3D Printed Dual‐Porosity Scaffolds: The Combined Effect of Stiffness and Porosity in the Modulation of Macrophage Polarization

Abstract

Tissue regeneration evolves toward the biofabrication of sophisticated 3D scaffolds. However, the success of these will be contingent to their capability to integrate within the host. The control of the mechanical or topographical properties of the implant appears as an ideal method to modulate the immune response. However, the interplay between these properties is yet not clear. Dual-porosity scaffolds with varying mechanical and topographical features are created, and their immunomodulatory properties in rat alveolar macrophages in vitro and in vivo in a rat subcutaneous model are evaluated. Scaffolds are fabricated via additive manufacturing and thermally induced phase separation methods from two copolymers with virtually identical chemistries, but different stiffness. The introduction of porosity enables the modulation of macrophages toward anti-inflammatory phenotypes, with secretion of IL-10 and TGF-𝜷. Soft scaffolds (<5 kPa) result in a pro-inflammatory phenotype in contrast to stiffer (>40 kPa) scaffolds of comparable porosities supporting a pro-healing phenotype, which appears to be related to the surface spread area of cells. In vivo, stiff scaffolds integrate, while softer scaffolds appear encapsulated after three weeks of implantation, resulting in chronic inflammation after six weeks. The results demonstrate the importance of evaluating the interplay between topography and stiffness of candidate scaffolds.

Rational design of hydrogels for immunomodulation

“…Hydrogels with varied pore size can also be obtained through modulation of temperature and concentration. These hydrogels both showed that larger pore size had greater potential to guide M1 to M2 transition and anti-inflammatory cytokines secretion compared with smaller ones [ 124 , 125 ]. The better anti-inflammatory effect of hydrogels could raise preferable angiogenic response in vitro and blood vessel formation in vivo .…”

Recent advances in nanomedicines for regulation of macrophages in wound healing

“…In contrast, gels with stiffness of 11 kPa and 88 kPa prime macrophages towards M2 phenotype with an increased production of IL-10. Camarero-Espinosa et al [ 89 ] fabricated scaffolds with various mechanical properties and stiffness using copolymer of poly(lactide-co-caprolactone) with different ratio of lactide:caprolactone monomers. It was found that scaffolds with Young’s modulus more than 40 kPa led to M2 phenotype polarization and increased secretion of IL-10 and TGF-ꞵ in vitro.…”

“…Camarero-Espinosa et al demonstrated that the porosity and mechanical properties of the poly(caprolactone-co-lactide) scaffolds can influence macrophage polarization. The macrophages with a higher surface spread area polarized towards M1 phenotype, while the cells with a reduced surface spread area polarized towards M2 phenotype [ 89 ]. Moreover, the impact of nanofiber alignment on macrophage polarization was evaluated by Jia et al [ 105 ].…”

Implantable Devices for the Treatment of Breast Cancer

“…Over the last one-decade, significant progress was made towards understanding the implantable therapeutic devices and its interaction with the human immune system [69,70]. Human immune cells play a significant role in successful implantation of these devices and their function in the body for an extended period [71][72][73][74]. In this regard, mouse or rat models play a significant role in understanding this process, even though it is not quite similar to the human immune system.…”