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

In the paper

“At 7 days post-transplantation a glucose tolerance test (GTT) was used to evaluate the kinetics of blood glucose correction and no significant delays were measured as a function of capsule geometry”

In the paper

“Western blot analysis of α-SMA expression within the cellular overgrowth on spheres showed a significant decrease as sphere size was increased”

In the paper

“These findings were further validated through a multiplexed inflammatory mouse cytokine profile (Figure 2e).”

In the paper

“In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals, and plastics, significantly abrogated foreign body reactions and fibrosis when compared to smaller spheres.”

In the paper

“q-PCR expression analysis of fibrosis markers, collagen 1a1 (Col1a1), collagen 1a2 (Col1a2), and αSMA, verified that increasing sphere size resulted in a significant reduction of fibrosis formation directly on spheres”

In the paper

“These analyses revealed that across all materials tested (SLG20 alginate, LF10/60 alginate, stainless steel, glass, polycaprolactone, and polystyrene) increasing sphere size led to a significant reduction of innate immune cell accumulation in peripheral tissue.”

In the paper

“q-PCR expression analysis of additional fibrosis markers, namely collagen 1a1 (Col1a1), collagen 1a2 (Col1a2), and αSMA, further indicated reduced cellular deposition as the sphere size was increased”

In the paper

“The difference in both BG normalization (Figure 4b) and fraction cured (Figure 4d) was significantly different (p<0.0001) between the 0.5 mm and 1.5 mm capsule groups following the initial failure in regulating BGs by the 0.5 mm group (~day 25) throughout the remainder of the experiment.”

In the paper

“We observed no significant differences in diffusion kinetics of glucose (Supplemental Figure S10) or insulin (Supplemental Figure S11) as a function of capsule geometry”

In the paper

“We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5 mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than 5-fold longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules.”

In the paper

“In contrast, expression of macrophage markers associated only with classical and wound-healing phenotypes was enriched on 1.5-mm spheres (Figure 5e and Supplemental Table S1).”

In the paper

“Significantly, alginate microspheres of 1.5 mm in diameter demonstrated an ability to ward off cellular deposition for at least 6 months.”

In the paper

“Fibrotic tissue obtained directly from the 0.5 mm-sized s showed increasing expression of markers associated with all three macrophage phenotypes.”

In the paper

“At all time points evaluated, we observed a significant increase in the accumulation of myeloid cells onto 0.5 mm-sized spheres compared to the 1.5 mm-sized spheres (Figure 5a).”

In the paper

“However, increased expression of markers associated with this macrophage phenotype was observed on days 4 and 7 in cells associated with the 0.5 mm spheres (Figure 5e).”

In the paper

“Confocal images acquired from retrieved 0.5 mm and 1.5 mm capsules showed positive Newport Green (islet viability marker) staining only in the 1.5 mm group”

In the paper

“Regulatory macrophage markers were not significantly up-regulated at any time point or in any compartment tested following implantation of 1.5 mm-sized spheres.”

In the paper

“Implantation of both 0.5 mm- and 1.5 mm-sized spheres resulted in an increased expression of markers associated with a wound healing phenotype in the intraperitoneal and peripheral omentum fat compartments (Supplemental Figures S15 and S16, and Supplemental Table S1).”

In the paper

“while we did not observe significant buildup of fibrosis on the capsules upon retrieval after 180 days”

In the paper

“PDX1 expression results were further verified using qPCR analysis of RNA isolated from retrieved capsules, and an ~8-fold higher levels of rat Pdx1 was detectable in the 1.5 mm capsules compared to 0.5 mm capsules group”

In the paper

“the mice in this treatment group lost blood glucose control after approximately 140 days.”

In the paper

“Combined our results suggest that grafts in 1.5 mm-sized capsules survived ~ 6 fold prolonged duration compared to those prepared in conventionally sized 0.5 mm capsules because the tuned geometry hydrogels were able to resists fibrosis for a longer duration.”

In the paper

“Overall, we observed significantly different gene expression patterns for cells associated with these tissues following implantation of 0.5 mm-sized spheres when compared to 1.5 mm-sized spheres (Supplemental Table S1).”

In the paper

“Modulating the spherical dimensions of a broad spectrum of materials encompassing hydrogels, ceramics, metals, and plastics also showed that spheres of 1.5 mm in diameter or greater significantly mitigated foreign reactions and fibrosis.”

In the paper

“In vivo Z-stacked intravital images obtained from implanted medium- and large-sized spheres at 1, 4, and 7 days post-implant indicate that macrophage cells extravasate from peripheral fat pad tissue and accumulate onto 0.5 mm spheres over that one week period, while very few macrophages can be observed near the 1.5 mm spheres (Figure 5d).”

• Also stated in: § Abstract · boosted

  “Z-stacked and time lapse intravital images of macrophage accumulation onto 0.5 mm and 1.5 mm sized spheres at 1, 4, and 7 days post-implantation confirm both a lack of macrophage activity and numbers surrounding 1.5 mm size spheres, and significant macrophage activity and numbers around 0.5 mm sized spheres (Supplemental Videos V3–V8).”

In the paper

“Notably, our evaluation of a spectrum of materials with a range of mechanical stiffness properties varying from soft (Alginate hydrogels, < 100 kPa)34 to hard (Stainless steel, 100s of GPa)35 demonstrates that size and shape rather than stiffness plays a critical role in biocompatibility.”

What the sources say

• Not checked yetcites [34] Papajova, E., Bujdos, M., Chorvat, D., Stach, M. & Lacik, I. Method for preparation of planar alginate hydrogels by external gelling using an aerosol of gelling solution. Carbohydr. Polym. 90, 472–482 (2012). source
• Not checked yetcites [35] Fujie, T. et al. Evaluation of substrata effect on cell adhesion properties using freestanding poly(L-lactic acid) nanosheets. Langmuir 27, 13173–13182 (2011). source

In the paper

“These results suggest our size-dependent fibrotic response observations in C57BL/6 mice also translate to other larger rodent species.”

In the paper

“Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved by simply tuning their spherical dimensions.”

In the paper

“because the tuned geometry hydrogels were able to resists fibrosis for a longer duration.”

In the paper

“In this model, a macrophage Fas-induced apoptosis transgene enable inducible/reversible apoptosis of macrophages using the mouse colony stimulating factor 1 receptor promoter (Csf1r) to drive expression of a mutant human FK506 binding protein 1A, 12kDa42.”

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

“however there is still no consensus on an ideal geometry21.”

What the sources say

• 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

“Spherical materials that are of 1.5 mm in diameter or greater proved to be significantly more biocompatible compared to their smaller-sized or counterparts.”

In the paper

“We believe that these data are consistent with macrophage activation in these compartments, that is reduced when the implanted material are 1.5 mm spheres.”

In the paper

“Salthouse et al. described that implant shape can profoundly affect macrophage behavior at the interface of percutaneous implants and observed that smooth, well contoured implants with no acute angles are more biocompatible20.”

What the sources say

• Not checked yetcites [20] Salthouse, T. N. Some aspects of macrophage behavior at the implant interface. J. Biomed. Mater. Res. 18, 395–401 (1984). source

In the paper

“this strain is known to produce a strong fibrotic and foreign body response similar to observations made in human patients31.”

What the sources say

• Not checked yetcites [31] Kolb, M. et al. Differences in the fibrogenic response after transfer of active transforming growth factor-β1 gene to lungs of “fibrosis-prone” and “fibrosis-resistant” mouse strains. Am. J. Respir. Cell Mol. Biol. 27, 141–150 (2002). source

In the paper

“When implanted into the intraperitoneal space of non-human primates or immunocompetent rodents, alginate microspheres elicit foreign body reactions and fibrosis29, 30.”

What the sources say

• Not checked yetcites [29] Dang, T. T. et al. Spatiotemporal effects of a controlled-release anti-inflammatory drug on the cellular dynamics of host response. Biomaterials 32, 4464–4470 (2011). source
• Not checked yetcites [30] King, A., Sandler, S. & Andersson, A. The effect of host factors and capsule composition on the cellular overgrowth on implanted alginate capsules. J. Biomed. Mater. Res. 57, 374–383 (2001). source

In the paper

“Combined our observations suggest that a lack of regulatory macrophage cell accumulation on large size spheres correlates with the truncated fibrosis responses.”

In the paper

“To ensure proper biocompatibility assessment in our studies we used an immunocompetent C57BL/6 mouse model for our initial screening”

What the sources say

• Not checked yetcites [31] Kolb, M. et al. Differences in the fibrogenic response after transfer of active transforming growth factor-β1 gene to lungs of “fibrosis-prone” and “fibrosis-resistant” mouse strains. Am. J. Respir. Cell Mol. Biol. 27, 141–150 (2002). source

In the paper

“Previously, we and others have shown that host recognition and fibrosis via cellular and collagen deposition on the surface of transplanted 0.5 mm sized alginate microcapsules results in encapsulated islet graft cell death and the failure of diabetic correction in STZ-treated C57BL/6 mice28, 37, 38.”

What the sources say

• Not checked yetcites [28] Dolgin, E. Encapsulate this. Nature Med. 20, 9–11 (2014). source
• Not checked yetcites [37] Dang, T. T. et al. Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug. Biomaterials 34, 5792–5801 (2013). source
• Not checked yetcites [38] de Groot, M., Schuurs, T. A. & van Schilfgaarde, R. Causes of limited survival of microencapsulated pancreatic islet grafts. J. Surg. Res. 121, 141–150 (2004). source

In the paper

“These results confirm that macrophages are indeed a key driver of the fibrotic responses we have observed in response to our transplanted materials.”

• Also stated in: § Abstract · hedged

  “Macrophages have been implicated as key drivers of the foreign-body reaction to implanted materials41.”

What the sources say

• Not checked yetcites [41] Shi, C. & Pamer, E. G. Monocyte recruitment during infection and inflammation. Nature Rev. Immunol. 11, 762–774 (2011). source

In the paper

“Host recognition and fibrosis of alginate capsules in humans, independent of donor tissue, is the key barrier to the clinical translation of encapsulated donor islets for treatment of type-1 diabetes26, 27, 28.”

What the sources say

• Not checked yetcites [26] Lim, F. & Sun, A. M. Microencapsulated islets as bioartificial endocrine pancreas. Science 210, 908–910 (1980). source
• Not checked yetcites [27] Scharp, D. W. & Marchetti, P. Encapsulated islets for diabetes therapy: History, current progress, and critical issues requiring solution. Adv. Drug Deliv. Rev. 67–68, 35–73 (2014). source
• Not checked yetcites [28] Dolgin, E. Encapsulate this. Nature Med. 20, 9–11 (2014). source

In the paper

“This likely suggests some islet viability loss after transplantation, which could be related to the long-term durability of the rat islets used in this treatment model.”

In the paper

“In summary, we have demonstrated that tuning the geometry of implanted materials we can influence their host recognition and propagation of foreign body reactions.”