**1. Introduction**

Up to 80% of human bacterial infections are biofilm-related, according to the U.S. National Institutes of Health [1]. Among these, implant-related infections in orthopedics and trauma still have a tremendous impact [2]. In fact, periprosthetic joint infection (PJI) (**Figure 1**) is among the first reasons for implant failure [3], posing challenging diagnostic and therapeutic dilemmas [4] and with high economic and social costs [5–7].

Local application of hyaluronic-based compounds has been demonstrated to be protective against various infectious agents, depending on HA concentration and molecular weight; furthermore, HA's ability to reduce bacterial adhesion and biofilm formation has been recently

Hyaluronic-Based Antibacterial Hydrogel Coating for Implantable Biomaterials in Orthopedics…

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High biocompatibility, safety profile and antiadhesive properties make HA and its composites a possible non-antibiotic option to reduce the impact of biofilm-related infections in various clinical settings. However, the use of HA in its pure form as an antibacterial coating does not appear suitable, due to its rapid degradation by hyaluronidases, enzymes naturally occurring in the human and animal body. Furthermore, due to its high hydrophilicity, a coating produced with a hydrogel of HA alone would not have sufficient mechanical stability when a

prosthesis is implanted in the body, which is an essentially water-based environment.

maxillofacial implants are also briefly reported.

to the implant surface [28].

**2. Antiadhesive and antibiofilm properties of HA**

with antibiotics in irrigating solutions for bacterial ocular infections.

To overcome these limits, a combination of HA with another biocompatible and biodegradable polymer, polylactic acid (PLA), was investigated [24]. In fact, PLA is a synthetic polyester, approved in the U.S.A. by the Food and Drug Administration (FDA) and widely used for orthopedic implants [25]. PLA unlike HA, shows a hydrophobic character; therefore, its presence could be exploited to control in appropriate way the hydrophilic and mechanical properties of a hydrogel based on HA, thus slowing down the susceptibility to hydrolysis. Here, after an overview of the antiadhesive and antibiofilm properties of HA, we summarize the development of a CE-marked, patented hydrogel coating, based on HA grafted to PLA (DAC®, "Defensive Antibacterial Coating," Novagenit Srl, Mezzolombardo, Italy). Some of the most relevant preclinical and clinical results that made this device the very first resorbable antibacterial coating for large-scale clinical applications in orthopedic, trauma, dentistry and

Pavesio et al. [26] were probably the first to describe HA nonfouling properties and its ability to resist bacterial adhesion, with particular reference to *Staphylococcus epidermidis* [27], proposing coated polymeric medical devices to reduce implant-related infections. In particular, a hydrophilic HA overlayer, linked to the surface of polymethylmethacrylate intraocular lenses (IOLs), was shown to be able to significantly reduce the adhesion of *Staphylococcus epidermidis*

In line with this observation, Kadry and coworkers, reported the ability of hyaluronan to reduce bacterial adhesion to IOLs of a *S. epidermidis* wild strain [29]; based on these findings, the authors proposed the use of HA as an antiadhesive, adjuvant therapy, in combination

More recently, Drago et al. reported on the *in vitro* antiadhesive and antibiofilm activity of HA toward bacterial species commonly isolated from respiratory infections [30]. In this experimental study, HA was shown to be able to reduce bacterial adhesion to a cellular substrate in a concentration-dependent manner. The antibiofilm action, exerted by HA in ear, nose and throat districts, has been recently reviewed [31]. The authors conclude that "its efficacy in treating

reported [23].

Similarly, surgical site infections after osteosynthesis, with a reported incidence ranging from 3.9 to 10% for closed fractures [8–11] and even more after open fractures [12], are associated with high morbidity and possible mortality raise [9] and elevated costs [13].

Whenever a biomaterial is implanted, a competition between host and bacterial cells occurs for surface colonization. In the event of bacterial adhesion to an implant, immediate biofilm formation starts, making the bacteria extremely resistant to host's defense mechanisms and to antimicrobials [14–16]. According to recent evidence, fully formed biofilm can be found few hours after the first bacterial adhesion [17]; thus, the destiny of an implant is decided at the very time of surgery.

To reduce or prevent bacterial adhesion and biofilm formation, a number of different antimicrobial finishing or coatings of implants are under study [18]. However, their clinical application appears particularly challenging, due to the many requirements they need to fulfill [19].

Hyaluronic acid (HA) is mucopolysaccharide, occurring naturally in mammals. It is abundant in skin and in connective tissues, being one of the main components of extracellular matrices. HA has several clinical applications in dermatology, esthetic surgery, dentistry, urology, orthopedics and ophthalmology [20]. In fact, due to its high biocompatibility, and nonimmunogenicity, hyaluronic acid is considered as an ideal biomaterial for medical and pharmaceutical applications [21, 22].

**Figure 1.** Infected, exposed, knee prosthesis in a 60-year-old woman. Approximately one million joint replacements are performed annually in Europe, and infection is currently among the first three most common reasons for failure of implants. Septic complications are associated with prolonged and complex medical and surgical treatments, often leading to implant removal. Poor functional results, possible infection recurrence, risk of amputation and increased mortality rate are all well known and feared consequences of periprosthetic and implant-related infections. Direct costs of treatment of periprosthetic infection exceeds 100,000 euros, per case, according to a recent analysis [7].

Local application of hyaluronic-based compounds has been demonstrated to be protective against various infectious agents, depending on HA concentration and molecular weight; furthermore, HA's ability to reduce bacterial adhesion and biofilm formation has been recently reported [23].

High biocompatibility, safety profile and antiadhesive properties make HA and its composites a possible non-antibiotic option to reduce the impact of biofilm-related infections in various clinical settings. However, the use of HA in its pure form as an antibacterial coating does not appear suitable, due to its rapid degradation by hyaluronidases, enzymes naturally occurring in the human and animal body. Furthermore, due to its high hydrophilicity, a coating produced with a hydrogel of HA alone would not have sufficient mechanical stability when a prosthesis is implanted in the body, which is an essentially water-based environment.

To overcome these limits, a combination of HA with another biocompatible and biodegradable polymer, polylactic acid (PLA), was investigated [24]. In fact, PLA is a synthetic polyester, approved in the U.S.A. by the Food and Drug Administration (FDA) and widely used for orthopedic implants [25]. PLA unlike HA, shows a hydrophobic character; therefore, its presence could be exploited to control in appropriate way the hydrophilic and mechanical properties of a hydrogel based on HA, thus slowing down the susceptibility to hydrolysis.

Here, after an overview of the antiadhesive and antibiofilm properties of HA, we summarize the development of a CE-marked, patented hydrogel coating, based on HA grafted to PLA (DAC®, "Defensive Antibacterial Coating," Novagenit Srl, Mezzolombardo, Italy). Some of the most relevant preclinical and clinical results that made this device the very first resorbable antibacterial coating for large-scale clinical applications in orthopedic, trauma, dentistry and maxillofacial implants are also briefly reported.
