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Host Integration and Immune Responses

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Video 1: Inflammatory Response to Biomaterials
Hello everyonein the previous lecture we studied some basics of immunology ah. In today's lecturewe will look atimmune responses to biomaterials and how we can design immunomodulatory biomaterialstoelicit desirable responses from the host host system to your biomaterial ah. This lectureis presented by meVasudha NMS scholar in Doctor Vignesh Muthuvijayans lab.So, in inflammatoryresponses to biomaterialsit has been observed that the duration and theintensity of the inflammation or the wound healing responseis dependent onvarious propertiesof the materials such as the materials physical and chemical propertiesit is sizeshapeandotherah biological aspects ah. And the inflammatory response to biomaterialsisa measure of thematerials biocompatibility andin response to thematerials placement inthe host system,various chemicals are released from the plasmathe cellsof the injured tissueandthese chemicals mediate the inflammatory response .So, these are the different Host responses towards biomaterials. So, upon biomaterialimplantationwhich is done through a surgical procedure,there is an injury accompanied bythe implantation. So,in the response to the injuryand inflammatoryresponses initiated in the host system and this starts with the formation of a provisionalmatrix ah. Usuallyoff usually which is collage and deposition or if you are implanting engineeredcell material hybridsthe cellular component of the material elicits an adaptive immuneresponse from the host. Or if you are implantingdegradable materialsdegradable devices or implantsotherthan the material itself. It is degradation products and the surface changes that occuron the material can elicitvarious immune responses .So, within a few nanoseconds of the contact of the material with the tissuevariousbloodproteins and also interstitial fluids get absorbed onto the material surface. And thislayer of proteins determines the activation of variouspathways such as the coagulationcascade the compliment systemand alsocauses activation of platelets and various immunecells. And this protein layer also guides the interplaybetween these pathways whichresults in the onset of the inflammatory response .So, at the onset of the inflammatory response, a fibrinogen can get absorbed to the surfaceof the biomaterial and adhesion of fibrinogen onto the biomaterial surface can induce someconformational change in fibrinogen ah, hence exposing some integrin binding domains. Andthese domains can then bind tovarious phagocytes andcausing the activation and thus initiatingan immune inflammatory response. And another class of proteins are serum proteins the complementproteinswhich are involved in immune response,they get activated upon binding to materials viathree different pathwaysthe classical alternative and the lectin pathway. And in case of biomaterialsit is the classical and the alternative pathway that are generally activated.And a activation is also always associated with the biomaterialabsorb the protein layer.So,immunoglobulin so such as IgG can bind to the protein layer which is absorbed ontothe biomaterial cell surface and helpingattachment of a various compliment complimentmolecules.Andand the pathway activation is initiatedwhen other members of the pathway are cleaved bycoagulation cascade members and hence causing the onset of the inflammatory response atthe site of implant. So, the onset of the responseresults in mastcell degranulation,increase in vascular permeability which causes extra visitation of immune cellsinto the tissue ah. Attraction and activation of granulocytes and monocytes,inducing therelease of reactive oxygen species and platelet adhesion and activation on the biomaterialsurfacewhich can propagate the coagulation cascade. And the coagulation cascade and thecompliment system closely interact with each other at the bio material surface and modulateeach other's activity and the crosstalk between the two systems operates synergistically inimplementary cell activation . Also ECM adhesion proteinssuch as fibronectinand vitronectin,can attach to the biomaterial surface and are critical in regulating theinflammatory response to biomaterials. And these proteins can alsopromote the fusionof macrophages to form something called foreign body giant cells if FBGC which we will lookat later. So,these e c m adhesion proteins can help in the fusion of macrophages to formFBGC on the biomaterial surface . So,basically cell adhesion and activationat the bio material surface,occurs where the interaction of adhesion receptors on the leukocyteswhich are usually integrinsand the adsorbed proteins which are present on thebiomaterialsurface and the Ligands for the integrins which are present on the leukocytes ah.On the bio materials surface the ligands for the integrins can be a fibrinogen fibronectinor the ECM components such as fibronectin and vitronectin. And the interaction betweenthe integrins and the ligands can induce phagocytises degranulation, a release of reactive oxygenspecies and cytokines and all these events play an important role in the inflammatoryresponse to biomaterials. So, in this image you can see thatthere isa in this image you can see the protein layer, in this image you can see the protein layerto which a molecule blood proteins such as a fibrinogen or a ECM components such as fiboronectinvitronectin can attach. And here you can see the different systems the coagulation systemthe compliment system ah. So, here the injured tissue is releasing tissuefactor one will brand factor,which can cause platelet activation. Alsoupon attachment tothe bio material surfacefactors such as factor 7 can undergoauto activation causing. Therelease of thrombinthe release of thrombin can further cause platelet activationthiscan cause clot formation and platelet activation as you can see can alsocause a polymorphicnuclear luco site and mono site priming. And in the compliment system here you cansee thatcleaved components ofcompliment system such as C3b can directly attached to the biomaterialsurface or components such as C1q they bind to the IgG moleculesimmunoglobulins, whichcanbe attached to the biomaterial surface. And whether the compliments are being activatedby the classical or alternative pathway, they all converge at C3 convertase. Which can thenrelease NFI low toxins such as C5a and C3 awhich can cause a PMN and monocyte priming.

Video 2: Danger Signals and Pattern Recognition Receptors
So, now we will look atdifferent danger signals and pattern recognition receptors which areinvolved incausing the inflammatory response to occur ah. Alarmins are endogenous equivalenceof pathogen associated molecular patterns, examples of some of them are heat shock proteinsATP uric acid and alarmins are released bycells which are dying in a non programmed way suchas a necrosis,as opposed to programmed cell death which is apoptosis.So, these alarmins can be recognized by macrophages and dendritic cells,which have pattern recognitionreceptors on them. So,examples of such receptors include scavenger receptors or toll like receptorsand C type lectins. So, when there is a damage at the implantsite alarmins are released and the release of alarmins can trigger danger signals orthedamage at the implant site can cause release of various proteolytic enzymes,which can againtrigger danger signals. The release of proteolytic enzymes can trigger a generation of extracellulardanger signals, such as cleaved ECM componentssuch as collagen and peptizer fibronectin and alsocauses the release of fibrinogen. So, here you can seethatupon injury to thetissue due to the caused by implantation, there is a release of alarmins and leakageof proteolytic enzymes. So, the release of alarminsis causingthese alarmins are beingrecognized by the pattern recognition receptors . So, these alarmins are being recognizedby the pattern recognition receptors, which are present on the polymorph nuclear leukocytescausingtheiractivation. And the leakage of proteolytic enzymes also causes the generation of alarminswhich can be a fibrinogen or cleaved ECM components and thesecleaved ECM component can also getabsorbed onto the protein layeron the biomaterial,which can cause further immune reactions.Also as we saw previously other than dendritic cells and macrophagespolymorph nuclear leukocytesahcan engage with the protein coated biomaterial surface and they can trigger phagocytic responseand degranulation,these arewhat we define as granular leukocytes .So, here you can see that when there is a damage at the implant site a chemo attractantsare released by host cells, such as activated platelets or endothelial cells and this causesa recruitment ofpolymorph nuclear leukocytes. Andthe PRR that is the pattern recognitionreceptors present on the PMN willinteract with the integrins present on the loop onthe cells and this causes phagocytic response and degranulation.PMN can secrete various proteolytic enzymes and reactive oxygen species and these arehighly destructive agents and can corrode materials surfaces and this has beenseen inthe case of polyurethane. And they can also damage the surrounding tissue,hence prolongingthe inflammatory response they also cause metabolic exhaustion and depletion of thegranulocytes oxidative resources ah. Due to the continuous release of ROS the microbialkilling capacity off PMN gets reduced, hence making the biomaterials more susceptible toinfections. PMN are aalso a significant source of immunoregulatorysignals such asinterleukin 8. As you can see here and autocrine attraction by interleukin8has beenshown to prolong the presence of granulocytes within cytosine materials.As we know chronic inflammation is a the persistent inflammation present at the implant site.So, at the site of implantation monocytes will arrive and these monocytes will differentiateinto tissue macrophages and these macrophages will foster invasion of additional inflammatorycells. And now we will look at the dual role of macrophages,which can act as inflammatorymediators and also wound healing regulators in foreign body reaction .And the macrophages have been found to be critical in wound healing and tissue regeneration.On the role of macrophages in wound healinginclude a phagocytises of the wound debris a releaseof various enzymes important for tissue reorganization and release of cytokines and growth factorsto induce fibroblasts migration and proliferation. So, a different functions are promoted bydifferent macrophage subset,based on the macrophage functions involved in maintaining homeostasistheyare classified as classically activated macrophages regulatory macrophages and wound healing macrophages.A different macrophage populations and generated in response to a different types of stimuli,whichcan be endogenous stimuli released by damaged cells orah stimuli from innate immune cells.Following injury or adaptive immune signals produced by antigen specific immune cells.So, here you can seethe different subsets of here you can see the different subsetsof macrophages, the wound healing the regulatory and the classical classically activated macrophagesah. So therefore, macrophages are a heterogeneous population of cellswith different phenotypeprofiles. So,we can make use of a their so we canimmune we can design immunomodulatorybiomaterials that can activate a particularphenotype of profile of macrophages.So, now we will look at a foreign body giant cell formation by macrophages. So, macrophagesthat attachto a foreign material show a classically activated phenotype ah. Where you can seelike heightened phagocytic activity and release of inflammatory cytokines ah. Usually likesingle macrophages can phagocytosea foreign material of about 5 micro meters in size.So, if the particle size is higher is larger than that then the macrophages attempt toto coalesce to form FBGC that is the Foreign Body Giant Cells andas you can also see inthe figureinterleukin 4 and interleukin thirteen help in the fusion of macrophages to formFBGC. And properties of the biomaterial surface are important for FBGC formationand the proteinstheprotein layer which is observed on the biomaterials surface causes thefusion of macrophages toFBGC. So, if the FBGC isdo not succeed in phagocytosing,the foreign material they remain at thebiomaterial tissue interface. So and then over time theydisplay reduced phagocytic activity and enhanced degradative of capacity and in an attemptto resorb the material which was which it was not able to phagocytose. The FBGC willsecrete proton enzymes and reactive oxygen species ok.Another class of enzymesare matrix metalloproteinase's then macrophage derived proteolytic enzymesah. So, they can be collagenase is or gelatinases MMP 8 MMP 13 here are collagenases, MMP 2MMP 9gelatinases MMP 9 is a key enzymeinvolved inhas been shown to be involved in degradationof collagen implant ah. Inwith combined action of other gelatinases and collagenases andincreased levels of MMP 9 has a is indicative of inflammation at poor wound healing .So, here we are looking at the fusion induced macrophage phenotype switch. So, upon fusionof macrophage to form FBGC it undergoes a change from the classical to alternative activationstate. And here as we saw before interleukin 4 and interleukin 13help in thefusion theyinduce the fusion of macrophages. And after biomaterial recognition the macrophage releasesvariouscytokines,such as i mean this is the these are the various cytokines that are released and this causesthephenotypic switch. At the site of implantation FBGC produce antiinflammatory cytokines also, such as interleukin 10 and interleukin 1 ra ah. This immunosuppressiveactivity is counter regulated by proteolytic and pro oxidant micro environment which iscaused due to the release of reactive oxygen species and degradative enzymes.So,the formation of the FBGC in the foreign body giant cellreleases profribotic factorssuch as transforming growth factor beta andplatelet derived growth factorin response to interleukin4. And this causes the activation of fibroblasts andactivation of fibroblasts causesexcessivecollagendepositioncausing fibrosis. Now, we will look at dendritic cell responsesto biomaterials,biomaterials activate dendritic cells by triggering receptors and signallingcascade of the pathogen recognition system ah. Dendritic cells may sensematerials usingthe pattern recognition receptors present on them such asthe toll like receptors andC type lectins. And the ligands for these receptors are youare there danger signalscoming from the adsorbed protein layer on the biomaterial surface anddifferent polymers have show different effects on dendritic cell maturation and activation. So therefore,depending on which pattern recognitionreceptor is engaged DC maturation can be promotedwhich leads to immunity or can be inhibited whichleads to tolerance. So, immunogenic dendritic cells prolong the immune response to biomaterialsand delay wound healing and tolerogenic dendritic cells down regulate the immune cells and resolveinflammation. So, what we can do here is, we if we are able to induce the tolerogenicdendritic cellsat the implant site then we can limit the immune response and promotewound healing and integration of the biomaterial into the host.So, now we look at T lymphocytes under responses to biomaterials a T lymphocyte. So, adhereto synthetic biomaterials in vitro it has been shownand they promote macrophage adhesionand fusion via paracrine effects ah. During the initial response to biomaterialsthe lymphocytesand the macrophages they release various inflammatory mediators. Such asvarious cytokines and chemokines,the release of interleukin one beta and two tumour necrotic factor alphadecline over timeand theyreleasetissue inhibitor of MMPthat isTIMP 1 and TIMP 2 which aremediators forECM remodeling and wound in wound healing. So,the question here issynthetic biomaterialsdo not serve as an antigen. So, how does T cell activation occur during a foreign bodyreaction. So, it has been suggested that synthetic biomaterials may present functional groupson their surfaces that can act as mitogens ah. Mitogens are lectins that can triggerlymphocytes by cross linking of glycoproteins on the lymphocytes surface.So, what are the implications? So, a key for long term survival and function of biomaterialsisto reduce the detrimental immune response to biomaterials. So, how do we avoid or controlsuchresponses. So, thisfor that a start would be tounderstandthecomplex reactions that occurbetween the host and thematerial andso that we can designimmunomodulating materialswhich canillicit desirable responses from the host system ah.An example would be minimally inflammatory scaffoldswhich can elicit a desirable B celland T cell responses and biomaterials are being developed to direct specific immunologicalprocesses. Andmajor propertiesof biomaterials to directimmunity arephysical dimensions of the materialit is epitope content and it is multi valency.Thank you .