Predicting biomaterial property-dendritic cell phenotype relationships from the multivariate analysis of responses to polymethacrylates

Abstract

Dendritic cells (DCs) play a critical role in orchestrating the host responses to a wide variety of foreign antigens and are essential in maintaining immune tolerance. Distinct biomaterials have been shown to differentially affect the phenotype of DCs, which suggested that biomaterials may be used to modulate immune response towards the biologic component in combination products. The elucidation of biomaterial property-DC phenotype relationships is expected to inform rational design of immuno-modulatory biomaterials. In this study, DC response to a set of 12 polymethacrylates (pMAs) was assessed in terms of surface marker expression and cytokine profile. Principal component analysis (PCA) determined that surface carbon correlated with enhanced DC maturation, while surface oxygen was associated with an immature DC phenotype. Partial square linear regression, a multivariate modeling approach, was implemented and successfully predicted biomaterial-induced DC phenotype in terms of surface marker expression from biomaterial properties with R2prediction = 0.76. Furthermore, prediction of DC phenotype was effective based on only theoretical chemical composition of the bulk polymers with R2prediction = 0.80. These results demonstrated that immune cell response can be predicted from biomaterial properties, and computational models will expedite future biomaterial design and selection.

In VitroEvaluation of a Novel Non-Mulberry Silk Scaffold for Use in Tendon Regeneration

“…59 In this context, our study used human monocyte-derived dendritic cells to give an indication of the type of early response that Spidrex may elicit in vivo, as dendritic cells are the most potent antigen-presenting cells, share a similar lineage to macrophages and their maturation in response to biomaterials is known to be indicative of in vivo responses. [70][71][72] In this study, we demonstrated that Spidrex increased dendritic cell maturation to similar levels as Fiberwire, the suture material currently used in rotator cuff repair. Spidrex also increased subsequent cytokine release from the dendritic cells, indicating that an in vivo immune response is likely postimplantation.…”

Molecular factors in dendritic cell responses to adsorbed glycoconjugates

“…[36] This assay has shown an excellent correlation between the IMF reporter and a total pro-inflammatory DC phenotype as validated by multiplex cytokine analysis and extensive flow cytometry. [36,54,55] Thus, using this assay as a screening technique for large glycan arrays was seen as an excellent proxy for in-depth cellular analysis, which wasn’t possible due to limited quantities of pure glycan structures. Using the HTP assay and a common non-immunogenic[19,58–62] protein carrier for glycans, BSA [56,57], the DC response to engineered surface adsorbed glycoconjugates was able to be assessed in a manner that has never been possible before in glycobiology.…”

Biomaterial Strategies for Immunomodulation

“…A high-throughput tool for assessing surface markers has been developed by Kou & Babensee (186); it looked at the fold change in CD86 (proinflammatory) over DC-SIGN (constitutively expressed) surface markers on DCs to assess proinflammatory DC activation. This tool was then used to assess DC activation on a library of titanium surfaces (187), as well as to elucidate which molecular properties of a library of polymethacrylates (188) were associated with DC activation. Thus, with no a priori knowledge of a material’s properties and of immune activation, the researchers were able to develop a model that showed that biomaterial surface chemistry was most important in determining induced DC phenotypes.…”

“…Thus, with no a priori knowledge of a material’s properties and of immune activation, the researchers were able to develop a model that showed that biomaterial surface chemistry was most important in determining induced DC phenotypes. Specifically, surface oxygen content was associated with iDCs, and increased surface carbon was associated with enhanced DC maturation (187, 188). In these studies, secreted cytokines were also measured using a fairly high-throughput multiplexed cytokine secretion assay and a NanoDrop Spectrophotometer (Thermo Fisher Scientific, Waltham, MA).…”

“…Reducing the necessary sample volume to a few nanoliters was key to decreasing the cost of reagents by more than three orders of magnitude and to being able to assess other high-throughput assay outputs, such as those developed by Kou et al(186–189) Anderson and colleagues (190) have provided another important approach to combining surface-characterized polymer microarrays in a high-throughput manner to elucidate the relationships between surface structure and function that drive cellular interactions. All of the systems biology approaches described above utilized statistical modeling (principle component analysis (187), partial least squares regression (188), cluster analysis (18), or pathway signatures analysis (182)) to glean insights from massive data sets. It is necessary to combine rich quantitative experimental data and knowledge of biochemical or cellular parameters in order to gain knowledge from these data sets.…”