TABLE 4.
Examples of biomaterial modification and their influence on the immune cell response and fibrous capsule formation. The table gives an overview of different materials used for scaffold designs and provides details about the modifications, the infiltrating immune cells, the size of the fibrous capsule, the mouse model used, and the delivery route tested. The cell numbers or percentages given in the table are the data that has been provided in the references or supplemental information and is the average per mouse.
| Biomaterial | Modification | Infiltration immune cells | Fibrous capsule | Mouse model and outcome | Delivery route | Ref |
|---|---|---|---|---|---|---|
| Silicon wafer coated with 25 nm gold | Unmodified | Total cells: 2∙106
Activated fibroblasts (Mac-1+): 5∙105 |
110 µm | BALB/c immunocompetent -CH3 modification results in thicker fibrous capsule. Both -OH and -CH3 modification results in increased immune cell infiltration (especially activated fibroblasts) |
Implantation in s.c. air pouch cavity, implant 0.5 x 0.5 cm2 | Barbosa et al. (2006) |
| -OH | Total cells: 3∙106
Activated fibroblasts (Mac-1+): 1.8∙106 |
70 µm | ||||
| -CH3 | Total cells: 3∙106
Activated fibroblasts (Mac-1+): 2.2∙106 |
120 µm | ||||
| -COOH | Total cells: 2∙106
Activated fibroblasts (Mac-1+): 1∙106 |
80 µm | ||||
| Polypropylene microspheres—measured after 2 weeks | Unmodified (-CH2) | CD11b+ inflammatory cells: 125.3 ± 31.2/mm2 | 65.1 ± 10.3 µm With high collagen deposition |
BALB/c immunocompetent Density of the chemical modification had only minor effects on the FBR. -OH resulted in increased capsule and immune cell infiltration while -COOH reduced the capsule formation and immune cell infiltration |
Injected s.c. with 18G needle, 100 mg particles (35 µm diameter) in 0.5 mL saline | Nair et al. (2008) |
| -OH (low (L), medium (M), and high (H) densities) | CD11b+ inflammatory cells: L: 366.3 ± 113.6/mm2 M: 326.3 ± 48.5/mm2 H: 322.6 ± 44.9/mm2 |
L: 134.4 ± 27.5 µm M: 109.2 ± 10.0 µm H: 101.8 ± 21.4 µm With high collagen deposition |
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| -COOH (low (L), medium (M), and high (H) densities) | CD11b+ inflammatory cells: L: 79.0 ± 14.0/mm2 M: 56.2 ± 10.7/mm2 H: 62.1 ±16.4/mm2 |
L: 30.0 ± 2.2 µm M: 37.0 ± 10.2 µm H: 37.4 ± 6.1 µm With minimal collagen deposition |
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| Polypropylene microspheres—measured after 2 weeks | Unmodified | CD11b+ inflammatory cells: 26.25 ± 8.13/mm2 | 55.3 ± 10.5 µm | BALB/c immunocompetent The chemical nature of the surface of s.c. implanted scaffolds modulate capsule thickness, cell infiltration depth, and cell number. With the -COOH modification resulting in lowest immune response |
Implanted s.c., 35 µm diameter | Kamath et al. (2008) |
| -OH | CD11b+ inflammatory cells: 135.25 ± 36.86/mm2 | Highest thickness, 251 ± 45.6 µm | ||||
| -NH2 | CD11b+ inflammatory cells: 261 ± 39.35/mm2 | 151.7 ± 35.3 µm | ||||
| -CFx | CD11b+ inflammatory cells: 50.25 ± 12.03/mm2 | 101.3 ± 35.9 µm | ||||
| -COOH | CD11b+ inflammatory cells: 11.75 ± 1.5/mm2 | 23.4 ± 2.8 µm | ||||
| Mesoporous silica microrod scaffold—measured day 5 | Unmodified | Total cells 1.4∙106, myeloid/neutrophils (Ly6GHighLy6CMid) 62% | ∼30 mg | Immunocompetent (C57BL/6J) PEG modification increased immune cell infiltration and capsule formation, PEG-RGD modification resulted in less immune cells and capsule compared to PEG only |
5 mg MSR injected s.c. in 150 µL PBS using 18G needle | Li et al. (2016) |
| PEG | Total cells 1.4∙107, myeloid/neutrophils (Ly6GHighLy6CMid) 78% | Heavier (∼95 mg), thicker and higher levels of IL-1β compared to unmodified | ||||
| PEG-RGD | Total cells 2.5∙106, myeloid/neutrophils (Ly6GHighLy6CMid) 55% | Similar to unmodified (∼40 mg) | ||||
| Mesoporous silica microrod scaffold—measured d3 | Unmodified (including 100 µg CpG, 50 µg OVA, 1 µg GM-CSF) | Total cells: 0.9∙106
Activated DCs (CD11c+CD86+/CCR7+): 0.062∙106 |
Not mentioned | Immunocompetent (C57BL6J) PEI modification did not increase total immune cell infiltration but did increase the number of recruited activated DCs |
5 mg MSR injected s.c. in 150 µL PBS using 18G needle | Li et al. (2018) |
| PEI modified (including 100 µg CpG, 50 µg OVA, 1 µg GM-CSF) | Total cells: 1∙106
Activated DCs (CD11c+CD86+/CCR7+): 0.135∙106 |
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| Silicon wafers alginate layer—measured after 1 month | PLL100 coated | Not quantified, high numbers of macrophages and fibroblast were found around the implants. 97.25 ± 5.5% of the implants had cellular overgrowth | Implants formed clumps (sticking to abdominal organs) and were caught in thick layers of fibroconnective tissue | Immunocompetent (Balb/c) Addition of the PEG-454-b-PLL50 diblock copolymer reduced the host immune response against alginate-PLL100 |
Injected with 16G needle via incision in the peritoneal cavity, at least 1000 capsules in 0.5 mL | Spasojevic et al. (2014) |
| PLL100-PEG454-b-PLL50 coated | Not quantified, 36.25 ± 27.8% of the implants had cellular overgrowth. Mostly, just a few cells, which were mainly macrophages and a few fibroblasts | Implants did not form clumps and no sticking to abdominal organs was observed | ||||
| Alginate microcapsule (hydrogel)—measured day 14 | Unmodified | Macrophages (CD68+CD11b+): 14∙104 per 100 µL retrieved capsule Neutrophils (Ly6G+CD11b+): 2.6∙104 per 100 µL retrieved capsule |
Thicker fibrous deposition ∼0.045 ng collagen/sphere |
Immunocompetent (C57BL/6J) The chemical modifications, all containing a triazole functionality, showed a lack of immune cell recruitment and activation on the surface. Moreover, limited fibrous deposition was observed |
Implanted in the peritoneal cavity, diameter of 300-350 µm, 350 µL in total | Vegas et al. (2016) |
| Triazole functionalized (Z2-Y12, Supplementary Figure S1) | Macrophages (CD68+CD11b+): ∼0.5∙104 per 100 µL retrieved capsule Neutrophils (Ly6G+CD11b+): ∼0.01∙104 per 100 µL retrieved capsule |
Almost no fibrous deposition ∼0.018 ng collagen/sphere |
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| Triazole functionalized (Z1-Y15, Supplementary Figure S1) | Macrophages (CD68+CD11b+): 2∙104 per 100 µL retrieved capsule Neutrophils (Ly6G+CD11b+): ∼0.1∙104 per 100 µL retrieved capsule |
Almost no fibrous deposition ∼0.018 ng collagen/sphere |
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| Triazole functionalized (Z1-Y19, Supplementary Figure S1) | Macrophages (CD68+CD11b+): 2∙104 per 100 µL retrieved capsule Neutrophils (Ly6G+CD11b+): ∼0.15∙104 per 100 µL retrieved capsule |
Almost no fibrous deposition ∼0.02 ng collagen/sphere |
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| Agarose hydrogel or agarose/HA composite hydrogel—measured at week 1, 2, 3, 4, 5, 6, 8, 10, and 13 | Agarose | Not quantified, a lot of macrophages and fibroblasts | Slight fibrous capsule | Immunocompetent (specific pathogen free Kunming) Composite hydrogel showed more rapid but lesser inflammatory response and improved degradation |
s.c. implantation | Zhang et al. (2012) |
| Agarose/HA composite | Not quantified, slight capsule of fibroblasts and macrophages | Slight capsule formation | ||||
| Clinical grade silicon rubber coated with meth(acrylate) and meth(acrylamide) monomers—measured at 28 days | No coating | Macrophages: 70 per cm2
Neutrophils: 10 per cm2 |
Collagen thickness around 40 µm | Immunocompetent (Balb/c) M2 coating resulted in least cells but the M0 coating resulted in least amount of collagen, indicating that the presence of both M1 and M2 (M0 coating) reduced fibrotic tissue formation. |
s.c. implantation | Rostam et al. (2020) |
| M0 coating (C398 or C408) | Macrophages: ∼50 per cm2
Neutrophils: ∼5 per cm2 |
Collagen thickness ∼20 µm | ||||
| M1 coating (H24 or C170) | Macrophages: ∼50per cm2
Neutrophils: ∼6 per cm2 |
Collagen thickness ∼30 µm | ||||
| M2 coating (C255 and C301) | Macrophages: ∼30 per cm2
Neutrophils: ∼3 per cm2 |
Collagen thickness ∼40 µm | ||||
| Alginate microcapsule (hydrogel)—measured day 14 | Triazole functionalized (Z1-A3, Supplementary Figure S1) | Showed less macrophage intensity (CD68) and less myofibroblast intensity (αSMA) compared to the control | Lower expression of αSMA and Colla1 indicating lower fibrosis and reduced collagen deposition | Immunocompetent (C57BL/6J) The hydrophilic PEG-linker-based small molecule leads work better when attached to hydrophilic alginates for cell encapsulation. |
s.c. implantation | Mukherjee et al. (2022) |
| Triazole functionalized (Z4-A10, Supplementary Figure S1) | Showed less macrophage intensity (CD68) and less myofibroblast intensity (αSMA) compared to the control | Lower expression of αSMA and Colla1 indicating lower fibrosis and reduced collagen deposition | ||||
| Medical grade silicone catheters—measured after 4 weeks | Unmodified | Fibrous capsule thickness: 125 µm | Immunocompetent (C57BL/6J) The hydrophobic lead showed better results when used to coat hydrophobic silicone catheters. |
s.c. implantation | ||
| Methacryloyl modified Z1-A3 (Supplementary Figure S1) | Fibrous capsule thickness: 50 µm | |||||
| Methacryloyl modified B2-A17 (Supplementary Figure S1) | Fibrous capsule thickness: 40 µm |