Video 1: Bioceramics and its Classification
Let us start with today’s lecture.So, today we will be talking about Bioceramics.So, we have primarily talked about polymers till now, because those are one of them mostwell studied class of materials for Tissue Engineering applications, especially for scaffolds.So, we will be talking about bioceramics today.So, this is a large class of inorganic non-metallic materials which is used in repairing and replacingskeletal and hard tissues such as hip joints, teeth, bone etcetera.They can have antimicrobial activity and they are resistance to pH change, acid base solutionsand high temperatures.They show better tissue responses than polymers and metals.So, I must, I am talking about polymers which are synthetic and not present in your body.So, in case of ceramics there are many ceramics which actually interact well with their bodyand integrate very nicely.They do not release any compounds into the human body which will cause foreign body responses.They are in general biocompatible to cells and can bind directly to bone.So, they fuse to bone to form one entity.So, they can be classified based on the source as natural and synthetic.So, natural would be coral-derived apatites and eggshell-derived apatites which have beenstudied.So, coral derived apatites have been studied for a long time they have, they are even FDAapproved for using as bone substitutes.Eggshell-derived apatite is something which is, which people are interested in and therehas been some momentum towards understanding, whether these can be used for bone tissueengineering and drug delivery applications.So, synthetic ceramics include alumina, zirconia and other calcium phosphates from differentsources which have been used for bone tissue engineering applications.Based on tissue response you can classify ceramics as bioinert or bioactive.So, bioinert is a ceramic which just not interact with the body’s environment, apart fromcausing the initial formation of a fibrous tissue.So, this fibrous tissue will coat the ceramic and further there is no other interaction.There is no aggressive foreign body response to these bioinert materials.At the same time, they do not bond with the tissue, with the bone tissue.So, bioactive ceramics can actually bond between the host tissue and the implants.So, the example for bioinert ceramics are alumina and zirconia.Bioactive ceramics interact with the body.So, that the tissue actually binds with the ceramic and there is an eventual incorporationof the implant into the body itself over a period of time.In growth of bone can be achieved for these bioactive ceramics.So, the examples would be bioactive glasses which are non-resorbable and you also haveresorbable bioactive ceramics like calcium phosphates such as tricalcium phosphate andhydroxyapatite.So, coral-based apatite is one of the older materials which were studied.So, these have interconnected pores with a skeleton which is similar to the corticular,cortical and spongy bones of your body.So, this has been used as an bone substitute and it was approved for use as bone substituteby FDA in 1992 and people have tried to use this.This is primarily calcium carbonate that can be transformed into hydroxyapatite using somechemical reactions.This shows better bone resorption in it is original state, one it, if it is used as calciumcarbonate it shows better bone resorption, yeah.Can you explain what bone resorption is?Bone resorption means it will be absorbed by your body.So, it gets replaced by the bone tissue, the actual bone tissue.But the what you calling the stitches which are there, which also get dissolved in a body.Are those resorbable?Resorbable, yes.yeah.So yeah, they are also called resorbable sutures.Sutures.So, Like how does that work? does the body kindof make a bone over it and then it will be dissolved like how? with these stitches arefine, stitches can just dissolve into the skin like this.Skin is already formed over there in period.How will this work?So, this also happens a same way.So, this is just like dissolving into the body, right.So, it gets absorbed by the body and new bone gets deposited in the place.So, depending on the rate of resorption and the rate of new bone formation you will havereplacement with the original tissue and so on.So, this coral-based hydroxyapatite can be used as growth factor carriers and it hasbeen shown to be osteoconductive and it shows excellent bone bonding capacity.So, in the sense that it can actually bind with the bone and form one entity.Conductive?So, there are some terminologies which you should know osteoconductive and osteoinductive.Osteoconductive is when new bone can, bone in growth is allowed, right.So, basically bones which are being formed can grow into the scaffold which you are placing.Osteoinductive is something which can trigger osteogenesis or new bone formation, ok.So, osteoconductive materials are bioactive.Bioinert materials are not osteoconductive, they will just act as a barrier.Alumina is a bioinert material, it is actually a white powder and it can be shaped and compressedand sintered to form a ceramic with, which has very high density and strength.It also has very good corrosion resistance and biocompatibility.It also has high water resistance.It can be machined and polished because of this reason, it is used in the hip joints.So, if you remember some of the images I had shown of the hip joints when we talked aboutintroduction.So, you, I would have shown some coating of ceramic on top in the ball, ball and socketjoints.So, these are usually alumina and these have also been studied for artificial bones anddental implants and for artificial auditory ossicles and for orthopaedic surgeries.So, there are different forms different structures of alumina, the rhombohedral alpha aluminais the one which has been used for biomedical applications.these are very stable and cannot be dissolved easily even in strong acids and bases.So, most hip replacement joints are made of ultra high molecular weight polyethylene andmetal.And what happens is, when you have these polymers, polymer to metal contact, there can be weardebri.So, this wear debri can lead to osteolysis which is the lysis of bone, bone cells andthis can lead to loosening of prosthesis.So, people who were in biomaterials class I would have talked about this.So, this is called aseptic loosening.And this will lead to the failure or the replacement itself, of the implant itself.So, to avoid this people are trying to use ceramic on ceramic joints.So, where you have a ceramic coating on both the socket and the ball, thereby you havelesser wear debri.So, alumina has very good wear resistance because of this people have tried to use aluminacoating for such applications.So, the advantages is, it has very high hardness and very low wear rate.It also has excellent biocompatibility; it does not cause any inflammatory responses.But the disadvantages is, it is brittle and can cause cracks because of this.Zirconia is another ceramic which is also a white powder this can be compressed andsintered to form a strong ceramic.So, the mechanical strength itself is better than alumina.And it is fracture toughness is also better; however, it does not have the same wear resistanceas alumina.So, when you have friction it is going to cause more of wear debri formed.There are different variants which have been used for zirconia implants.Phase transition can be done from metastable tetragonal grains to form a stable monoclinicphase.This causes an increase in volume and a reduce, reduction in compressive stress, which actuallyhinders from the crack from continuing.So, this provides it is fracture toughness.So, when you have this phase transition whatever crack is actually formed does not progress.So, only when the crack, crack progress is going to cause bigger failure so, but thisalso decreases the mechanical strength of the material.So, people have tried to use partially stabilized zirconia where Yttria is doped along withzirconia and tried to use it as a, stable variant of this zirconia ceramic.Presence of water can actually cause the phase transformation to happen more rapidly, thisaffects it is in vivo applications.So, because of this alumina has been used more extensively compared to zirconia.Calcium sulfate is one of the most well studied and one of the earlier materials that wasused.So, the first successful use of calcium sulfate was reported in 1892.So, it has been more than a century where people have been trying to use this.So, it is also called as gypsum or plaster of Paris.So, this was approved by FDA in 1996.The advantages are it has a structural similarity to bone, it is also osteoconductive and itis very inexpensive.And it is available in different forms either as hard pellets or as injectable fluids therebyyou can actually inject it into the site where you need to form a particular shape or structure.Calcium sulfate also has a crystalline structure onto which the bone capillaries and perivascularmesenchymal tissue; tissue can invade.So, this helps in integration with the body.It can be resorbed rapidly within 1 to 3 months.Resorption causes pores that can help in bone growth, bone ingrowth, the usually for boneingrowth happen you need to have pores.And this resorption can create these pores which can help in the bone ingrowth.However, this resorption rate is very fast, so bone formation takes up to 4 months andresorption of calcium sulfate can start within a month or so.So, this means it cannot actually be used way for, where you need new bone growth beforethis can be removed.So,.So, ideal state would be well both of these are balanced.Yeah it has to be comparable.So, you can have the resorption to be slower than new bone growth formation, it would,provided it has not causing any negative effects.So, then it would not be a problem, you can have something there and it will still integratewell with your body, but if it is faster than you have a problem ok.So, this is neither nor osteoinductive or osteogenic, in the sense that it does nottrigger new bone formation, it only helps in bone ingrowth.So, this can also cause redness and swelling at the site of implantation which can causediscomfort and which can also cause serious pain which would lead to failure of implants.
Video 2: Bioactive Glasses
Bioactive glasses material is a ceramic which was developed in 1970s and originally silicateswhere coupled with other minerals which are present in your body like calcium, sodiumoxide and hydrogen and phosphorous.The original bioglass which is the 45S5 bioglass basically contains 45 percent silica, 24.5percent calcium oxide, 24.5 percent sodium oxide and 6 percent phosphorous pentoxide.So, this bioglass has been bioactive and it has been used for different applications.So, when exposed to aqueous solution or body fluids what happens is, the surface of thisbioglass has the silica, calcium oxide and phosphorous pentoxide rich gel layer, whichis formed.And this gel layer is subsequently mineralized to form a hydroxycarbonate within a few hoursof implantation.So, because of this it promotes bone ingrowth.So, it is biocompatible and osteoconductive, it can offer a porous structure which willpromote resorption and bone ingrowth.And the porosity itself can be achieved with a way you fabricate the material.So, this does not induce any inflammatory response and silica based bioglass is usuallyresorbed in about 6 months.Phosphate and borate based bioglasses have also been developed and they are also beingstudied.So, borate based bioglasses are easy to manufacture and they show faster degradation; however,this degradation can be altered by changing the composition of the material itself.Phosphate based bioglasses have controllable solubility which makes them desirable foryour applications because you can actually tailor the way the material gets resorbed.So, they show a strong bond to the bone and can withstand, the stresses in the site ofimplantation.The disadvantage itself is, it is quite brittle; all these bio glasses are quite brittle andhave very low mechanical strength and decreased fracture resistance.So, this is a glass right, it is a type of glass, so it is going to be brittle.The problem with that is, it does not mean you cannot use it, you would have, you cannotuse it in load bearing applications or you would have to judiciously use it for specificapplications and specific sites.And you might have to fabricate it in a way that it will be suitable or use it along withother materials to provide the desirable mechanical properties.Hydroxyapatite is the most commonly used material today because hydroxyapatites are part ofthe apatite family which are crystalline with a hexagonal lattice.So, they have a specific chemical formula which is Ca10 PO4 6 times OH twice, ok.So, it is calcium to phosphorous ratio is 1.67.So that, that is characteristic of hydroxyapatite.So, hydroxyapatite is what is present in your body.So, the mineral which is present in your bone and teeth is hydroxyapatite.So, because of this, it is extremely biocompatible and does not promote, does not cause any inflammatoryresponse.So, you can use it for bone and teeth tissue engineering, dental tissue engineering withoutany issues.So, you can have a natural hydroxyapatite or synthetic hydroxyapatite.The natural hydroxyapatite is porous with various porosity depending on, the porositydepending on where it is being extracted from.So, if you are going to take hydroxyapatite from trabecular bone, it is going to haveabout 65 percent porosity with pores ranging from 100 to 200 micrometers in size.So, these pores helps in the osteoconductive property of hydroxyapatite.They have very slow resorption rate.So, they are going to be present in your body for a long period of time, they can actuallybe maintained in your body for up to 3 years.And this allows slow bone ingrowth and cell colonization.It makes sure that your implant is going to be there; because it is hydroxyapatite whichis present in your body.It is going to integrate very nicely with your body as well, right.So, it is going to bind with the bone and become a part of the new bone itself.It has very good mechanical properties with compression stresses which are close to 160megapascals.So, which is good, but it is not, still not as good as your bone, right.Your bone compression stresses are usually in 10 to 30 gigapascals.So, this has very good properties.Synthetic and natural HA have been used.So, to get better properties what people try to do is use hydroxyapatite along with tricalciumphosphate.So, this mixture which is called as biphasic calcium phosphate is preferred to using generalhydroxyapatite or tricalcium phosphate independently.People have also tried using hydroxyapatite collagen composites which is what your bonesECM is, right.So, your bone ECM primarily contains collagen and hydroxyapatite.So, this enhances osteoblasts differentiation and promotes osteogenesis, new bone formationimproves.So, the ductile properties of collagen actually make sure it can be prepared in the shapesand it provides mechanical properties which are desirable for the bone itself.So, you can actually prepare these nano composites where hydroxyapatite nano particles are preparedand dispersed in collagen.Thereby, you get structures which are very close to what your bone tissue would be.Calcium phosphates cement were invented in 1986 and this was approved for non-load bearingbone defect treatment in 1996.These are bioresorbable material which can stay in your body for about 2 years.So, these consists of calcium phosphate powder which is mixed with a liquid.And there is an isothermal reaction leading to the hardening of this in 15 minutes toabout 80 minutes.So, this is what is used in your dental fillings and so on.So, the result, this after the reaction it results in the formation of nanocrystallinehydroxyapatite, which makes the calcium phosphate cements osteoconductive.So this, the advantage of using these is, it can actually be used to fill gaps and cavitiesand because it is paste, it will actually fill the, it will take the shape of the cavityin which you have used it.So, injectable cements have also been used for vertebroplasty and kyphoplasty which isbasically injuries to your spinal bones and your disc problems; like if we have a compressionfracture of your spine then these kinds of cements have been used.So that it can be used for healing the fracture.So, these are brittle and the clinical outcome is not better than that of methylmethacrylate.Because of this people still sometimes preferred to use methylmethacrylate, PMMA kind of alternativesinstead of cements.Beta tricalcium phosphate is the most commonly used bone substitute, it is a pure hexagonalcrystal structure with high biocompatibility and bioresorbability.The porosity regulates the osteoconductivity of this material and the resorption is actuallyslower than other calcium phosphates; however, it gets completely resorbed in about 13 to20 weeks, this is faster than hydroxyapatite do.Reports suggests that there, they have ability to influence angiogenesis as well.So, bone is actually a very highly vascular tissue.So, it has a lot of blood vessels and it is important to create a bone substitute whichwould have these vascular networks.So, beta tricalcium phosphate has indicated that, it can influence how the bone, how theangiogenesis happens.So, some of the commercial materials where, which use beta tricalcium phosphate are Orthograftand Osferion.So, these are used for bone replacements and regeneration.The biphasic calcium phosphate is a combination of hydroxyapatite and beta tricalcium phosphate.As I said it is preferred to HA and beta tricalcium phosphate being used independently.So, this has the advantages of both these materials.So, it is highly osteoconductive, biocompatible; it is safe and non allergic.It also promotes bone formation, new bone formation, so in the sense it is osteoinductive.It enables faster and higher bone ingrowth rate compared to hydroxyapatite alone.It offers better mechanical properties that beta tricalcium phosphate alone.So, the strength is still lower than the cortical bone compression strength.So, optimizing this to get desirable mechanical properties is always a challenge.
Video 3: Ceramic Fabrication Techniques
So, we looked at different fabrication techniques for scaffolds earlier.So, the techniques which we looked at where all primarily for polymers, right.So, those are scaffolds which we can prepare from polymers, different types of polymers.So, similarly for ceramics there are different techniques which can be employed and we willjust quickly go through some of the techniques.So, one of the most common techniques is foaming method.So, as I said porosity is crucial for ceramics because that is what will, regulate osteoconductivity.So, bone ingrowth will happen when you have a porous structure.So, the techniques which we will be looking at will have ability to create these porousstructures.So, foaming method is capable of producing highly porous ceramics with pores, which canrange from 20 micrometers to up to 1 to 2 millimetres.So, what happens here is, you disperse a gas in the form of bubbles into a ceramic suspensionor colloidal solutions.And this is done by incorporating an external gas by mechanical frothing or by injectionof a stream of gas along with this suspension or introduction of an aerosol propellant.You can also have, create evolution of gas in situ either through in situ polymerizationor so, techniques like that.So, this suspension is then solidified and eventually the gases are released, the foam,the foaming agent is released thereby creating porous structures.So, this is similar to one of the techniques which we looked at for polymers.So, where again you used things like ammonium carbonate where carbon dioxide can come out,creating the pores.So, the disadvantage is, it is difficult to achieve high pore interconnectivity and alsothere is a non porous external surface.So, the pores are present only in the inside and it might not be present on the surface,which can cause problems.You need to have a porous surface for the bone ingrowth to be better and for cell infiltrationto happen.Amongst these foaming methods there are a few different types.So, H2O2 foaming is one of the more commonly studied and a simpler technique to use.So, what is done here is the ceramic powder is mixed with an aqueous solution of H2O2,where H2O2 is the foaming agent.So, the mixture is cast into molds and stored in an oven at 60 degree Celsius.The H2O2 hydrogen peroxide decomposes and oxygen is released in the form of bubblesin the slurry which causes the foaming process.And as these, as these bubbles come out you create the pores.And finally, the sample is sintered and the percentage porosity and the pore size canbe modulated by using different concentrations of H2O2 and so on.The pores are interconnected only in the, in a laminar manner, which results in poorinterconnection in the direction which is perpendicular to the laminae.So, it can only be connected in one direction.So, another technique which is used, which is an eco friendly technique is the starchconsolidation technique.So, corn, rice or potato derived starch granules are used as pore formers and binders.So, what is done is, the starch granules, ceramic powder and water are mixed to forma suspension.And the suspension is continuously stirred and maintained at 60 to 80 degree Celsius.And finally, these are cast where the starch starts swelling because starch can absorba lot of water and forms a gel like material.Then it is thermally treated.So, in the sense it is heated to burn out the organic phase and sinter the ceramic phaseand because of the starch granules which occupy the cavities in between where the ceramicis sintered, you will have pores which are formed.However, the pores are not interconnected in this case.Because only the starch granules occupy the pores and there is no way to create interconnectedpores.So, sponge replica method is the most common method which is used for commercial materials.So, what you see here are commercial bone grafts, which are manufactured using spongereplica method.So, the technique itself was patented in 1963 and this has been quite popular and very effective.So, what you do is, you basically impregnate an open cell porous template with a slurryof ceramic powder and a binding agent.So, you first create a template, the shape in which you want to create the scaffold.And thus, this is usually made out of some natural or synthetic polymer and you thenload it along with the ceramic slurry which is present along with it.And the sponge is squeezed to remove any excess slurry.And this, the ceramic is used to coat the sponge on the struts and the curves whichare present are coated with a ceramic as a thin layer.And then this is dried and the coated template is pyrolyzed to remove the sacrificial template.So, now you have only the ceramic which is remaining.So, you create a positive mold.So, whatever mold you created, you have the exact shape in a form of a ceramic.So, this ceramic coating is sintered at high temperature.So, that you get the porous ceramic with the same architecture and during sintering, thesacrificial template is lost.So, the most crucial step in this sponge replica method is to get uniform coating on the polymers,polymeric structure.Because if you have uniform coating then you are not going to have reproduce the same structure.So, the factors which influence this are the rheology of the material and how well thissuspension can adhere to the struts in the sacrificial template.The rheology is crucial because, it needs to be, the suspension needs to be sufficientlyfluid for it to allow penetration.It needs to reach all the areas of the template, so that it can coat it completely.At the same time, it needs to be sufficiently viscous, so that it does not just drain offafter coating.So, after coating it needs to stick there and remain there.So, that will happen only if you have the right viscosity.So, the limitation with this method is you may not get desirable mechanical properties;you would get something which is slightly weak.So, other than these techniques you also have the solid free form fabrication techniques.So, these are broadly called as the rapid prototyping techniques.So, these are moldless technologies where people use layer by layered deposition usingcomputer generated 3D models.There are different strategies stereolithography, selective laser scenting, sintering and powder-based3D printing are the most common ones which have been used.And all of them seem to have their own advantages and disadvantages.So, I am not going to go into details of the advantages and disadvantages, but you cango through these review articles.I think I have already uploaded them I am not sure, but if not, I will upload them today.So, these would, these review articles and book chapter actually give you enough informationabout ceramics and I have given you an overview of what ceramics are.So, with these we come to the end of the different materials which are used as scaffolds.So, we will talk about cells, the cell sources, cell types which can be used and also tissuehomeostasis regarding cell adhesion, migration, proliferation and so on in the next few classes.So, thank you.