## 2 Implant-Associated Infections  
One of the major problems ensuing orthopedic implant surgery is a bacterial infection, resulting in osteomyelitisitis and prosthetic joint-associated infections (PPIs) [113]. Gentamicin is an aminoglycosotide antibiotic [114] with potent bactericidal activity against Gram-negative bacteria and the Gram-positive _S. aureus_, which is the most vicious bacterial infection associated with osteomyelitisitis and PPIs [115]. Although gentamicin is thermally stable [113; 116], its main disadvantages are its nephrotoxicity,otoxicity [114], and poor penetration into deep bone surgery sites. Therefore, local treatment would attain the stunning advantages of gentamicin and avoid its disadvantages [113; 116]. Multimodal treatment could outpace orthopedic implant-associated infections. This multimodal treatment comprises systemic antibiotic administration, local slow-releasing gentamicin-loaded beads, and the debridement of necrotic and infected tissue [116; 117; 118]. This local gentamicin therapy crucially supports systemic antibiotic administration, preventing orthopedic implant-associated infections [119], and it remains important to achieve concentrations that exceed the MIC of infecting pathogens [118]. Regarding debridement, the resulting bone defects could be either filled with autologous (bone or muscle) tissue or with implants (beads), such as polymethylmethacrylate (PMMA) [113]. PMMA beads loaded with gentamicin have been clinically applied in practice over the past 45 years, incorporating gentamicin between chains during the exothermic polymerization process [113; 116; 118]. Gentamicin release from PMMA beads is a diffusion phenomenon classified into two phases. First, an initial burst release lasts from minutes to hours following implantation, where the surface gentamicin dissolves from PMMA into body fluids. Second, a prolonged, slower sustained release lasts from several days to years, where water-soluble gentamicin diffuses from the PMMA (hydrophilic material attracting water molecules) following the in-depth penetration of water containing body fluids [118; 120]. The main issue pertinent to PMMA beads is the necessity for secondary surgery to remove the non-absorbable beads. The beads could also act as a surface for the colonization of secondary bacterial biofilms after releasing gentamicin [116] and specifically if the released concentration is insufficient (sub-lethal concentration) [118]. Sub-lethal antibiotic concentrations drive the formation of _S. aureus_ biofilms and offer a chance for biofilm cells to switch into persisters [79]. Several other attempts have been made to avoid the drawbacks of gentamicin and PMMA beads, such as the attempt of [PERSON] et al. [121] using Expert Tibia Nail (ETN) PROtect(tm) coated by a biodegradable gentamicin-laden polymer, which does not release gentamicin into the circulation, avoiding its systemic drawbacks and preventing osteomyelitisitis [121]. However, if biofilms are formed, the shortage of oxygen and nutrients within them makes bacteria tend to shuffle into anaerobic metabolism, increasing the acid production that reduces the activity of gentamicin [113, 114]. Moreover, the slow, sustained gentamicin release from the beads incurs the development of SCVs. _S. aureus_ SCVs were isolated from four patients with a history of previous treatment with gentamicin beads. The treatment strategies for patients with SCVs end in failure, even though the administered antibiotics were effective in vitro against _S. aureus_ progenitors (i.e., MICs of gentamicin ramped up to 32-fold higher for SCVs) and recurrent infections. Conversely, patients with no SCVs suffered no recurrent infections [117]. Tackling the puzzle of SCVs, two _S. aureus_ (wild-type and SCV) strains were recovered from a patient with an implanted knee suffering PJI during the acute and recurrent phases. The resistance of _S. aureus_ SCVs overweighs the resistance of the wild-type strain via multi-complex protective approaches against the host inflammatory and oxidative responses.