**5. Immune response**

### **5.1 Alginate purity effect on immunogenicity**

Crude unpurified alginate has been shown to provoke the immune system which then causes fibrosis around the microcapsule [91]. This overgrowth of immunecells and fibroblasts interferes with the transfer of nutrients, hormones, and other proteins via the semi-permeable membrane of the capsule [92]. This is a difficult problem to avoid especially since the industrial processing used for extraction can leave contaminates in the alginate like polyphenols, endotoxins and algal proteins [92, 93]. Purification is a technique utilized to minimize the amount of contaminations in the alginate gels. Commercially available sodium alginate can be purchased in several different purified states including "ultra-purified" form from companies like Novamatrix® for use in hydrogel production [94–96]. Although this is highly purified there are still small concentrations of contaminants in the alginate that can prompt a severe foreign body response [91, 97]. If the alginate biomaterials

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inflammatory period.

*Current Perspective and Advancements of Alginate-Based Transplantation Technologies*

hold living tissue within a drug-delivery system, the foreign body reaction tends to

The human immune system is broken into two parts, the innate and adaptive immune systems, which both work in tandem to defend and destroy external bacteria, viruses and various other microbes that may infiltrate a host's body [99]. The first aspect of the foreign body response (FBR) is the innate immune system which has no flexibility or memory to foreign antigens. This is followed by the adaptive immune system which generates a custom response to each specific pathogen while simultaneously building an immunological memory [92]. Alginate hydrogels used in implantations are highly purified so as to not present antigens on their surface and thus should not cause T cell activation due to antigen-presentation [100]. Despite lacking these immunoreactive properties, within nanoseconds of entering a host, biomaterials initiate an inflammatory FBR due to biomaterial surface interactions with tissue, proteins, and blood [100, 101]. The foreign body response results in fibrotic overgrowth surrounding the implanted alginate hydrogels which essentially isolates the biomaterial from host's body [102]. This fibrotic overgrowth is initiated by a sequence of cascading events including injury formation, recruitment of immune cells and fibroblasts, and cell adhesion which leads to fibrous tissue deposition [103]. Two stages of inflammation, namely acute followed by chronic, facilitate the foreign body response once alginate biomaterials are implanted [102]. It was determined that the immunogenic properties of alginate polymers were not directly responsible for the overgrowth around capsules but do contribute to is formation. In order for the immune cells to adhere to the cell surface, there must be a significant amount of protein adsorption or anchor sites for immune cell adhesion [92, 102]. Instead, the immune response occurs in the tissue immediately surrounding the alginate structure [92]. Studies have demonstrated that within a few days after alginate biomaterial implantation into animals, immune cells and differentially activated macrophages (i.e., stadia, granulocytes, and basophils) collect around, but not on, the alginate surface [92, 104]. This acute inflammatory period is characterized by the recruitment of macrophages and neutrophils in addition to the release of histamine and fibrinogen adsorption from mast cells to surrounding tissue [92, 102]. This is all done without significant immune cell adhesion to alginate biomaterials. A key player in immune cell recruitment are pattern recognizing receptors (PRRs) which act as sensors on cells of the innate immune system by responding to evolutionary conserved molecules with can contaminate alginate biomaterials [92]. Even after purification, lipoteichoic acid and LPS, the most commonly known endotoxin, can remain and are recognized by Toll-like Receptors (TLRs) [52]. It has been demonstrated that recognition of PAMPs by TLRs causes the activation of macrophages through the NF-κB pathway [105]. NF-κB results in the transcriptional upregulation of genes most associated with cytokine and chemokine production which serve to intensify humoral response [105]. Within a week, the initial acute inflammatory period transitions to a chronic

The chronic inflammatory stage is characterized by the accumulation of lymphocytes and monocytes, among other mononuclear cells, in the tissue surrounding the alginate biomaterial [106, 107]. It was discovered *in vitro* that lymphocytes can adhere to alginate biomaterial surfaces, but when placed in co-cultures with macrophages, they appeared to attach predominantly to the macrophage rather than the alginate microcapsule surface [100]. Further research has suggested that macrophage adhesion and fusion to biomaterial surface is

*DOI: http://dx.doi.org/10.5772/intechopen.87120*

reduce the survivability of those tissues [92, 98].

**5.2 Inflammation and the foreign body response**

hold living tissue within a drug-delivery system, the foreign body reaction tends to reduce the survivability of those tissues [92, 98].
