So, you would not want that.So, physical crosslinking does not require this crosslinker, makes it very safe thatway.So, you know for sure that the material you are using is the only thing which you areputting inside the body.So, it is also relatively easy to form; however, the mechanical strength is low for most ofthe physical crosslinking because these are just weak interactions, right.So, the common physical crosslinking which are used are ionic interactions and hydrogenbonds.It can also be created using heating and cooling cycles and crystallization.See ionic interactions and hydrogen bonds you would understand what it is.So, heating and cooling cycles in crystallization of polymers is done using this kind of process.So, what happens is in a heating and cooling cycle, you end up forming these kinds of coils.So, when you heat and cool.So, you keep doing this cycle multiple times these coils are going to be formed.And finally, in the second step you do the same heating and cooling along with ions likesodium ions or potassium ions.So, these are then stabilized.So, there by forming physical crosslinking which forms the hydrogels.So, this is usually done for PEG, PLA, PEO and so on, ok.So, crystallization is another common method which is used for crosslinking PVA and Xanthan.So, what is done here is, it is freezing and thawing.So, the polymer solution is taken and it is frozen and then thawed and this is repeatedmultiple times.So, that the, and this coils are formed and finally, you freeze it.So that these coils interact with each other and form a very strong hydrogel.So, crystallization is actually a technique which can provide reasonably good mechanicalstrength.So, in many cases crystallization can even give mechanical strength better than yourchemical crosslinking.So, chemical methods consist of forming irreversible covalent crosslinking.The chemical crosslinking is basically a direct reaction between the polymer or its brancheswith a bifunctional component with small molecular weight which is the crosslinking agent orthe crosslinker.So, you would use something which is bifunctional.So, that what happens is, one side of the functional group will interact with one polymerchain and the other side of the functional group, other functional group will interactwith the other polymer chain; thereby it forms the crosslinks.So, glutaraldehyde is one such molecule which is very commonly used.So, you have two aldehyde groups.So, it can easily react with amines and other molecules.So, it will immediately form crosslinks.So, that is a very common crosslinker which is used.So, chemical crosslinking methods involve crosslinking of polymer chains themselveswhich is what I am talking about with respect to glutaraldehyde.You can also have grafting where polymerization of a monomer is performed on the backboneof a preformed polymer.So, you might just be forming branches using other polymeric, another monomeric moleculeand cause this polymerization to create a hydrogel ok.So, these are some of the chemical processes which are used.If you have, depending on the functional group you have, you would choose what kind of crosslinkingyou can perform, ok.So, if you have a vinyl group, then you can use radical polymerization.If you have carboxylic acid, then you can do something called carbodiimide coupling.So, carbodiimide coupling is where carboxylic acid group is activated using a carbodiimideand this activated carboxylic group can then interact, react with either alcohol groupslike hydroxyl groups or with amine groups.So, with amine groups, it will form amide bonds and with hydroxyl groups, it can formester bonds.So, once you have this activated carboxyl group, it is easier to cause reactions.Amines are actually easy to work with using Schiff’s base reactions with aldehydes oryou can use carbodiimide coupling to interact with carboxyl groups.Hydroxyl groups can also be used.If you have hydroxyl groups, you can activate these hydroxyl groups and create crosslinkingusing carbonyl diimidazole.And sulfhydryl groups which might be present can be used for chemical crosslinking usingMichael’s addition or disulfide bond formations.So, this basically summarizes all the physical and chemical hydrogels with the differentcrosslinking techniques.I am not going to go in to the details of everything.This anyways, this is just I am putting it there for you to look up while I upload theslides.So, with that we come to the end of this lecture.We will talk about stimuli responsive hydrogels in the next class.Thank you.