Implantable antimicrobial biomaterials for local drug delivery in bone infection models

Abstract

Increased use of implantable biomedical devices demonstrates their potential in treating a wide variety of ailments and disorders in bone trauma and orthopaedic, reconstructive, and craniofacial applications. However, the number of cases involving implant failure or malfunction due to bacterial infection have also increased in recent years. Implanted devices can facilitate the growth of bacteria as these micro-organisms have the potential to adhere to the implant and grow and develop to form biofilms. In an effort to better understand and mitigate these occurrences, biomaterials containing antimicrobial agents that can be released or presented within the local microenvironment have become an important area of research. In this review, we discuss critical factors that regulate antimicrobial therapy to sites of bone infection, such as key biomolecular considerations and platforms for delivery, as well as current in vivo models and current advances in the field. STATEMENT OF SIGNIFICANCE: This review outlines the important factors that are taken into consideration for the development of biomaterials for local delivery of therapeutics to the site of bone infections. An overview of important criteria for development of this model (such as type of bone defect, antimicrobial therapeutic, and delivery vehicle) are provided, along with current research that utilizes these considerations. Additionally, this review highlights recent clinical trials that have utilized antimicrobial therapeutics for treatment of osteomyelitis.

Keywords: Antimicrobial; Bone defect; Implantable biomaterials; Local delivery; Orthopaedic infection.

Figure 1.

Common bone defect models for modeling infection study. (a) Sclerotherapy involves the introduction of compound such as sodium morrhuate, that causes necrosis at the surface of bone before introduction of bacteria (green). (b) Open fractures are typically induced through the use of a tool such as a 3-point bending (indicated with black triangles), after which is stabilized using either an internal or external fixation device. (c) Segmental defect occurs when a critically-sized segment of bone is removed, after which support is provided either through an internal or external fixation device (exception being when either the ulna or radius is involved).

Figure 2.

Antimicrobial peptides can be classified by their secondary structure: (a) α-helical, (b) β-sheet, (c) extended/flexible. Red regions indicate hydrophobic residues for the configuration of magainin, defensin 5, and indolicidin, respectively. N refers to the N-terminus, while C refers to the C-terminus.

Figure 3.

(a) Schematic diagram detailing the model set-up for encapsulation of lysostaphin within a hydrogel matrix for localized infection mitigation and fracture healing in a bone defect model. (b) Bacterial counts 7 days postfracture of the tissue, femur, and stabilization needle for the following conditions: bacterial strain within hydrogel (UAMS-1), bacteria and lystostaphin within hydrogel (UAMS-1 + Lst), bacteria and lysostaphin without crosslinked hydrogel (UAMS-1 + soluble Lst), bacteria and prophylactic antibiotic injections (UAMS-1 + oxacillin), and a sterile control (sterile). (c) Histological sections of femurs stained with H&E, Saf-O/FG, and Gram. Arrows indicate sites of gram-positive bacteria. Reproduced with permission [71].