Engineering biomaterials to prevent post-operative infection and fibrosis

Abstract

Implantable biomaterials are essential surgical devices, extending and improving the quality of life of millions of people globally. Advances in materials science, manufacturing, and in our understanding of the biological response to medical device implantation over several decades have resulted in improved safety and functionality of biomaterials. However, post-operative infection and immune responses remain significant challenges that interfere with biomaterial functionality and host healing processes. The objectives of this review is to provide an overview of the biology of post-operative infection and the physiological response to implanted biomaterials and to discuss emerging strategies utilizing local drug delivery and surface modification to improve the long-term safety and efficacy of biomaterials.

Keywords: Bacterial adhesion; Biomaterials; Fibrosis; Infection; Inflammation; Surface modification; Sustained release.

Figure 1.

Stages of biofilm formation and strategies to prevent infection. Bacteria adhere to biomaterial surfaces via non-specific adhesion and proliferate to form biofilms. Modifying surface properties of the biomaterial such as biocidal patterning and polymer conjugation have been shown to be effective in preventing biomaterial associated infections in animal models. Biomaterials can also act as drug depots which can release bactericidal small molecules locally circumventing systemic delivery barriers.

Figure 2.

(A) Antibiotic-eluting ophthalmic sutures prevent S. aureus infection in a rat model of corneal keratitis (** indicates p<0.01). (B) Scanning electron micrographs (scalebars represent 2 μm) of commercial nylon sutures (top), 8% (middle) and 16% Levofloxacin loaded nanofiber sutures (bottom) explanted from the corneal stroma after bacterial challenge with S. aureus. (C) H&E stained corneal tissue showing reduced inflammation in eyes which received drug eluting suture 48 h after bacterial inoculation. (D) Breaking strength of drug loaded sutures scaled with suture diameter. Dashed green lines indicate minimum breaking strength requirement for absorbable sutures of 10–0, 9–0 and, 8–0 diameters. Modified with permission from [68].

Figure 3.

Local cellular response to implanted biomaterials. Proteins from blood or extracellular fluids adsorb to biomaterial surfaces upon implantation. Innate immune cells like neutrophils and monocytes adhere to protein coated surfaces through non-specific binding interactions. Neutrophils undergo degranulation and deposit neutrophil extracellular traps. Monocytes differentiate into macrophages which can fuse to form giant cells in an attempt to phagocytose biomaterials. Crosstalk between immune cells and stromal cells is an important step in wound healing and is a promising target for engineering biomaterials that can modulate host response.

Figure 4.

(A) Colony stimulating factor-1 receptor inhibition (CSF1R inh.) mitigated fibrotic overgrowth on intraperitoneally injected alginate spheres in mice as compared to vehicle only and CXCL13 neutralized wild type mice. (B) Histological examination of intraperitoneal alginate spheres in non-human primates. (C) Macrophage populations (green) and fibrosis associated α-smooth muscle actin (red) around explanted alginate spheres from non-human primates as visualized by confocal imaging. Modified with permission from [113].