The intersection of fracture healing and infection: Orthopaedics research society workshop 2021

Abstract

Infection is a common cause of impaired fracture healing. In the clinical setting, definitive fracture treatment and infection are often treated separately and sequentially, by different clinical specialties. The ability to treat infection while promoting fracture healing will greatly reduce the cost, number of procedures, and patient morbidity associated with infected fractures. In order to develop new therapies, scientists and engineers must understand the clinical need, current standards of care, pathologic effects of infection on fractures, available preclinical models, and novel technologies. One of the main causes of poor fracture healing is infection; unfortunately, bone regeneration and infection research are typically approached independently and viewed as two separate disciplines. Here, we aim to bring these two groups together in an educational workshop to promote research into the basic and translational science that will address the clinical challenge of delayed fracture healing due to infection. Statement of clinical significance: Infection and nonunion are each feared outcomes in fracture care, and infection is a significant driver of nonunion. The impact of nonunions on patie[Q2]nt well-being is substantial. Outcome data suggests a long bone nonunion is as impactful on health-related quality of life measures as a diagnosis of type 1 diabetes and fracture-related infection has been shown to significantly l[Q3]ower a patient's quality of life for over 4 years. Although they frequently are associated with one another, the treatment approaches for infections and nonunions are not always complimentary and cannot be performed simultaneously without accepting tradeoffs. Furthermore, different clinical specialties are often required to address the problem, the orthopedic surgeon treating the fracture and an infectious disease specialist addressing the sources of infection. A sequential approach that optimizes treatment parameters requires more time, more surgeries, and thus confers increased morbidity to the patient. The ability to solve fracture healing and infection clearance simultaneously in a contaminated defect would benefit both the patient and the health care system.

Keywords: Osteomyelitis; fracture healing; fracture infection; open fracture; orthopedic infection.

Figure 1:. Locations of bacteria in osteomyelitis.

Three primary locations of bacterial localization can include within an abscess (a-e), on the surface of implants (f-j), or within bone (k-m). Biofilm formation begins with bacterial adhesion (f) and results in a glycocalyx mesh that adheres to surface of implants (g-i), and clusters of bacterial colonies form (j). Bacteria can invade canaliculi (k) and spread through lacunar network (l-m) to evade immune detection. Reproduced from Masters et al., Bone Research 2019.

Figure 2:. Considerations for in vivo fracture infection studies.

Figure 3:. Dual-purpose implants for infection clearance and bone healing.

Bioengineered grafts for segmental bone defects in rats were developed with the goal of clearing infection through release of vancomycin from the graft for 6 weeks and also simulate bone healing through release of BMP-2 for 2–3 weeks. These grafts have demonstrated effectiveness of bacterial clearance similar to antibiotic cement beads, with the added benefit of providing fracture stabilization and stimulation on bone healing. Reproduced from Guelcher et al. Journal of Orthopaedic Trauma 2011.

Figure 4:. Non-antibiotic antibacterial agents.

1. Antimicrobial peptides (AMPs) and polymers can cause bacterial cell lysis through membrane disruption. Some of these peptides are proposed to cause bacterial death through membrane translocation followed by disruption of natural processes such as DNA/RNA synthesis, protein synthesis and protein folding leading to cell death. 2. Antimicrobial enzymes lyse bacteria. For example, lysostaphin binds to the peptidoglycan layer of the bacterial cell wall in Gram positive bacteria such as S. aureus and cleaves the cell wall leading to lysis and cell death. 3. Bacteriophage infect bacteria, replicate, and lyse host bacteria. Adapted from Kalelkar et al., Nat Rev Mater.

Figure 5:

Lysostaphin-delivering hydrogels eliminate bacteria in infected bone fractures. (A) Diagram of mouse femur infection model with intramedullary fixation. Quantification of S. aureus recovered from (B) tissue surrounding the femur, (C) femur bone, and (D) stabilization needle at 7 d post-fracture. Dashed line indicates detection limit. *P < 0.05, **P < 0.01. (E) Histological sections of femurs at 7 d post-fracture stained for H&E, Saf-O/FG, and Gram. Black arrows indicate gram-positive bacteria. Ox., oxacillin (i.p.); Sol., soluble. Mean ± SD. Reproduced from Johnson et al, PNAS 2018.