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Trends in Bone Tissue Engineering

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Video 1: Growth Factors
Good afternoon again, I welcome you all for my third final session of Bone Tissue Engineering.So, I will just explain in a diagrammatic representation, say this is the producer cell,this produces signalling molecules.These are signalling molecules which are nothing but growth factors and this one is the targetcell.So, we need to elucidate biological response in this target cells.So, this target cell has the binding receptors on its surface, ok.So, these are the binding receptors on the surface of the target cell.These signalling molecules go and bind to these receptors.These are the signalling molecules are nothing but the growth factors and they go and bindto these receptors and then it regulates the signal transduction pathways; pathway whatit do is, it regulates transcription of gene present in the nucleus, ok.Say this is the nucleus and DNA, it undergoes transcription, this is the activation of gene.So, this enhances the biological response.This is how the growth factors act.So, signalling molecules go and bind to the receptor present on the target cell, thenthey regulate the signal transduction pathway and they regulates gene transcription thenthey elucidate the biological response.So, this producer cell has changed this response of the target cell with help of growth factorthis how it works.And so, in nothing in general they are the secreted proteins that exert their effectsby interacting with specific receptors on the cell surface as I say and through paracrine.Paracrine is nothing but where they act on the neighbouring cells, the signal transfertake place in the neighbouring cells.In autocrine as it defines like it acts on itself the same cell.Endocrine where it is transfer in the blood and tissues and it transported through theblood and in the targeted site, it will enhance its property or elucidate its response.So, these all about the growth factors signalling or the signalling molecules.And they these are, this table shows the certain growth factors which are responsible in bonetissue engineering application.So, BMP -2 which is Bone Morphogenetic Protein 2 and bone morphogenetic protein 7 are FDAapproved growth factors and they are used in commercially available products, wherethey help in the differentiation and migration of osteoblast cells.Osteoblast cells helps in the formation of bone, responsible for the formation of bone.And HGF which is hepatocyte growth factor where its function is proliferation migrationand differentiation of mesenchymal stem cells which are very important cells.This mesenchymal stem cells, it can develop into n number of lineages not only the bone,it can also develop into cartilage, tendon or marrow any kind of lineages it can developand IGF which is nothing but insulin like growth factor, it cell proliferation and inhibitionof cell apoptosis.Apoptosis is nothing but cell death it inhibits that IGF growth factor.And PDGF which is platelet derived growth factor, which are responsible for embryonicdevelopment, proliferation, migration and growth of endothelial cells.So, endothelial cells are important for, very much important for vascularisation which helpsin the formation of new tissue.And TGF beta is nothing but transforming growth factor helps in the proliferation and differentiationof bone forming cells, antiproliferative factors for epithelial cells.And VEGF Vascular Endothelial Growth Factor migration, proliferation and survival of endothelialcells again it is for vascularisation techniques.So, these are the several; there are several growth factors, I just picked up the few importantgrowth factors in terms of bone tissue engineering application.So, the both there are two distinct strategies for biomaterial presentation of growth factors.It can be chemically immobilized into the substrate like polymeric substrate or thematrix or physically encapsulation, physical encapsulation can be done.So, there are two mechanism on which growth factors are encapsulated into the matrix,the first one is chemical immobilization; where it involves chemical binding or affinityor interaction between the growth factor containing polymer substrate and a cell or a tissue.And this will produce the strong localised and localised interaction in that area.However, it is mainly based on the physical and chemical properties of the substrate aswell as the growth factor dose.And the physical encapsulation of growth factors in the delivery system, it is achieved byencapsulation, diffusion and programmed release of growth factor from the substrate into thesurrounding tissue.And for this very good example where which we saw in the last session is video, wherewhere can you guess where the physical encapsulation or the physical stimulus of growth factoris done?In which mechanism?Yes ultrasound.So, through external stimuli we are delivering the growth factors.So, these are all about the growth factor strategies and what are growth factors andthe two main strategies for growth factors and so, to combine everything all the scaffold,cells and growth factors and I development of an ideal bone graft substitute.So, this picture clearly depicts the properties of the ideal bone graft substitute first.The first one, there is the fractured bone there is a defect in the bone.So, first thought we need to think what kind of base material we need to select eithernatural material, it can be natural or synthetic polymer material, but it should be mechanicallystable, angiogenic and it should support the cell growth should be supported by the substitutematerial.So, the initial thinking should be about the matrix which is nothing but the scaffolds.So, scaffold can be natural or synthetic, but it should be nontoxic, mechanically stableand highly interconnected porosity, then the osteoconduction.So, osteoconduction is nothing but the formation of new bone on the surface.Then the recruitment of MSC cells a mesenchymal stem cells, which then differentiated intoprecursor cell and then in to osteoblast.So, that undergoes with osteoinduction.Recruitment of mesenchymal stem cells, differentiates into precursors cells and then osteoblastthen the osteogenesis takes place.Osteogenesis is nothing but the formation of new tissue which is helpful, which is whichcan be done with the combination of growth factors which are nothing but bone morphogeneticproteins where it regulate, recruits, differentiate and regenerate mesenchymal stem cells.So, osteogenesis takes place and this bone is healed completely.So, any process it should have any ideal bone graft should have three major processes osteointegrationfirst.First it should be osteointegrative.So, it should have all the four properties osteointegration, osteoconduction, osteoinductionand osteogenesis.These all four important process is needed to develop a bone to develop a bone graftto enhance and repair the bone defect without any side-effect and it can heal completelyand it also accelerates the wound healing.So, the next few slides I will be talking about commercially available bone graft substitutes.The first one is osteograft which is made up of ceramic material and these all FDA approvedbone graft substitutes.Osteograft which is the name or the commercial product name and thus it is made up of ceramicand major properties are osteoconductive, limited osteoinductive when mixed with bonemarrow.It has to be mixed with bone marrow in order to become an osteoinductive materials.Bone marrow has lot of mesenchymal stem cells and they have used for bone void filler.Then next product is Novabone, where it is bioactive glass.Bioactive glass is nothing but the silicates.So, it is osteoconductive, limited osteoinductive when again mixed with bone marrow and fillingsurgical and traumatic bone gaps.And the third one is Osteosat, where it is surgical grade calcium phosphate.Again it is osteoconductive and bioresorbable helps in hip and knee joint repair.The next one is Calceon 6 where it is made up of calcium sulfate, osteoconductive andbioresorbable it as properties again bone void filler and it provides strength.These all the ceramic and ceramic derived composites which are used for bone graft substitutes.As I said in the first second session the biomaterials where osteoinductive biomaterials,ceramic plays a role.As in the to be straight ceramic based materials are very much used in bone graft substitutes.Because, we also we already know that bone is organic, bone is composite material whichis made up of inorganic hydroxyapatite.Again hydroxyapatite comes under ceramic family as well as the organic collagen matrix.So, there are many works based on ceramic based materials and the next one is Norian,where it has been prepared by monocalcium phosphate and tricalcium phosphate and calciumcarbonate, it gives very good compressive strength and used in skull bone defect andcraniofacial reconstruction and also it is an injectable paste format.And the third one is Hard tissue replacement, where they have used poly methyl methacrylatewhich is a synthetic polymer.And so, ceramic based, now it is an synthetic polymer based bone graft material and goodstrength durable and surface osteoconductive, it is used for craniofacial reconstruction.The next one again ceramic based material Alpha BSM which is made up of calcium phosphatecement and it shows good compressive strength, it is used in dental application for boneand cartilage defects.The next is CopiOS paste and which is made up of calcium phosphate and type I bovinecollagen, natural and synthetic composites polymer.And it provides significantly more calcium and phosphate ions at equilibrium then eitherof beta TCP or HA, hydroxyapatite.It acts as the osteoconductive scaffold for the growth of new bone, osteoconductive scaffold.And the Collagraft which is the mixture of tricalcium phosphate, bovine collagen andhydroxyapatite, again it is bioresorbable and osteoconductive, it can be used for thetreatment of long bone fracture and void filling.And the last one is mainly based on growth factors which I already told like BMP -2 andBMP- 7 are FDA approved ones, BESTT and OP-1 Putty and BMP -2 with along with collagenmatrix and it is highly enhances vascularization, osteoconductive and helps in healing of bonefracture.And the next one OP-1 Putty which is again BMP- 7 with collagen matrix, osteoconductiveand bioresorbable it helps in the healing of bone defects.So, there are so many bone graft material approved and they are still in progress, Ihave just picked up few bone graft materials mainly based on calcium and few on polymerand polymer and ceramic and few on natural and synthetic polymer and some FDA approvedbone graft substitute based on growth factor, growth factor strategies.And the cell since the first one is fresh bone marrow cells, since it is autologous,no need for FDA approval.And the current trends in.

Video 2: Current Trends in Bone Tissue Engineering
So, that is all about the commercial available bone grafts and few examples of commerciallyavailable products and now the current trends in bone tissue engineering.So, currently people have shown more interest in developing mechanically strong porous scaffolds,that can retain proper vascularization and host integration.The major pitfall of bone tissue engineering is lack of sufficient and timely vascularizationsof the scaffold.For example, if you place a scaffold in the construct, see the there should be an immediateacceptance of the construct with the host or the vascularization should be should happendeep into the construct.It should not stop at the upper layer of the construct.So, it happens at many stages and there are many failure because of this kind of issues.So, vascularization is an very important phenomenon or strategy for an successful ideal bone graftmaterial.So, should we should know about vascularization.So, vascularizations is nothing, but the formation of new blood vessels.So, the greatest amount of new bone formation occurs in the most vascularized area, whereas inadequate vascularization at bone defect sites also associated with decreased bonetissue repair and regeneration.So, vascularization has been identified as the major pitfall to for the successful tobone tissue engineering grafts.So, what people have done is to enhance vascularization, we have strategies proposed to enhance vascularizationthereby to increase the success of the bone graft material.So, scientists have proposed several methods to accelerate onset of neovascularization,which is nothing but the formation of new tissue, for the survival and integration ofbone grafts with host tissue that includes scaffold design.First in scaffold design itself they have changed many fabrication techniques, wherethey have started doing 3D printing, where did we have seen few examples of first generationof second generation scaffold biomimetics scaffolds, which are nothing but 3D printedscaffolds done by fusion deposition modelling and inclusion of angiogenic growth factorsfor the enhancement of endothelial cell.And there are two techniques in vitro prevascularization and in vivo prevascularization.In vitro prevascularization is nothing, but coculture of endothelial cells and osteogeniccells in in vitro and then we transfer into in vivo and check for the vascularization.In vivo prevascularization is nothing but two there are two more, where we place thescaffold in vivo techniques where we place that is scaffold in an vascularized area subcutaneouslyor intramuscular region.After two weeks or after certain time we harvest that scaffold out and we place that scaffoldin the bone defect, but this method requires two surgeries.So, first we need to place the scaffold to get it vascularized, then we have to removethat scaffold and place it on the defect sites.So, it requires lot of pain, surgeries, time and everything.On the second method is like where we have vessels which are responsible for jugularvein for example, jugular veins we place inside this construct and we place in the in vivowhereas the second method happens to be kind of successful although, but still it is veryunclear which method is best for the successful in vivo application and maybe the combinationof all the methods may prove to be more effective for enhancement of vascularization.Then about vascularization now again about immunomodulatory strategies is becoming increasinglypopular for modulating the hosts foreign response, body response, that is fibrous tissue encapsulation.See once the construct has been placed immediate reaction will be inflammatory response thenfollowed by the fibrous tissue encapsulation.So, we need to modulate that.So, incorporation of immunomodulatory strategies, it is becoming popular to avoid the kind ofencapsulation and that is one of the current trend where we researches ongoing in bonetissue engineering, one is mainly on vascularization techniques and scaffold design and in incorporationof immunomodulatory strategies, then the main important challenge or a critical challengesis the availability of animal models.Animal models pose another critical challenge to test various bio bone tissue engineeringgraft approach preclinically.And preclinically load bearing large animal models should generally be used to accessgraft functionality and this is one of the major pitfall, where we face in order to checkfor the bone graft properties.So, future direction for bone tissue engineering to become a widespread clinical reality, itmust incorporate the recent technologies that utilizes all the necessary components likescaffolds, cells and growth factors.So, we need to utilize all the new recent technologies in order to develop a best scaffold,ideal scaffold and also with the cells, seeded with the cells and also for the growth factorsfor the successful bone repair and regeneration.And also, some of the efforts must be made to establish efficient intraoperative cellseeding methods as well.To minimise in vitro culture of the bone tissue engineering constructs, which allows bonetissue regeneration that allow bone tissue regeneration for in in vivo studies.So, these are the few future directions where we need to focus mainly on to develop an idealbone repair and regeneration.So, thank you.So, overall picture where we studied about the bone its basic functions and its anatomyof the bone and the modelling and remodelling of the bone and the tissue engineering strategies,scaffolds, growth factors, cells and the commercially available products and the current trendsand the future directions.Thank you.