Gelatin-based nanoparticles and antibiotics: a new therapeutic approach for osteomyelitis?

Abstract

The result of infection of bone with microorganisms is osteomyelitis and septic arthritis. Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for most of its cases (more than 50%). Since MRSA is resistant to many treatments, it is accompanied by high costs and numerous complications, necessitating more effective new treatments. Recently, development of gelatin nanoparticles have attracted the attention of scientists of biomedicine to itself, and have been utilized as a delivery vehicle for antibiotics because of their biocompatibility, biodegradability, and cost-effectiveness. Promising results have been reported with gelatin modification and combinations with chemical agents. Although these findings have been suggested that gelatin has the potential to be a suitable option for continuous release of antibiotics in osteomyelitis and septic arthritis treatment, they still have not become routine in clinical practices. The most deliver antibiotic using gelatin-derived composites is vancomycin which is showed the good efficacy. To date, a number of pre-clinical studies evaluated the utility of gelatin-based composites in the management of osteomyelitis. Gelatin-based composites were found to have satisfactory performance in the control of infection, as well as the promotion of bone defect repair in chronic osteomyelitis models. This review summarized the available evidence which provides a new insight into gelatin-derived composites with controlled release of antibiotics.

Keywords: antibiotics; biocompatibility; gelatin-based nanoparticles; osteomyelitis; sustained release.

FIGURE 1

Treatment failure of Staphylococcus aureus osteomyelitis through multiple mechanisms; (A) Invasive staphylococcal infections are characterized by abscesses. Staphylococcal abscess community (SAC) is composed of bacteria inside the abscess core enclosed by a pseudocapsule containing fibrin and other extracellular matrix proteins of host, which subsequently lead to the recruitment of immune cells such as viable and non-viable neutrophils. Strong antibiotic resistance can be observed for bacteria inside a SAC. (B) Invading bacteria form an abscess and severe inflammation in osteomyelitis, which endangers the blood supply to the bone and therefore develops necrosis. This necrosis results in sequestra tissue lesions in chronic osteomyelitis, as a nidus during continuous infection. New bone is formed in reaction to the sequestrum, thereby forming the pathological lesion of the involucrum. The efficacy of systemic antibiotic therapy is greatly reduced due to infection-caused vascular disorders. (C) Bacteria achieve significantly longer persistence as a result of biofilm formation on bone within bone infection and show greater tolerance to antibiotics. The formed biofilm can prevent the diffusion and subsequent penetration of antibiotics into deeper layers. The environment of biofilm, which contains large amounts of nutrients and oxygen, intensifies the development of antibiotic-resistant bacteria, such as small colony variants [SCVs]: “pink cocci,” and persisters: “organ cocci.” (D) S. aureus invading resident bone cells (such as osteoblasts and osteoclasts) and professional phagocytes (such as macrophages) can survive inside these cells, leading to increased antibiotic tolerance because the majority of antibiotics have an extracellular action, so that the evidence showed that the intracellular host environment promotes the construction of persisters and SCVs. (E) Osteocytes are the main cells in the bone matrix found in lacunae structures and connected to each other through canaliculi, a 3D network of canals. Chronicity of osteomyelitis caused by S. aureus occurs through colonization of the osteocyte lacuno-canalicular network (OLCN) due to the absence of the antibiotic concentration required to eradicate the bacteria. Bacteria inside the OLCN may also remain hidden from the host response (Gimza and Cassat, 2021).

FIGURE 2

The preparation of valacyclovir (VC)-loaded GNPs via a two-step desolvation process (Sahoo et al., 2015).

FIGURE 3

The preparation of gelatin nanoparticles by the nanoprecipitation method (Khan and Schneider, 2013).

FIGURE 4

A schematic depiction of a widely utilized traditional technique for nanoparticle (NP) generation namely, the dropwise method (A), is presented. Microfluidic chips (B) with diverse designs can be employed for NP production, depending on the type of flow utilized. This includes single-phase flow systems (B1) featuring either two-way (B1.1) or three-way channels (B1.2), as well as multiphase flow configurations (B2) such as liquid–liquid (B2.1), gas–liquid (B2.2), and liquid–liquid-gas (B2.3) systems (Gimondi et al., 2023).

FIGURE 5

Schematic of the synthesis of self-assembled hexanoyl-modified GNPs (Li et al., 2011).

FIGURE 6

A Janus nanoplatform (Janus-CPS) has been developed for the simultaneous early detection and combined treatment of rheumatoid arthritis (RA). This platform consists of CeO2-Pt nanozyme on one side and periodic mesoporous organosilica (PMO) on the other. Micheliolide (MCL), known for its anti-osteoclastogenesis properties, is encapsulated within the mesopores of PMO to synergistically complement the soothing properties of nanozymes, thereby effectively managing RA. To achieve the desired efficacy in early RA detection, Janus-CPS loaded with indocyanine green (ICG) utilizes NIR-II fluorescence imaging (Huang et al., 2024).

FIGURE 7

Schematic of the potential mechanisms of antibacterial drugs delivered by gelatin nanoparticles that can be useful in the treatment of infectious diseases (Madkhali, 2023).