Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates

In the paper

“Z-stacked confocal imaging of the retrieved 1.5 mm spheres confirms minimal cellular deposition, a lack of immune macrophages, and fibrosis-associated activated myofibroblast coverage”

In the paper

“Immunofluorescence stained z-stacked confocal images of retrieved materials showed a significant decrease in macrophage (CD68) and myofibroblast (αSMA) deposition across all materials tested, and significantly, large SLG20 alginate, LF10/60 (endotoxin containing alginate), glass, and stainless steel spheres had negligible cellular deposition”

In the paper

“Dark field phase contrast images from retrieved capsules show that the 1.5 mm spheres are largely devoid of cellular deposition while the 0.3 mm sized spheres are covered with deposited cells and are clumped together in fibrotic tissue”

In the paper

“Bright-field images from retrieved materials 14 days post-implant revealed significant cellular deposition on the medium-sized versions of all materials tested. Interestingly, all materials tested at an increased size led to a marked reduction of the thickness of cellular overgrowth deposition”

In the paper

“Bright field and Z-stacked confocal images obtained from retrieved glass microspheres show that the large spheres are devoid of any cellular deposition while the smaller spheres are significantly clumped together and embedded within a thick fibrotic capsule”

In the paper

“The obtained in situ images reveal that the 1.5 mm-sized spheres remain translucent and are not embedded into host omentum/fat tissue after 14 days; conversely, the 0.5 mm sized spheres are impeded in to the omentum/fat tissue”

In the paper

“All mice (n = 5) in the 0.5 mm capsule group failed (i.e. BG above 200 mg/dl for 3 consecutive measurements), on average, by 30 days following transplantation, while in the 1.5 mm capsule group (n = 5), stayed cured, on average, even until 175 days (greater than a 5-fold increase) post-transplantation”

In the paper

“Dark field imaging revealed that the 0.5 mm capsules were covered in cellular deposition and clumped but the 1.5 mm capsules were largely clean and void of cellular deposition”

In the paper

“To ensure that the size-modulated fibrotic response effect is not simply a function of surface area, we implanted spheres of two sizes, 0.5 mm and 1.5 mm, normalized in total surface area.”

• Also stated in: § Abstract · plain

  “Dark field phase contrast images of the retrieved spheres revealed only limited cellular deposition on the 1.5 mm-sized spheres and significant cellular deposition on the 0.5 mm sized spheres”

In the paper

“Dark field phase contrast images from retrieved spheres show a marked reduction in cellular deposition onto spheres as their size is increased”

• Also stated in: § Abstract · plain

  “Interestingly, the larger spheres had significantly reduced fibrotic deposition”

In the paper

“At both 14 and 28 days post implantation retrieval time points the 1.5 mm-sized SLG20 alginate spheres were not embedded in host tissue and freely dissociated from the implant site upon incision with a biopsy punch”

• Also stated in: § Abstract · plain

  “extensive embedding and fibrosis buildup (up to 100 μm thick) is visible enveloping the implanted cylinders and medium sized spheres.”

In the paper

“4 out of 5 mice in the 0.5 mm capsule group had comparatively diminished PDX-1 expression and all 5 mice showed high levels of alpha smooth muscle expression; conversely, high levels of PDX-1 and minimal alpha smooth muscle actin were detected in capsules retrieved from all 5 mice in the 1.5 mm capsule group”

In the paper

“This phenotype was elevated at day 4 for both sizes of spheres implanted in mice, and decreased by day 7 for the 1.5 mm-sized spheres.”

In the paper

“Notably, on 1.5 mm-sized spheres we observed negligible numbers of neutrophil cells and a limited number of myeloid and macrophage cells at all time points.”

In the paper

“Dark field microscope images of the retrieved spheres revealed only limited cellular deposition onto spheres implanted in mice with depleted macrophages and conversely significant cellular deposition onto spheres received from mice with macrophages (Supplemental Figure S13).”

In the paper

“In probing macrophage and neutrophil cells, by four days post-implantation we observed significantly increased accumulation on 0.5 mm-sized spheres, which appears to plateau by day 7 (Figure 5b and c).”

In the paper

“Macrophage cells have remarkable plasticity that allows them to efficiently respond to environmental signals and change their phenotype to address the implicated stimuli43.”

What the sources say

• Not checked yetcites [43] Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003). source

In the paper

“The surface roughness of material spheres we evaluated here only included relatively smooth surfaced materials (<1 μm roughness)32, 33.”

What the sources say

• Not checked yetcites [32] Lekka, M., Sainz-Serp, D., Kulik, A. J. & Wandrey, C. Hydrogel microspheres: Influence of chemical composition on surface morphology, local elastic properties, and bulk mechanical characteristics. Langmuir 20, 9968–9977 (2004). source
• Not checked yetcites [33] Shellenberger, K. & Logan, B. E. Effect of molecular scale roughness of glass beads on colloidal and bacterial deposition. Environ. Sci. Technol. 36, 184–189 (2002). source

In the paper

“At the macro level (>100 μm in size), it is generally held that thicker materials produce a proportionally higher magnitude of foreign body responses and fibrosis3, 21.”

What the sources say

• Not checked yetcites [3] Nichols, S. P., Koh, A., Storm, W. L., Shin, J. H. & Schoenfisch, M. H. Biocompatible materials for continuous glucose monitoring devices. Chem. Rev. 113, 2528–2549 (2013). source
• Not checked yetcites [21] Helton, K. L., Ratner, B. D. & Wisniewski, N. A. Biomechanics of the sensor-tissue interface-effects of motion, pressure, and design on sensor performance and the foreign body response-part I: Theoretical framework. J. Diabetes Sci. Technol. 5, 632–646 (2011). source

In the paper

“Among the shapes tested, circular rods produced the least amount of foreign body responses followed by pentagonal, and then triangular.”

What the sources say

• Not checked yetcites [19] Matlaga, B. F., Yasenchak, L. P. & Salthouse, T. N. Tissue response to implanted polymers: The significance of sample shape. J. Biomed. Mater. Res. 10, 391–397 (1976). source

In the paper

“Meanwhile, a regulatory macrophage phenotype has been characterized to correlate with elevated expression of Interleukin 10 (IL10), TNF superfamily member 14 (Light), and Sphingosine Kinase 1 (Sphk1)44, 45, 46.”

What the sources say

• Not checked yetcites [44] Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008). source
• Not checked yetcites [45] Murray, P. J. et al. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 41, 14–20 (2014). source
• Not checked yetcites [46] Gordon, S. & Martinez, F. O. Alternative activation of macrophages: Mechanism and functions. Immunity 32, 593–604 (2010). source

In the paper

“They found that increasing the size of implanted materials resulted in larger foreign body reactions, and the formation of a thicker layer of fibrosis around the implant23.”

What the sources say

• Not checked yetcites [23] Ward, W. K., Slobodzian, E. P., Tiekotter, K. L. & Wood, M. D. The effect of microgeometry, implant thickness and polyurethane chemistry on the foreign body response to subcutaneous implants. Biomaterials 23, 4185–4192 (2002). source

In the paper

“Furthermore, an EGFP transgene included in this model enables the in situ fluorescent monitoring of macrophage cells42.”

What the sources say

• Not checked yetcites [42] Burnett, S. H. et al. Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene. J. Leukocyte Biol. 75, 612–623 (2004). source

In the paper

“There is a broad spectrum of macrophage activations which can be categorized into three states namely, classical activation (pro-inflammatory, MClassic), alternative activation (pro-healing, MWound), and regulatory activation (MReg)44.”

What the sources say

• Not checked yetcites [44] Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008). source

In the paper

“A pro-wound healing phenotype of macrophage correlates with up regulation in expression of Dendritic Cell Immune Receptor (Dcir), Stabilin 1 (Stab1), chemokine (C-C motif) ligand 22 (CCL22), Chitinase-like 3 (YM1), and Arginase 1 (Arg1)44, 45, 46.”

What the sources say

• Not checked yetcites [44] Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008). source
• Not checked yetcites [45] Murray, P. J. et al. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 41, 14–20 (2014). source
• Not checked yetcites [46] Gordon, S. & Martinez, F. O. Alternative activation of macrophages: Mechanism and functions. Immunity 32, 593–604 (2010). source

In the paper

“This effect was demonstrated to be independent of total implanted surface area and visible with all materials tested.”

In the paper

“Further, our finding suggests that simply increasing implant size is insufficient to resist foreign body responses and that a spherical shape is also integral for resisting host fibrosis/rejection.”

In the paper

“A pro-inflammatory macrophage phenotype correlates with elevated expression of Tumor Necrosis Factor α (TNF α), Interleukin 1 (IL1), and Interferon Regulatory Factor 5 (IRF5)44, 45, 46.”

What the sources say

• Not checked yetcites [44] Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008). source
• Not checked yetcites [45] Murray, P. J. et al. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 41, 14–20 (2014). source
• Not checked yetcites [46] Gordon, S. & Martinez, F. O. Alternative activation of macrophages: Mechanism and functions. Immunity 32, 593–604 (2010). source